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+{"text": "Alcohol use disorder (AUD) characterized by heavy and prolonged alcohol intake could cause various forms of alcoholic liver disease (ALD). The spectrum of alcoholic liver disease (ALD) consists of steatosis, steatohepatitis, cirrhosis and hepatocellular carcinoma depending on the duration and severity of alcohol intake ,2. Inter"}
+{"text": "Knowledge of service use and costs and wider societal costs in Europe is limited; (2) Method: Using an international sample, we analysed services and costs in 357 children (4\u20136.99 years) with ASD based on parent reports. Costs were transformed into EU-28 average using purchasing power parity; (3) Results: 122 children (34%) received specialist autism services; 149 (42%) received sensory/motor therapy; 205 (57%) received speech/language therapy; 35 (10%) received play therapy; 55 (15%) received behavioural interventions; 31 (9%) received social skills training; 47 (13%) participated in therapeutic recreational activities; and 59 (17%) received other services. The total number of hours for these services combined over two months was M = 34 . Estimated total costs of health-related services were M = 1210 EUR (SD = 2160 EUR); indirect societal costs were M = 1624 EUR (SD = 1317 EUR). Regression analyses suggested that costs rise with age and presence of intellectual disabilities, but not with severity of autism; (4) Conclusions: The high extent of community-based services indicates good accessibility but also considerable variation in the receipt of services. The costs of autism services are considerable. Further research is needed to investigate whether services received match individual needs. Autism spectrum disorder (ASD) refers to a range of lifelong neurodevelopmental conditions characterized by the presence of early appearing symptoms in two core domains: impairments in reciprocal social communication and the presence of restricted interests and repetitive behaviours DSM-5; ICD-11) . ASD aff; ICD-11 https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders, accessed on 1 April 2020) recommend evidence-based psychosocial interventions including behavioural treatment and parent skills training programmes which can minimalize limitation in communication skills and social behavioral skills with improving well-being and quality of life for both individuals with ASD and their parents. Based on current best evidence, guidelines developed by Autism-Europe [It is important to provide individuals with ASD and their families with support to live their best possible life. There is no cure for autism nor one care package that suits everyone. People with autism require different support at each age of their lives, and it is therefore essential to ensure the right type of evidence-based therapy at the right time. Relevant guidelines often emphasize general principles in the absence of more specific evidence. One relevant policy overview by World Health Organization  , we analDetails on study procedures were described separately , while aType of therapy or intervention ;Institutional stay ;Outpatient treatment ;Dietary supplement and medication ;Special diet ;Working hours spent on treatment as described above, including driving, of all private care givers (weekly average in hours);Work situation (working or not working);Reduced hours due to the child\u2019s needs (in percentage);Employing anybody privately to help care for the child ;Any additional assistant/aide in school/at home for the child ;Care giver investment:TIME-A used assessments by blinded clinicians as well as reports by parents/caregivers collected at several time points. For the current study purpose, only data collected at baseline on scores of the ADOS and ADI-R, IQ level, as well as costs and concomitant treatments were included. Parents answered a detailed questionnaire regarding services received and out-of-pocket expenses during the past two months. The following data were collected:Respondents were asked to reply with regard to the last 2 months. The limited recall time frame was used to minimalize the recall bias following other economic evaluations e.g., ,36. The https://data.oecd.org/conversion/purchasing-power-parities-ppp.htm, for 2018, accessed on 4 March 2021). All health services costs  were sourced from personal communication and represent typical costs in Austria, a Central European country and one of the countries where data were collected. Heath services costs were set up to be 84 EUR per 60 min (one session) based on 1:1 setting, and discounted for group settings, assuming a group size of 5. Costs of institutional stay (310.08 EUR per day) and outpatient treatment (167.10 EUR per contact/visit) were retrieved from a report of Unit Costs of Health and Social Care [https://ec.europa.eu/eurostat/en/web/products-datasets/-/ILC_DI08, accessed on 4 March 2021), the following unit costs were obtained: 1946.08 EUR per month for full-time work where both parents had a university degree; 1391.42 EUR per month where both parents had 12 or more years of education; and 1129.42 EUR per month where at least one parent had less than 12 years of education or education level was unknown. No unit costs were imputed for medication and special diets because these costs were found to be negligible in children with ASD [https://ec.europa.eu/eurostat/tgm/table.do?tab=table&init=1&language=en&pcode=tec00118&plugin=1, accessed on 4 March 2021).Unit costs were inserted where a service was used but parents reported no expense for the service. Costs were transformed into EU-28 average using purchasing power parity , and intellectual disability (below-average intelligence) and health services costs and societal costs. Following literature that the age and severity of autism symptoms are significant predictors of costs for children at preschool age  and in an = 140).A sensitivity analysis was used to determine how data retrieved from non-European countries affected the obtained health services costs and societal costs. In order to determine the robustness of our results by examining the extent to which results of health services costs and societal costs are affected by country of origin, we calculated costs including only 217 children from Europe  and excluding individuals from other non-European countries  and clinical judgement (n = 140), the results of which indicate that 47% of children (n = 163) had IQ below 70. The majority of individuals attended to school (62%), while 22% to full-time care and 11% to part-time care. More details can be found in the top half of The total of 357 children (83% boys) were included with a mean of age 5.4 years (SD = 0.9). As can be seen from In regard to parents\u2019 situation of work, the majority of mothers were homemakers (34%) followed by 26% being part-time employed, while the majority of fathers were working full-time (74%). Regarding education, many parents had a university degree , followed by education equivalent to high school , and less than high school . The bottom half of Of 357 children, 122 (34%) received specialist autism services; 149 (42%) received sensory/motor therapy; 205 (57%) received speech/language therapy; 35 (10%) received play therapy; 55 (15%) received behavioural interventions; 31 (9%) received social skills training; 47 (13%) participated in therapeutic recreational activities; and 59 (17%) received other services . The totThe sum of indirect societal costs was M = 1624 EUR  over the last 2 months with a wide range . It can be seen that the SDs are relatively high compared to the means; sometimes higher than the means. This reflects the skewed nature of these data, which is a common phenomenon in health economic data ,41.p < 0.048) and intellectual disability (p < 0.005) on health costs  attended school, 91 of included children (25%) attended kindergarten ; while 5 (1%) attended none of aforementioned. Regarding other services, 10 children (3%) had an institutional stay over the last 2 months; 24 (7%) received outpatient treatment; 55 (15%) received medication; and 38 (11%) a special diet. It can be seen from the data in n = 85; 24%); 111 had reduction in working hours (31%) due to a child care assist  and required an additional aide at school or home .The results about schooling indicate that the majority of individuals from European counties . It may be explained by the fact that communication problems belong to the core autism symptoms; thus, children may benefit the most from this kind of treatment at this early stage of life. The second and most frequently chosen form of therapy was sensory and motor therapy . High use (42%) of this intervention might be due to the core nature of sensory symptoms in individuals with ASD, particularly to sensory over-responsivity . On the Estimated total costs of health-related services were M = 1210 EUR for a 2-month period, while specialist autism services contributed to these costs the most (315 EUR) followed by behavioural intervention (284 EUR) and speech/language therapy (251 EUR).Roggie and Janssen  in theirThe present results indicated a high diversity among children\u2019s needs and therefore health care services used. Institutional admissions occurred in 12 cases (3% of cohort), while visits to psychiatric, somatic, or other specialized outpatient services occurred in 37 cases (10%). Even though our data indicated a relatively low mean cost of institutional stay (3 EUR) and outpatient services (1 EUR) over a period of two months when averaging across the whole sample, the wide range of costs show that there were families who incurred very high costs  related to these services, whereas other families did not have these costs at all. A large and growing body of literature has investigated healthcare utilization expenditures for individuals with autism. Other research in medical and healthcare costs has emphasized the higher costs for individuals with autism compared to individuals without ,19,21,22One third (31%) of the included families in our sample experienced some costs related to medication. Even though the present data indicate a relatively low cost of medication (approx. 6 EUR) over a period of two months, the range of costs (from 0 to 290 EUR) emphasizes that there were families who incurred very high costs related to these services, and families who did not have these costs at all. There is a large volume of published studies e.g.,  describiSeventeen percent of the included children in our study experienced costs associated with a special diet; across all included children, the cost of special diet was on average 7 EUR over a period of two months. The broad range of these costs from 0 to 455 EUR indicates that some families have had a very high cost associated with a special diet. These results are likely to be related to a possible relationship between nutritional status and general condition of ASD children. Peretti and colleagues  emphasizResults of the present study indicated the indirect societal costs to be around 1624 EUR over a period of two months. In terms of societal costs, an additional aide at school or home contributed the highest costs (621 EUR), followed by reduction in working hours (M = 524 EUR), childcare/school (M = 461 EUR), and child care help (M = 18 EUR).Our findings seem to be consistent with other research which found a high economic burden linked with ASD on society . For insFamilies of individuals with ASD face significant economic burden due to reduction or interruption of employment . The resData from our study indicate that the reduction in working hours was linked with costs of 524 EUR; child care help with additional costs of 18 EUR over a period of two months. Our findings have confirmed previous results ,30 that It was hypothesized that younger participants with a diagnosis of autism with intellectual disability will bear higher costs compared to those with older age, with broader ASD category and with intellectual disability. Regression calculation of costs confirmed that health costs change with age for children with ASD during ages 4\u20137 and with presence of intellectual disabilities, but not with societal costs. Our results indicated that health costs increased by 213 EUR per additional year of child\u2019s age and by 566 EUR for children with intellectual disability, indicating that both age and intellectual disability are significant factors related to total health costs. However, such a relationship was not observed for the social costs.Our results are in line with earlier findings. Research by J\u00e4rbrink  found thThe results of our study did not confirm the predictive role of symptoms severity in the health costs and societal costs measured by ADOS total score, which is consistent with another study . HoweverLittle is known about autism-related costs in Europe. Total costs including health services costs and societal costs were estimated to be around 2834 EUR for the whole sample size compared to 2489 EUR for individuals from Europe. The results obtained from the sensitivity analysis showed that for children from European countries the pattern of services used is similar (but not exactly the same) for those from non-European countries. Children outside Europe attended more often health care services in the pre-school period, which has a direct impact of health services costs (1210 EUR vs. 740 EUR for the 2 months). Speech/language therapy; behavioural intervention; and sensory/motor therapy were associated with the highest costs for children from Austria, Israel, Italy, Norway, UK; while for the whole sample the main cost drivers were specialist autism services followed by behavioural intervention and speech/language therapy. Estimated societal costs  were relatively close both in Europe and outside  with the same key cost driver .The generalisability of these results is subject to certain limitations. For instance, the most important limitation lies in the fact that the study used self-reported data of costs threatened by self-reporting bias as: social desirability and recall bias , but theThe present research explores, for the first time, the costs of services received and associated costs for children with ASD bason on 5 European countries  and 4 non-European countries . Total costs including health services costs and societal costs, were estimated to be around 2834 EUR over last 2 months with a wide range from 84 EUR to 26,051 EUR. Estimated total costs of health-related services were around 1210 EUR  and indirect societal costs were 1624 EUR (with a wide range from 0 to 6263 EUR). Specialist autism services; behavioural intervention; and speech/language therapy were key cost driver in this group  followed by sensory/motor therapy (213 EUR) play therapy (32 EUR), therapeutic recreational activities (23 EUR) and social skills training (12 EUR). Among indirect societal costs the important cost driver was an additional aide at school or home (621 EUR) followed by reduction in working hours (524 EUR), childcare/school (461 EUR) and child care help (18 EUR).The current findings add to a growing body of literature on services and costs for children with ASD by confirming that families of children with ASD bear higher costs related to the child\u2019s age  and child\u2019s intellectual functioning . This study has also shown that the diversity of approaches recommended in guidelines across countries. The pattern of services used by children with ASD from European countries is similar (but not exactly the same) for those from non-European countries. The high extent of community-based services indicate good accessibility but also considerable variation in the receipt of these services. Notwithstanding the limitations, these results suggest that the costs of autism services are considerable. There is still abundant room for further progress in evaluating data on services received by individuals with ASD and associated costs for Europe. To develop a full picture of costs additional studies targeting adolescents and adults with ASD is recommended. Further research is needed also to investigate whether services received match individual needs."}
+{"text": "The Centers for Medicare & Medicaid Services defines a hospital readmission as an inpatient stay that begins within 30 days of the discharge date of an index admission, to the same or a different hospital. The aims of the study were to analyze the recurrent readmissions of older persons admitted to a community hospital with diagnoses of: Chronic Obstructive Pulmonary Disease (COPD), Pneumonia (PNA), and Congestive Heart Failure (CHF). Based on the results, we will develop additional strategies that can be used to reduce the rate for hospital readmission for older patients. A retrospective chart review of hospitalizations was conducted. Among 30 readmissions, the mean age was 79.5\u00b114. The index disposition was distributed among three destinations: self-care (27%), home health organization (40%), and to skilled nursing home (33%). Most of the readmissions were for CHF (27%), COPD (10%), and PNA (13%), the only other large category include respiratory failure (10%). The readmission disposition was different from the index disposition: self-care (7%), home health organization (47%), and to skilled nursing home (20%). After hospital readmission within 30 days, older persons were more likely to be discharged to home health care organization than self-care, p<0.05. Actions that can be taken by hospitals to reduce 30-day readmissions to maintain older person independence include: clinical readiness of patients for discharge, proper infection prevention techniques, reconciling medications, good communication, and adequate patient education. This study reports that that older persons are at higher risk for unplanned hospital re-admissions and often lose their independence."}
+{"text": "While Alzheimer\u2019s disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association is unclear. Using a novel, 3-step study design we examined the role of cholesterol catabolism in dementia by testing whether 1) the synthesis of the primary cholesterol breakdown products (bile acids (BA)) were associated with neuroimaging markers of dementia; 2) pharmacological modulation of BAs alters dementia risk; and 3) brain BA concentrations and gene expression were associated with AD. We found that higher serum concentrations of BAs are associated with lower brain amyloid deposition, slower WML accumulation, and slower brain atrophy in males. Opposite effects were observed in females. Modulation of BA levels alters risk of incident VaD in males. Altered brain BA signaling at the metabolite and gene expression levels occurs in AD. Dysregulation of peripheral cholesterol catabolism and BA synthesis may impact dementia pathogenesis through signaling pathways in the brain."}
+{"text": "The expression of the chosen genes was confirmed by RT-qPCR technique. Thus, it can be assumed that the identified genes involved in the regulation of growth and development of muscle tissue and the processes of protein metabolism in the examined cattle breeds may be responsible for the greater gain of muscle mass in beef-breed bulls.The aim of the study was to compare the transcriptomic profiles of fully differentiated skeletal muscle derived from bulls belonging to different breeds of varying performance. Microarray analyses were performed to determine the differences in the expression profiles of genes between semitendinosus muscles of 15-month-old beef-breed bulls (Limousin\u2014LIM and Hereford\u2014HER) and dairy-breed bulls (Holstein Friesian\u2014HF). These analyses allowed for the identification of those genes the expression of which is similar and characteristic of fully differentiated muscle in beef breeds, but differs in skeletal muscle of a typical dairy breed. The analysis revealed 463 transcripts showing similar expression in the semitendinosus muscle of beef breeds (LIM/HER), in comparison with the dairy breed (HF). Among the identified genes, 227 were upregulated and 236 were downregulated in beef breeds. The ontological analyses revealed that the largest group of genes similarly expressed in LIM and HER was involved in the processes of protein metabolism and development of muscle organ. In beef breeds, some genes involved in protein synthesis and proteolysis showed an upregulation, including The online version of this article (10.1007/s13353-020-00577-1) contains supplementary material, which is available to authorized users. The quality of livestock meat is very important from an economic point of view, and hence, research has been carried out over the past few decades to increase the production of beef, accelerate the growth rate of cattle, and improve the quality of meat  cattle breed  and the early-maturing Hereford (HER) breed (with a large proportion of well-marbled muscle) are both beef breeds, whereas the early-maturing and poorly muscled Holstein Friesian (HF) is a typical dairy breed. The gains of muscle mass up to the 16th month of life are about 1000\u20131300, 850\u20131400, and 800\u20131000\u00a0g per day in LIM, HER, and HF breeds, respectively. The reason for these differences observed in the gain of muscle mass is not sufficiently explained, and the genes determining the rate of growth and metabolism of muscle tissue in these breeds remain to be identified  skeletal muscle in cattle depending on their breed and performance. The analysis allowed for a better understanding of the genetic regulation of the development of muscle tissue, as well as determining the putative genes involved in myogenesis and development of muscle tissue in beef-breed bulls.It was assumed that the results obtained will enable the selection of those genes that are involved in the process of myogenesis and maturation of skeletal muscle and modification of their expression for achieving greater gains of muscle mass in beef-breed bulls.All the procedures related to animal experiments were approved by the Local Ethics Committee.n\u2009=\u20094), HER , and HF  used as a reference. The bulls were housed, fed, and slaughtered at the age of 15\u00a0months as described earlier  and total RNA isolation and validation were done as described in previous papers  of 15-month-old bulls from beef breeds Limousin (LIM) and Hereford with bulls of the Holstein-Friesian (HF), a dairy breed (reference), was done using the GeneSpring software , t test with p\u2009\u2264\u20090.05 and fold change \u2265\u20091.3 as the criteria of significance. Each comparison was performed individually, in four biological repetitions. In the subsequent stage, a comparative analysis of both transcriptomes was performed, aiming at identifying common genes with different expression in the muscles of bulls from beef breeds . The data obtained from the microarray experiment were deposited in the NCBI  Gene Expression Omnibus database and numbered GSE137565 (HER vs. HF) and GSE137566 (LIM vs. HF).The gene expression profile was analyzed using Bovine (V2) Gene Expression Microarray 4\u2009\u00d7\u200944\u00a0K oligonucleotide slides  and Two-Color Microarray-Based Gene Expression Analysis kit . Probe labeling, hybridization, signal detection, and data extraction were done as described in a previous paper  was used as a nonregulated, reference gene for normalizing the expression of the verified genes  was applied. The mRNA sequences of the genes selected for validation were obtained from the NCBI Nucleotide database. Primer sequences were designed using the Primer3 and Primer-Blast software (NCBI database) and then checked using Oligo Calculator as described previously . For the purpose of publication, the color immunoblot images were converted into black and white in the Odyssey software.The protein extracts obtained from the skeletal muscle tissues were lysed with RIPA buffer  supplemented with protease inhibitor cocktail and phosphatase inhibitor cocktail  for 30\u00a0min at 4\u00a0\u00b0C. The lysates were cleared for 30\u00a0min at 14000\u00a0rpm, and the supernatants were collected. The concentration of protein in the lysates was determined using Bio-Rad Protein Assay Dye Reagent according to the manufacturer\u2019s instructions . The proteins (50\u00a0\u03bcg) were resolved by SDS-PAGE and transferred onto a PVDF membrane . For immunostaining, the membranes were blocked with 5% nonfat dry milk in TBS  containing 0.5% Tween 20. The membranes were then incubated with the following primary antibodies: monoclonal anti-mouse GDF-8 antibody  (1:100) and polyclonal goat GAPDH antibody  (1:500). Then, the membranes were washed three times for 15\u00a0min and incubated further with appropriate secondary antibodies conjugated with an IRDye 680 or IRDye 800 CW fluorophore  (1:5000). An Odyssey Infrared Imaging System  was used to analyze the fluorescence. The scan resolution of the instrument was set at 169\u00a0\u03bcm, and the intensity at 4. The integrated optical density (IOD) was quantified using the analysis software provided with the Odyssey scanner  and normalized to GAPDH. Immunoblot analysis was performed on the samples obtained from four individuals of each breed , two (**), and three (***) asterisks, respectively. The data are shown as means \u00b1 SEM (standard error of the mean).Statistical analysis of the microarray data was performed using the GeneSpring software . The results of qPCR and Western blot were analyzed using Prism 5.0 . Statistical significance was checked using the one-way ANOVA  with Tukey post hoc test. The differences at the level of http://www.pantherdb.org) with a statistical overrepresentation test with Bonferroni correction; DAVID  (https://david.ncifcrf.gov/), and Pathway Studio Web . In addition, during the development of data from microarrays, numerous internet databases, grouped in NCBI, such as GenBank, OMIM, PubMed, and iHOP, were used.The results were subjected to ontological analysis using the following online available databases: Panther Classification System  was performed in terms of biological processes, in which products of expression of these genes might be involved. Ontological analysis demonstrated their relationship with 13 biological processes, including the following: metabolic processes 236 genes), cellular processes (161), regulation of biological processes (101), developmental processes (63), localization (54), response to stimulus (53), cellular component organization or biogenesis (39), immune system processes (35), multicellular organismal processes (26), cell adhesion (17), apoptosis (11), reproduction (5), and locomotion (1) , followed by phosphate-containing compound metabolic process (31), nitrogen compound metabolic process (27), biosynthetic process (17), catabolic process (11), generation of precursor metabolites and energy (5), coenzyme metabolic process (3), sulfur compound metabolic process (2), and vitamin metabolic process (1).Further functional classification of DEGs demonstrated that among 195 genes involved in primary metabolic processes, the highest share was exhibited by the genes involved in protein metabolic process (99), nucleobase-containing compound metabolic process (91), lipid metabolic process 20) carbohydrate metabolic process (17), and cellular amino acid metabolic process (5) Fig. . The mul0 carbohyUsing the Pathway Studio software, a network of relationships was performed for the differentially expressed genes assigned to the processes associated with protein metabolic process. This enabled a visualization of interaction between DEGs and additionally demonstrated the affiliation of genes to two major processes associated with protein metabolic process: protein synthesis 36 genes) and proteolysis (33 genes) , mesoderm development (19), anatomical structure morphogenesis (19), ectoderm development (12), apoptosis (11), cell differentiation 5), embryonic development (3), pattern specification process (2), and endoderm development (1) . Supplementary Table In addition, an ontological analysis was performed using the Pathway Studio software, which assigned the DEGs with the same direction of expression change 454 genes) to 473 biological processes  and lower level of expression of 5 genes  in semitendinosus muscle of beef breeds (LIM and HER), compared with the dairy breed (HF). These results confirm the results obtained with microarray analysis and exhibited the same direction of expression change as in the microarray experiment.In order to verify the results of transcriptomic analysis, validation of gene expression with the use of qPCR technique has been performed. For the purposes of result verification, seven genes were selected, demonstrating similar changes of expression in both beef breeds (LIM and HER) compared with typical dairy breed (HF), associated with the processes of muscle tissue development and protein metabolism processes. Results of verification with real-time qPCR are presented in the form of block diagrams. The level of mRNA expression is presented as \u0394\u0394Ct Fig. . The qPCp\u2009\u2264\u20090.05) difference in the expression of MSTN in bulls from LIM and HER breeds compared with HF breed bulls. Expression of the active form of myostatin (26\u00a0kDa) in the semitendinosus muscle tissue was lower in beef breeds compared with dairy breed , the key protein inhibiting the process of myogenesis, may be one of the factors influencing differences in the musculature of bulls from beef breeds , compared with bulls of the dairy breed (HF)  and myostatin (mstn). The present study demonstrated higher expression of follistatin and lower expression of myostatin in beef bulls (LIM and HER) compared with bulls from dairy breed (HF)  is another gene identified using the microarray technique, whose expression level was lower in bulls of beef breeds than in the dairy breed  and bmpr2  in mature 15-month-old muscle tissue in LIM and HER breeds compared with HF breed   assigned this gene to protein metabolism process  Fig. , also kngsk3\u03b2 expression in beef breeds  expression in the muscle of LIM and HER bulls  and atrogin 1. The authors observed that as a result of sirt1 overexpression, reduction of the protein degradation degree occurs and their synthesis is intensified, which resulted in increased muscle mass. Koltai et al.  and ctsf (cathepsin F)  and fhl3  genes, which are associated with the development of muscle organ  and decreased expression of genes responsible for inhibition of synthesis and intensification of protein degradation . Increased level of follistation expression and decreased myostatin expression level in skeletal muscles of beef breed bulls indicate the role of follistatin as antagonist of myostatin in the regulation of myogenesis, and it may play a significant role in stimulating development and growth of muscles in these breeds, and as a consequence greater gains of muscle mass. Moreover, the faster growth and development of muscle tissue in beef bulls can be associated with the elevated expression of fhl2 and fhl3 genes encoding FHL proteins , playing putative role in the process of skeletal muscle differentiation including formation of myotubes and expression of proteins characteristic of muscle fibers. The genes identified in this study, involved in the regulation processes of growth and development of muscle tissue and protein metabolism processes in the tested cattle breeds, may be responsible for greater muscle mass gains in bulls from beef breeds and may constitute a new cattle selection tool towards highly efficient meat production, which may be of considerable economic importance.Comparison of transcriptomic profiles of fully differentiated skeletal muscle originating from 15-month-old bulls from various breeds with different performance enabled formulation of the following conclusions. Greater growths of muscle mass in bulls from beef breeds  than in the dairy breed (HF) stem from the differences in protein transformations and are associated with elevated expression of genes stimulating synthesis and inhibiting degradation of proteins (ESM 1(DOCX 73\u00a0kb)"}
+{"text": "Given extended life expectancy, family caregivers are needed to provide care for older adults at home. Research has documented the deleterious effects of caregiving on mental and physical health for many. The Caregiver Health and Well-Being Initiative is a systems approach to support family caregivers of older adults by standardizing processes for identifying caregivers in ambulatory and inpatient settings, assessing caregivers\u2019 needs, and providing relevant services and resources, including caregiver health services, a Teach Back clinic for skills development, and extended goals of care conversations. N=104 caregivers have completed assessments. Participants reported the following at baseline: depressive symptoms (54%); anxiety symptoms (69%); health being affected by the care situation (59%); financial situation decreasing (58%); feeling torn between demands of their family and demands of care (63%); and some feelings of burden from caregiving (97%). Intervention components will be discussed along with a larger systems change framework for implementation."}
+{"text": "Bioscience Reports 39(12) https://doi.org/10.1042/BSR20190744) would like to correct several data calculation points. In the original article, they had made a mistake in extracting the minimum allele frequency (MAF) of rs10830963 polymorphism from one included study [The authors of the original article A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus (Figures and tables have been updated in order to reflect this, and can be found in their correspondence piece ."}
+{"text": "A 42-year-old patient without structural heart disease was referred for catheter ablation of salvos of outflow tract ventricular tachycardia (VT). Activation mapping of the clinical VT (VT1) revealed the earliest ventricular activation site at the right ventricular outflow tract (RVOT). Catheter ablation at this site led to a slight QRS shift of the VT morphology (VT2). Activation mapping of VT2 established the site of origin at the commissure between the right (RCC) and left (LCC) coronary cusps. This case is indicative of the presence of myocardial fibers displaying preferential conduction properties from the RCC\u2013LCC commissure to a breakout site at the RVOT. The QRS morphology was suggestive of a right ventricular outflow tract (RVOT) site of origin (SOO). An electrophysiologic study was performed in a fasting state without sedation. Antiarrhythmic drugs (\u03b2-blocker) were stopped at least five half-times before the procedure. High-density activation mapping of the clinical VT (VT1) was performed using a three-dimensional nonfluoroscopic mapping system  via a multipolar catheter . A contact force-sensing catheter  was used for validation of the earliest activation site and ablation (contact force up to 8 g).A 42-year-old patient was referred for catheter ablation of symptomatic salvos of idiopathic ventricular tachycardia (VT). Structural heart disease was excluded by means of transthoracic echocardiography, cardiac magnetic resonance imaging, and exercise stress testing. The electrocardiogram (ECG) during VT displayed a left bundle branch block pattern (LBBB) with an inferior axis, R-wave in lead I, and precordial transition in lead V4  and 2C. The unipolar signal at this site displayed a small initial r-wave with a steep negative dV/dT. Radiofrequency (RF) energy delivery  at this site led to a slight QRS shift of the VT morphology. The ECG morphology of the second VT (VT2) was characterized by LBBB with an inferior axis, a lower-amplitude R-wave in lead I, and a precordial transition in lead V4 . Of note, the most prominent change was seen in lead V1, where the rS pattern shifted to a QS pattern with notching on the downward deflection, which is suggestive of a right coronary cusp (RCC)\u2013left coronary cusp (LCC) commissure SOO. Following the change in QRS morphology, an additional attempt of RF delivery was performed at this site but failed to suppress the arrhythmia. Meticulous activation mapping of the VT2 was subsequently performed at the RVOT, the left ventricular outflow tract (LVOT) including the coronary cusps, and the coronary venous system [great cardiac vein (GCV)]. The new activation mapping attempt revealed the earliest activation site at the RCC\u2013LCC commissure (\u221225 ms)  and 2C. Catheter ablation  at this site led to suppression of the arrhythmia. Of note, very low voltage and fragmented bipolar signals were recorded at the successful ablation site . On the contrary, the unipolar signal exhibited an initial r-wave with a less steep negative dV/dT as compared with during VT1. VT2 was not inducible by atrial or ventricular stimulation with or without isoproterenol infusion 30 minutes after ablation. The patient remained free from arrhythmias six months after the procedure.Activation mapping of the RVOT revealed the earliest activation site at the posterior septum (\u221223 ms) This case report is suggestive of the presence of myocardial fibers displaying preferential conduction properties from the RCC\u2013LCC commissure to a breakout site at the RVOT.1 Of 202 patients with monomorphic VT or premature ventricular contractions (PVCs) originating from the outflow tract, six patients (3%) showed changes in QRS morphology following RF energy delivery, requiring an additional RF application at a different site, which was often the LCC. Yamada et al. reported that VAs originating from the coronary cusps display preferential conduction to the RVOT and an insulated myocardial fiber across the ventricular outflow septum may exist in these cases.2 Especially, in 25% of patients with VAs of a coronary cusp origin, pacemapping from the RVOT yielded a closer match of the QRS morphology than pacing from the coronary cusp. In these cases, pacemapping identified the preferential breakout site.2 In the study by Shirai et al., a QRS morphology shift following catheter ablation at the earliest activation site was observed in 4% of cases of idiopathic outflow-tract VAs. The shifted VT or PVC demonstrated a distinct ECG QRS pattern supporting the notion that different preferential QRS exit sites within the outflow tract were operative in these cases. After remapping, the earliest activation site of the second VT or PVC moved to a different anatomical structure adjacent to the initial ablation site in 65% of cases, which was most frequently the LVOT region (coronary cusps).Tada et al. initially investigated the prevalence and characteristics of idiopathic outflow-tract ventricular arrhythmias (VAs) with altered QRS morphology following RF catheter ablation.3 An intramural SOO with preferential conduction channels to specific sites of the outflow tract  may explain this phenomenon.3 The presence of preferential conduction can be unmasked by ablation at the first earliest activation site when the first preferential exit of the VT/PVC is eliminated.3 Unipolar signals displaying an rS pattern at both the earliest activation sites, as seen in our case, favors the presence of an intramural SOO.The complexity of the myocardial network around the outflow tract with the potential for preferential/alternative conduction and multiple exiting sites has been suggested to explain subtle variations in the QRS morphology of idiopathic outflow-tract VAs following RF ablation.In conclusion, a QRS morphology shift following catheter ablation of idiopathic outflow-tract VAs is not an uncommon phenomenon. Meticulous activation mapping usually reveals the true SOO in an adjacent site, which is more commonly the coronary cusps."}
+{"text": "The Mong Cai pig is an indigenous breed and popularly raised as maternal line in northern Vietnam. In this study, the complete mitochondrial genome sequence of the Mong Cai pig is reported. The total length of this mitochondrial genome is 16\u00a0632\u2009bp, including 1 non-coding control region (D-loop region), two ribosomal RNA genes, 13 protein-coding genes and 22 transfer RNA genes. The phylogenetic tree of 162 pig complete mitogenomes reveals a very close relationship between Mong Cai pig in Vietnam and Bama miniature pig in southern China. This complete mitochondrial genome sequence of Mong Cai pig is useful to further genetic studies on adaptation and performance. Mong Cai pig is one of the unique and indigenous pig breeds in Vietnam. It is originated from Mong Cai district of Quang Ninh province and is farmed widely in northern Vietnam. With its high fertility, Mong Cai pigs are commonly used as basic sows for crossing with Yorkshire and Landrace pig breeds Tra . Mong CaHere, we sequenced the complete mitochondrial genome of a Mong Cai pig in Son La province, Vietnam . The ear sample was stored in the Key Lab of Agricultural Animal Genetics and Breeding, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University (ID: 20151011mongcai14). The sequence was amplified using 35 pairs of primers  similar to other mammalian mitochondrial genomes (Lin et\u00a0al."}
+{"text": "Lipoprotein(a) has long been regarded as a risk factor for cardiovasculardisease; however, its routine use in clinical practice has been hampered bydifficulties inherent in the measurement of this complex lipoprotein. The majorchallenges relate to its size heterogeneity and related issues including (1) useof appropriate calibrators (2) standardization of calibration protocols (3)traceability and (4) reporting units. In the UK, results from the current EQAschemes for lipoprotein(a) suggest that there is considerable work required tostandardize lipoprotein(a) measurement. This is becoming increasingly pertinentwith the increasing recognition of lipoprotein(a) as an independent risk factorfor cardiovascular disease in international guidelines and the emergence ofnovel antisense therapies to effectively reduce lipoprotein(a). This articleraises awareness of the importance of measurement of lipoprotein(a) for theassessment of cardiovascular disease risk and gives guidance to clinicallaboratories regarding choice of appropriate assays. Remarkably, Lp(a)plasma concentrations within the population can therefore vary by 1000-fold. Thepathophysiology underpinning Lp(a)\u2019s role in atherosclerosis is thought to be two-fold:12,13 firstly, a pro-thrombotic effect by inhibiting fibrinolysis due to thesequence homology of apo(a) to plasminogen and secondly, a pro-atherogenic effectthrough its ability to accumulate in the intima of arteries. Epidemiological andgenetic data have now confirmed Lp(a) as an independent risk factor for coronaryheart disease, stroke and calcific aortic valve stenosis.1416Composed of an LDL-like particle, in which a single apolipoprotein B100 (apoB) iscovalently linked by a disulphide bond to a single apolipoprotein(a) (apo(a)) , Lp(a) pA personal or family history of premature atherosclerotic cardiovasculardisease (<60 years of age).First degree relatives of those with high Lp(a) plasma concentrations(>200 nmol/L).Familial hypercholesterolaemia (FH), or other genetic forms ofdyslipidaemia.Calcific aortic valve stenosis.A borderline increased (but <15%) 10-year risk of a cardiovascularevent.HEART UK (Hyperlipidaemia Education and Atherosclerosis Research Trust UK) recentlypublished a consensus statement that makes recommendations regarding the use ofLp(a) measurement in clinical practice and also reviews current and emergingtherapeutic strategies to reduce plasma Lp(a) concentrations to decrease risk ofCVD. HEART UK recommends Lp(a) measurement in the following groups: 17 to grade this risk on the basis of percentile distributions as follows:32\u201390\u2009nmol/L minor; 90\u2013200\u2009nmol/L moderate; 200\u2013400\u2009nmol/L high; >400 nmol/L veryhigh. Further studies are required to derive ethnicity-specific ranges, appropriateto the UK population as Lp(a) concentration varies by race/ethnicity.18As plasma concentrations of Lp(a) are predominantly genetically determined, they arerelatively stable over a lifetime. Therefore, Lp(a) may only need to be measuredonce, unless a secondary cause is suspected or a specific treatment is instituted inorder to lower its plasma concentration. The cardiovascular risk conferred by Lp(a)may be graded depending on the lipoprotein(a) particle concentration and HEART UKhave employed data from the ongoing Copenhagen General Population Study19 and over the past two decades the questionable performance of these assayshas hampered the incorporation of Lp(a) measurement into routine clinical practice.20 However, the recent demonstration that the genetic risk of variants in theLPA gene is fully captured by measurement of Lp(a) particlenumbers (expressed in nmol/L) using commercial immunoassays standardized andcalibrated to minimize isoform sensitivity21 shows that reliable methods for assessment of Lipoprotein(a) associated CVDrisk are available on modern high throughput platforms. There is now an urgent needfor assay harmonization to allow reliable clinical decision making.Despite the efforts of the International Federation of Clinical Chemistry (IFCC) todevelop a reference material for standardization of analytical methods (WHO/IFCCSRM-2B), shortcomings of commercially available immunoassays for this complexparticle, primarily due to their sensitivity to apo(a) isoform size variation, havelong been apparent22 The antibodies used against apo(a) are usually polyclonal and cross-reactwith the multiple KIV-2 repeats thereby overestimating Lp(a) plasma concentrationsin individuals with large isoforms and underestimating the concentrations in thosewith small isoforms.22 As a consequence of this bias, the strength of the relationship between Lp(a)and CVD risk has appeared inconsistent and has frequently been underestimated. Morerecent studies using a monoclonal antibody-based ELISA22 assayinsensitive to apo(a) isoform size variability show a consistent positiverelationship between high levels of Lp(a) and CVD, whereas earlier studies usingisoform sensitive assays have missed this important relationship. In particular, twoinfluential epidemiological studies  which reported negative results, were repeated using the isoform insensitiveELISA assay and were clearly positive.23 This highlights the importance of using suitable and standardized methods forLp(a) measurement to accurately assess CVD risk.The large heterogeneity in apo(a) size between, as well as within individuals becauseof the inheritance of two different apo(a) alleles, has been a major challenge tothe accurate measurement of Lp(a).10,11 Concerted effort was made by the IFCC to select and characterize a suitablereference material and to develop a multistep standardization protocol to be used bymanufacturers and clinical laboratories. However, traceability to the WHO/IFCCSRM-2B improves assay comparability but does not eliminate the isoform sensitivityof the analytical methods.24 The target value assigned to the reference material is in nanomoles per litreof Lp(a) protein, reflecting a mole for mole interaction of antibody with apo(a).Lp(a) has historically been expressed in mass units (mg/dL) encompassing the mass ofthe entire particle, including the content of apo(a), apoB-100, cholesterol,cholesteryl ester, phospholipid, triglyceride and carbohydrate. This ismetrologically unsound because what is measured by immunoassays is the proteincomponent of Lp(a) and not its lipid and carbohydrate content. Therefore, the mostappropriate units of measurement of Lp(a) are nmol/L. Lp(a) concentrations shouldnot be converted from nmol/L to mg/dL, or vice versa, as all conversion factors areinherently isoform dependent.25Many studies have shown differences between Lp(a) assays.2628 Of the commercially availablemethods measurement are inherently isoform insensitive.methods , theDenCheck that the accuracy of the assay has been certified by the NorthwestLipid Research Laboratory in Seattle making sure the certificationapplies to the specific instrument.Do not convert results to mass units.External quality assurance programs should distribute samples with knownapo(a) isoform composition and Lp(a) values assigned by a methodvalidated to be independent of apo(a) size polymorphism and calibrationtraceable to the WHO/IFCC SRM-2B reference material.External quality assurance samples should cover the clinically meaningfulrange, especially the management threshold range of 90\u2013200 nmol/LWe suggest the following to improve harmonization of Lp(a) assays: In the UK, there is a long way to go with assay harmonization. The vast majority oflaboratories report Lp(a) concentration in mass units , with no22 However, Lp(a) particles have been found to associate noncovalently withtriglyceride-rich lipoproteins which could result in overestimation of Lp(a)measured by immunoassays based on the apo(a) capture/apoB detection approach.22,29 Another approach to circumvent the effect of apo(a) size variability, is thedevelopment of methods that are not antibody-based. Mass spectrometry methods havealso been reported30 or are under development. However, to be of the greatest clinical utility,new assays should provide the same high throughput as the analytical platformscurrently used in clinical labs as this will facilitate a more widespreadmeasurement of Lp(a).There is clearly a need for innovation in the development of isoform insensitiveLp(a) assays. One approach could be a sandwich immunoassay with antibodies detectingthe apoB component of Lp(a) or monoclonal antibodies to apo(a) directed to a uniqueepitope not present in kringle IV type 2.31,32 Currently, lipoprotein apheresis is the only reliable means of achieving asubstantial reduction of plasma Lp(a); however, its use is limited by its high cost,low capacity and lack of accessibility. Injectable antisense oligonucleotidestargeting hepatic LPA RNA have been shown to reduce apo(a)production and apo(a) assembly with apoB, leading to >90% reduction in Lp(a)particle concentrations. These agents are now in Phase 3 trials (NCT04023552) andthe results will confirm whether selective reduction of Lp(a) levels reduces CVrisk. The need for clinical laboratories to deliver timely, accurate andstandardized measurements of this enigmatic lipoprotein has become one of vitalimportance for us all to address.There is now an urgent need for the standardization of Lp(a) assays firstly, to meetgrowing demand with the recognition in international guidelines of this important,largely unmeasured cardiovascular risk factor and secondly, due to the prospect ofnovel treatments to dramatically lower Lp(a)."}
+{"text": "We compared indicators of influenza activity in 2020 before and after public health measures were taken to reduce coronavirus disease (COVID-19) with the corresponding indicators from 3 preceding years. Influenza activity declined substantially, suggesting that the measures taken for COVID-19 were effective in reducing spread of other viral respiratory diseases. Public health measures, including public education and physical distancing, were implemented in Singapore to reduce transmission of coronavirus disease (COVID-19). However, instead of a lockdown, Singapore kept schools and workplaces open and did not advise the routine use of masks for persons who are well during the initial phase of the outbreak in January\u2013February 2020. We examined the effect of these COVID-19 measures on influenza incidence as a proxy to determine the overall potential reduction in respiratory virus transmission.>38\u00b0C) and cough. Data included number of visits to government primary care clinics for ILI per day, ILI samples tested per week, and percentage influenza positivity. We estimated number of influenza cases per day by multiplying ILI visits per day by the proportion of ILI patients who tested positive for influenza, which better reflects influenza infection rates than either indicator alone (We obtained routine sentinel surveillance data on influenza-like illnesses (ILI) from a national network of primary care clinics and the National Public Health Laboratory. ILI was defined as fever . Influenza activity peaked in epidemiologic week 1 of 2020 but declined to below the average of the preceding years by epidemiologic week 5 (We compared indicators of influenza transmissibility in 2020 against the average from corresponding periods in the 3 preceding epidemiologic years (2016\u20132019). We performed weekly paired difference c week 5 . Percent0) than seasonal influenza (0 of 2.2 (Public health efforts to control COVID-19 probably reduced influenza transmission in February 2020 because both viruses have similar modes of transmission through respiratory and contact routes. Even if COVID-19 has a potentially higher basic reproduction number (ROur study has several limitations. First, a decrease in influenza transmission is expected in February\u2013March, given the yearly bimodal pattern of influenza incidence in Singapore (In conclusion, we found a marked decline in ILI in Singapore after the implementation of public health measures for COVID-19. Our findings suggest that such measures are effective in reducing spread of viral respiratory diseases and could mitigate the impact of the COVID-19 pandemic."}
+{"text": "As increasingly more older adults in the general population utilize smartphones to access health services, the digital divide between older adults with serious mental illness (SMI) and the general older adult population continues to widen. The purpose of this study was to examine older adult peer support specialists\u2019 and older people with SMI\u2019s perspectives of barriers and facilitators to utilizing Medicaid Safelink smartphone services. Data from two focus groups and five semi-structured interviews from older adult peer support specialists (N=10) and older adults with SMI (N=15) were analyzed using the Consolidated Framework for Implementation Science Research. A mixed methods convergent design integrated quantitative with qualitative data. Older adults with SMI (N= 15) had a mean age of 55 years and were mainly women (70%) and White (100%). Certified peer specialists (N= 10) had a mean age of 52 years (age range 45-67) and were mainly female (75%), 66% identified as White, and 33% identified as African American. Four themes that were identified across different aspects of barriers included technology knowledge, technology adoption, design features , and Safelink policies and procedures. Facilitators included free and continuous services, access to technical support, and smartphone capabilities to enable healthcare communications and facilitate the delivery of services. Improving upon the themes identified as barriers to utilizing Safelink may promote a continuum of care for older adults with SMI, closing the gap of services that occurs between in-person therapy and other interventions."}
+{"text": "This review aimed to synthesize the most up-to-date evidence regarding the prevalence of urinary incontinence (UI) among adolescent female athletes. We conducted a systematic review of studies regarding UI in female athletes less than 19 years of age. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRIMSA). The electronic databases of PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science (WOS) were searched between October and November 2020. After blinded peer evaluation, a total of 215 studies were identified and nine were included. Risk of bias was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. This review identified a prevalence of UI in adolescent female athletes between 18% to 80% with an average of 48.58%. The most prevalent sports were trampolining followed by rope skipping. The prevalence of UI among adolescent female athletes practicing impact sports was significantly prevalent. There is a need for further research, education, and targeted interventions for adolescent female athletes with UI. Urinary incontinence (UI) is defined as any complaint of involuntary loss of urine . Mostly The younger female athletes seem to display isolated symptoms of pure stress UI which is an uncomplicated SUI without other symptoms of urge incontinence or bladder dysfunction . High-imThe underlying mechanisms by which young nulliparous female athletes show higher levels of UI as compared to their sedentary females ,17 are sElite female athletes experiencing UI at an early stage are more likely to report UI symptoms later in life . This isThe conduct and reporting of this systematic review complied with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) guidelines .A systematic search of electronic databases including PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science (WOS) was carried out between October and November 2020 independently by two blinded authors. No restrictions on language or publication timeline were applied. The search strategy used keywords, mesh terms, and Boolean connectors (AND/OR) including: \u201cStress urinary incontinence\u201d OR \u201curine loss\u201d OR \u201cpelvic floor muscles\u201d AND sport OR athlete OR \u201cfemale athlete\u201d. Search results were limited to species (human) and age (birth\u201318 years) and source type .Retrieved titles and abstracts were assessed for eligibility for inclusion, and duplicate entries were removed. The same two authors independently reviewed the text of the studies for eligibility. Articles published up to November 2020 were eligible for inclusion. The criteria for inclusion were: (1) study participants included adolescent females participating in sport or athletic activities; (2) study provides an assessment of UI symptoms; (3) study published in a peer-reviewed journal in any language. Randomized controlled trials (RCTs) with two or more parallel groups and crossover trials, non-RCTs were eligible for inclusion if they met the previously mentioned criteria. The criteria for study exclusion were: (1) participants > 19 years old; (2) participants who underwent any type of pelvic floor surgery; (3) participants during their pregnancy and postpartum period and; (4) systematic review, meta-analysis, or case study.For each study, data were extracted on the characteristics of the population and intervention such as: (1) last name of the first author; (2) years of publication; (3) study design; (4) sample characteristics ; and (5) instrument assessing symptoms of UI. Risk of bias was assessed independently by two authors using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist . The samThe search strategy yielded 500 potentially relevant studies. After the removal of duplicates, 321 records were screened. Of those, 215 potential titles were selected after the database filter insertion. Among those, only nine studies met the criteria for inclusion and were selected for analysis in this systematic review. The study selection flow chart is shown in 2, and 6\u201319 h of training per week. We calculated a mean of prevalence of 48.58% for all the samples that were involved in different sports. Almost all study designs were cross-sectional (n = 8) where one had a pilot cross-sectional design. The risk of bias was assessed with the STROBE checklist for cross-sectional studies [Our systematic review identified nine studies published between 2002 and 2020. The total sample was 633 female athletes, with an average age of 16.15 years, BMI ranging from 18.9 to 21.7 kg/m studies . Figure  studies . ClarityThis systematic review identified a range of UI prevalence rates ranging from 18.2% to 80% and yielding a mean prevalence of 48.58%. In reports that assessed UI in one specific sport, the highest prevalence rates were found in trampolining (80%) followed by rope skipping (75%) and soccer (62.8%). On the other hand, the lowest rates of UI were found in practitioners of rhythmic gymnastics (31.8%).The main outcome for assessing UI symptoms was the International Consultation on Incontinence short form questionnaire (ICIQ-SF), which was used in 5 of the 9 studies. Only one study used a quantitative measurement of UI through the pad-test . Almost The aim of the present review was to systematically review the prevalence of UI among adolescent female athletes. Notably, we found a wide range of UI prevalence rates among young female athletes varying from 18% to 80%, with an average prevalence of UI symptoms in female adolescent athletes about 50%. Our results are slightly higher than the meta-analytic data presented by Teixeira et al.  for femaOur review included a total sample of 633 young nulliparous female athletes practicing a wide range of sports. Several studies included samples of athletes practicing different sports. We applied a classification of sport impact based on the study by Groothaussen and Siener  that has2 and 6 to 19 h of training per week. Collectively, these observations suggest that the high volume and intensity of training along with low energy availability could be potential risk factors for developing UI in adolescent female athletes.The benefits of sports practice early in life are well established; however, young female athletes are not immune to suffering sport-related injuries or illness . ParticuB\u00f8 and Sundgot-Borgen described that the presence of UI early in life is a strong predictor for UI later in life (ORR of 8.57) ,21. Due Limitations of this review are the small sample size, heterogeneity, and variability of outcome measures as well as the lack of reliable quantitative outcome measures for UI. The selected studies used validated questionnaires to assess urinary symptoms in young athletes. However, these questionnaires were validated in adult populations. More reliable diagnostic outcomes would improve the quality of the studies. In addition, the analysis of co-founding factors specific to the female adolescent athlete such as menstrual cycle and nutritional status would improve the quality of the studies. We recommend the use of the STROBE checklist for risk of bias study assessment to improve the scientific report of these studies and a classification of sport characteristics and impact, which would additionally improve their comparison and assessment. The development and validation of a specific questionnaire for assessing UI symptoms in adolescent females is warranted.UI during exercise and sports is a concern for young female athletes. Our findings highlight a 48.8% prevalence rate among adolescent female athletes where practitioners of high-impact sports show the highest prevalence rates. Given the high prevalence of UI among adolescent female athletes involving impact sports graded 2 and 3, concerted efforts are needed to provide early education and implement prevention measures before young female athletes experience the burden of UI. Future research is needed to guide our understanding of the underlying physiopathology and unique characteristics of the adolescent female athlete\u2019s pelvic floor muscle activity during impact sports."}
+{"text": "A collaborative research team lead by an investigator from the Lyon Neuroscience Research Center and Lyon University Hospital and Lyon 1 University studied epileptogenicity of tuber and its surrounding cortex using stereoelectroencephalography (SEEG) in patients diagnosed with tuberous sclerosis complex (TSC) . A collaborative research team lead by an investigator from the Lyon Neuroscience Research Center and Lyon University Hospital and Lyon 1 University studied epileptogenicity of tuber and its surrounding cortex using stereoelectroencephalography (SEEG) in patients diagnosed with tuberous sclerosis complex (TSC) . A study cohort of eighteen patients (11 children) who underwent presurgical SEEG evaluation between 2004 and 2018 was identified from four French tertiary epilepsy centers. The electrodes were implanted bilaterally in 14 patients, and the total number of electrodes ranged from 8 to 16 per patient. The total number of tubers in each patient ranged from 3 to 30 [Epileptogenicity Index (EI)  was usedThe dominant tuber was the most epileptogenic P < .001) of the five ROI. Seven patients with a focal tuber EZ organization had 80% Engel IA postsurgical outcome and the following 4 tuber characteristics: continuous interictal discharges (100%), fluid-attenuated inversion recovery (FLAIR) hypointense center (86%), stimulation \u2013 induced seizures (71%), and center-to-rim EI gradient. A combination of the first three characteristics showed a 98% specificity for a focal tuber EZ organization. Six patients with a complex EZ organization showed 40% Engel IA outcome with nearby cortex (4 patients) and distant cortex (1) as the most epileptogenic region. The authors concluded that tubers with focal EZ organization are much like type II focal cortical dysplasia, and that identification of these tubers relate to EZ hypothesis generation and invasive EEG/resection strategies. [ of the fCOMMENTARY. Talarirach and Bancaud developed \u201cstereoencephalographie\u201d in the 1960s as a tool to aid in defining the EZ. Their definition of EZ was an ictal electro-clinical concept based on SEEG recordings. Over the past 50 years, the concept of EZ has evolved due to invention of sophisticated localizing tools. Hans L\u00fcders et al. (2006) defined EZ as \u201cthe minimum amount of cortex that must be resected to produce seizure freedom .\u201d UltimaThe authors reported the following results in consideration of EZ identification in TSC: 1. A combination of the three characteristics - continuous interictal discharges, FLAIR hypointense center, and stimulation-induced seizures, showed a 98% specificity in localizing the dominant tuber; 2. Nearby cortex (4 of 6 patients) was the most epileptogenic  in the presence of a dominant tuber that lacked center-to-rim gradient in EI. Importantly, these results may contribute to development of an effective implantation strategy of intracerebral electrodes in further defining EZ in TSC, as one of the challenges of using SEEG is determining targets and trajectories based on presurgical data and EZ hypothesis. Experience and skill of a functional neurosurgeon who places intracerebral electrodes to confirm/modify/reject the hypothesis of EZ may also influence outcome. The current work is a welcome and laudable contribution to further our understanding of epileptogenicity in TSC.The authors have declared that no competing interests exist."}
+{"text": "The nursing home (NH) industry has experienced a shift toward care specialization. This study used NH-level panel data from 2011 to 2017 to describe unique care specialization groups in urban areas using latent profile analysis (LPA) . We focused on urban NHs because NHs specialize in care due to competition and memetic pressure, more likely to be the case for urban NHs. To identify care specialization profiles, LPA was applied using different types of specialist staffing levels  and the share of special care units aimed at chronic conditions like Alzheimer\u2019s Disease and AIDs. Model diagnostics and information criterion guided selection of the best fitting model. Model stability over time, interpretability of results, and parsimony were also taken into consideration. The final results indicated a 4-profile model fit the underlying data best and the patterns remained comparatively stable over seven years. The 4-classes are uniquely identified as: high use of specialists of all types (3%), moderate use of specialists of all types (7%), mixed use of specialists and special care units (26%), and low specialization use (64%). From 2011 to 2017, the size of the \u2018low specialization\u2019 group became smaller, whereas the high and moderate groups grew larger. In addition to describing a clear trend towards increased care specialization, our findings indicated great heterogeneity in NHs\u2019 care specialization patterns in urban areas. Future studies should examine market and organizational characteristics, as well as performance outcomes for different specialization groups."}
+{"text": "The genomics and genetic data of pigmented and non-pigmented Malaysian rice varieties are still limited. Hence, we performed the genome resequencing of two black rice varieties , two red rice varieties  and two white rice varieties (MR297 and MRQ76) using Illumina HiSeq 4000 platform with 30x sequencing coverage. We aimed to identify and annotate single nucleotide polymorphisms (SNPs) from the genome of these four pigmented and two non-pigmented rice varieties. The potential SNPs will be used in developing the functional SNP markers related to nutritional  and quality (i.e. aromatic) traits. Raw data of the pigmented and non-pigmented rice varieties have been deposited into the European Nucleotide Archive (ENA) database with accession number PRJEB29070 and PRJEB32344, respectively. Specifications Table\u2022The pigmented and non-pigmented genome data provide genomics and genetics data of Malaysian rice varieties, which can be utilized in investigating their genetic basis.\u2022Molecular markers such as single nucleotide polymorphisms (SNPs) and microsatellites can be discovered from the genomes and will be useful in facilitating genetic improvement of rice varieties in order to enhance their nutritional and quality traits.\u2022These genome data are valuable for evolutionary study and the identification of domestication genes.Value of the Data1https://www.ebi.ac.uk/ena) under the studies accession numbers PRJEB29070 (pigmented) and PRJEB32344 (non-pigmented).The genomes of four Malaysian pigmented and two non-pigmented rice varieties were sequenced using Illumina HiSeq 4000 sequencing technology, with the read length of 150\u202fbp at each end. We used a 30x depth of sequencing coverage. Approximately 88 Gb raw data sequenced were generated from the genomes of four Malaysian pigmented and two non-pigmented rice varieties. After filtering the low-quality data, we obtained 87 Gb clean reads and these clean reads were used for further analyses, such as reads mapping and SNPs calling. 22.1The genomic DNA was extracted from the young leaves of each pigmented and non-pigmented rice varieties using Murray The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Elder mistreatment (EM) complexity, while described anecdotally, lacks an empirical foundation for measurement. Improved knowledge on the range and nature of concurrent issues that complicate EM intervention would inform the development of more effective solutions and enable greater precision of evaluation research. The purpose of this qualitative study was to explore factors contributing to complexity in a sample of EM cases that was selected based on difficulty reaching resolution. The sample was drawn from those reviewed by an experienced EM Multidisciplinary team (MDT) and determined to require long-term case management (n=39) beyond the capacity of the MDT\u2019s usual response. Case manager narrative documentation of ongoing assessment and social service records were qualitatively coded by two researchers. Inductive content analysis, with iterative code reconciliation, was used to identify issues and problems both related and concurrent to EM. Eighteen themes and 74 sub-themes emerged, with 93% initial coding agreement between researchers. The most frequent themes were problems with Caregiving (80%), Cognition (80%), Physical Health (80%), Behavioral Health (69%), Socialization (64%), and Finances (62%). Refusal of formal services was common (90%), yet all accepted visitation by the case manager, suggesting informal support may be effective. Diversity, interconnectedness, and emergence of issues along the duration of case management indicates a system approach to intervention design and evaluation is warranted. This research underscores the need for holistic intervention for highly complex EM, and lays the foundation for objective measure of complexity to standardize selection for specialized intervention."}
+{"text": "This paper presents a semi-analytical approach for investigating the nonlinear buckling and postbuckling of spiral corrugated sandwich functionally graded (FGM) cylindrical shells under external pressure and surrounded by a two-parameter elastic foundation based on Donnell shell theory. The improved homogenization theory for the spiral corrugated FGM structure is applied and the geometrical nonlinearity in a von Karman sense is taken into account. The nonlinear equilibrium equation system can be solved by using the Galerkin method with the three-term solution form of deflection. An explicit solution form for the nonlinear buckling behavior of shells is obtained. The critical buckling pressure and the postbuckling strength of shells are numerically investigated. Additionally, the effects of spiral corrugation in enhancing the nonlinear buckling behavior of spiral corrugated sandwich FGM cylindrical shells are validated and discussed. Due to their excellent thermo-mechanical properties, functionally graded materials (FGMs) have been applied in engineering structures, such as military structures, nuclear reactors, civil engineering structures, and other technology areas . ResearcBased on Love\u2019s shell theory, Arshad et al. ,3,4 studFor corrugated cylindrical shells, some previous studies have focused on experimental and numerical analyses of the mechanical behavior of these structures. Yang et al.  establisDue to their excellent load carrying capacity and conformance with manufacturing technology, spiral corrugated cylindrical shells are often used in engineering structures. According to the best of the authors\u2019 knowledge, there is currently no semi-analytical approach for investigating the mechanical behavior of spiral corrugated cylindrical shells made of sandwich FGM surrounded by an elastic foundation. This paper presents a semi-analytical approach for examining the nonlinear buckling responses of spiral corrugated sandwich FGM circular cylindrical shells using a homogenization technique . The spConsider a spiral corrugated sandwich FGM cylindrical shell with an axial length Based on the geometrical calculations, the relation between the angle of corrugation and the number of full waves of corrugation in a loop coil can be established asThe geometrical parameters of the cross section of corrugations The force and moment results of a sandwich cylindrical shell  are expressed by applying the homogenization procedure for corrugated structures established by Xia et al. , as(4){The stiffness matrix terms of non-corrugated shells can be determined asBased on the coordinate transformation technique, the force and moment results of the corrugated sandwich FGM shells in the As can be recognized, the spiral corrugated sandwich FGM cylindrical shells are equivalent to the non-corrugated sandwich FGM cylindrical shells with the new stiffness matrix presented in Equation (6).Based on the nonlinear strain\u2013displacement assumption of von Karman and Donnell shell theory, the strains at the mid-plane of non-corrugated sandwich FGM cylindrical shells can be expressed as (9)\u03b5x0=uThe strains across the shell thickness at a distance From Equation (9), the deformation compatibility equation can be directly established asThe nonlinear equilibrium equations of a non-corrugated cylindrical shell based on Donnell shell theory areConsidering the first two equations of Equation (12), a stress function Substituting Equations (6) and (13) into the third equation of (12), the nonlinear equilibrium equation is obtained in a new form, asFrom the constitutive relations of Equation (6), the inverse relations can be established, taking into account Equation (13), asBy substituting Equation (15) into the deformation compatibility Equation (11), the equation can be rewritten asConsider a spiral corrugated sandwich FGM cylindrical shell under external pressure The solution of the deflection satisfying the boundary condition in Equation (17) in an approximate sense can be applied as a three-state form:Clearly, the simply supported boundary conditions in Equation (17) are approximately satisfied.Substituting Equation (18) into Equation (16), the form of the stress function Substituting the solution form of deflection Equation (18) and stress function form Equation (19) into Equation (14) and then performing the Galerkin procedure in the integral domain Unlike the cylindrical panel, the circumferential closed condition in an average sense must be satisfied for all revolution shell types, asUsing Equations (15) and (18), the closed condition Equation (23) becomesEliminating When the nonlinear amplitude of the postbuckling state The critical buckling pressure By using Equations (20)\u2013(22), the maximal deflection of a shell located at The postbuckling curves of spiral corrugated sandwich FGM cylindrical shells can be determined by combining Equation (25) and Equation (27).In this section, the accuracy of the semi-analytical approach presented for the critical buckling pressure of isotropic cylindrical shells and sandwich FGM cylindrical shells under external pressure is compared with the results reported by Shen et al. , Vuong aAs can be seen in 2 and Alumina 2, and the Poisson ratio was assumed to be a constant value of Numerical investigations were performed to predict the nonlinear buckling responses of spiral corrugated sandwich FGM cylindrical shells subjected to external pressure and surrounded by an elastic medium. The sandwich FGM corrugated cylindrical shells with the following geometrical parameters were considered: The effect of elastic foundation moduli is presented in The postbuckling curves of round spiral corrugated sandwich FGM cylindrical shells are shown in The effect of geometrical parameters of corrugation Corrugated sandwich FGM shells are homogenized to non-corrugated sandwich FGM shells;(2)The critical buckling pressure of a corrugated sandwich FGM cylindrical shell is greater than that of a corresponding non-corrugated sandwich FGM cylindrical shell;(3)The geometrical parameters of the cross section of corrugation and the material properties strongly influence the buckling and postbuckling behavior of sandwich FGM cylindrical shells.Some significant results have been obtained as follows:"}
+{"text": "RAD51 (rs1801320) and XRCC2 (rs3218536) genes polymorphism having association with colorectal cancer risk. For this reason the aim of this study is to ascertain their interrelation with colorectal cancer occurrence in Bangladeshi population. In case of Bangladeshi population, no report is observed till now showing the genetic variations of A case control study was conducted where 200 colorectal cancer patients and 200 healthy volunteers were figured for this research using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). RAD51 (rs1801320), G/C heterozygous genotype was found significant . On the other hand, G/G genotype was not found statistically significant  and significance was observed for GC+GG . In case of XRCC2 (rs3218536), C/T heterozygous genotype was remarked statistically significant . The T/T genotype was not recorded statistically significant  but significance found for CT+TT . Moreover, it is found that the risk factor of developing CRC is observed in G/C, C/T heterozygote and GC+GG, CT+TT (heterozygote+ mutant) in RAD51 (rs1801320) and XRCC2(rs3218536) respectively although no significance is observed in case of G/G and T/T mutant. Here, in case of RAD51 (rs1801320) and XRCC2 (rs3218536) genes polymorphism with colorectal cancer risk is observed in Bangladeshi population.So, the association of  In Bangladesh, cancer can be said as one of the uppermost reasons of expansion of death and morbidity in the approaching years. According to International Agency for Research on Cancer, in 2030 the death rate will be 13% and it was 7.5% in 2005 which determines the proportion is appraised to be precisely twofold compared to 2005 . Presumption says, by 2040 the figure will be expanded from 18.1 million to 29.5 million. Colorectal cancer is attributed as the most usual malignant tumours affecting the parts of alimentary canal appeared from large intestine due to unusual extension of cells having potential to invade several parts of human body . Depending on the initiating point, these types of cancers can be said either as colon or rectal cancer. Colon cancer is noticed to be identified in two-third cases and remaining one-third as rectal cancer . 75% of CRC can be remarked as sporadic. In tumour development, a part of modification in case of other genes can be observed and the occurrence of ultimate addition of supplementary malicious attributes such as intrusiveness of tissue and the ability to metastasize takes place .Several risk factors related to CRC are individual study of adenomatous polyps, one\u2019s own record of inflammatory bowel disease, genealogical account of colorectal cancer or adenomatous polyps and inherited genetic risk factors, coronary artery disease notably . Familial Adenomatous Polyposis (FAP) as well as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) also called Lynch syndrome are the most frequent inherited conditions and approximately 5 to 10% of CRCs are a sequel of accepted hereditary condition . The probability of colorectal cancer is actively governed by diet where modification in nutritional habits might diminish up to 70% of CRC implication . High meat consumption, diets with high fat specifically animal fats has also been bundled in colorectal cancer continuation . At adolescent period, several aspects like physical inactivity and corpulence, smoking, strong drink consumption are responsible for the starting of colorectal cancer. Evidence shows that continuing regular use of aspirin along with Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) lessen the probability of CRC considerably . 5-fluorouracil (5-FU) capecitabine, oxaliplatin and irinotecan are utilized predominantly in chemotherapy for the patients of CRC. Targeted therapy is regarded as an advanced sector of drug evolution. It is engaged with targeted therapy which consequences from expanded apprehension of the molecular differences necessitated in cancer occurrence. Particular molecules engaged in tumor magnification and development are featured by these drugs having divergent and generally less serious after effects compared to traditional chemotherapy drugs .RAD51 is up regulated in different cancers. Attachment of the DNA with RAD51 protein takes place at the site of a break and encompassed in a protein case which is indispensable introductory step in the restoring operation. RAD51 gene is an extremely protected well-designated DNA repair protein . The scheme of RAD51 along with molecular regulation has not yet been completely confirmed .The protein, indispensable for reconstructing the damaged DNA is formed by instructions provided with RAD51 gene which plays a fundamental role in homologous recombinational repair. It is evident from innumerable studies that XRCC2 (X-ray repair cross complementing 2) is 7q36.1 which is a member of the RAD51-related protein family. Chromosomal fragmentation, translocations and deletions are thought to be repaired by XRCC2. Additionally, this gene is found to be necessitated in the HR repair (HRR) pathway of DNA double-stranded breaks (DSBs). An association between XRCC2 (rs3218536) single-nucleotide polymorphisms (SNPs) and cancer incidence risk are found to be the most common mutation observed by numerous studies . The increment of cancer risk is appeared due to two known epigenetic causes of XRCC2 deficiency. One of them is the XRCC2 exponent methylation and epigenetic repression of XRCC2 by over-expression of EZH2 protein. Depletion of homologous recombinational repair and epigenetic repression of RAD51 paralogues including XRCC2 are accompanied by increased expression of EZH2. Over-expression of EZH2 protein between 40%-75% is found in breast cancer and EZH2 mRNA is up-adjusted, about 7.5-fold .The location of RAD51 (rs1801320) and XRCC2 (rs3218536) genes have been perceived in different ancestral groups. A case-control study on Bangladeshi population was conducted recently where the high risk association between altered gene expression of RAD51 (rs1801320) gene polymorphism and breast cancer development was detected. In different ethnicities, RAD51 (rs1801320) and XRCC2 (rs3218536) gene polymorphisms are certified to be a threat aspect of colorectal cancer and RAD51 (rs1801320) gene polymorphism in breast cancer evolution in Bangladeshi population. A possibility may arise basing on a correlation between RAD51 (rs1801320) and XRCC2 (rs3218536) polymorphisms with colorectal cancer risk in Bangladeshi population. Moreover, no related investigation has been supervised concerning this feasible association in Bangladeshi populace. We, consequently, presume to find out that predictable relationship of RAD51 (rs1801320) and XRCC2(rs3218536) genetic polymorphisms with colorectal cancer risk in Bangladeshi citizenry for the very first time.As a probable element for breast, colorectal, lung, prostate, endometrial as well as gastric cancers both Study populationRAD51 (rs1801320) and XRCC2 (rs3218536) polymorphism with clinic pathological characteristics of patients are mentioned in RAD51 (rs1801320) and XRCC2 (rs3218536) polymorphisms, patients who have primary location of cancer in rectum are found to be more susceptible to have colorectal cancer as statistical significances are observed; RAD51  and XRCC2  and in both cases the p values observed are less than 0.05. No other factors are found to be significantly associated with RAD51 (rs1801320) and XRCC2 (rs3218536) polymorphisms. Approval of the study protocol was done by the ethical committees of the respective hospitals and the research was executed according to the descriptions of Helsinki and its following editions . An informed consent document was signed by each patient and control subject after briefing the motive of the study. The genotyping scrutiny was done in the laboratory of Biotechnology, Faculty of Pharmacy, The University of Asia Pacific, Dhaka-1205, Bangladesh.A case control research was co-ordinated on 200 colorectal cancer patients and 200 healthy volunteers basing on age, weight and sex. Colorectal cancer patients were enlisted from Ahsania Mission Cancer and General Hospital and National Institute of Cancer Research and Hospital (NICRH), Dhaka, Bangladesh. After that, physical analysis of controls were picked by matching age and genetic history to colorectal cancer patients. The age of patients ranged from 13 years to 89 years (mean 51 years). Most of the patients are observed having tumour stages I, II and IV (mostly stage II). Age, sex, diet, weight, BMI, TNM staging, demographic characteristics, lifestyle factors data were stockpiled via interrogations by skilled attendants in presence of specialized doctors. The demographic characteristics of the patients and the controls are presented in Genotyping RAD51 (rs1801320) and XRCC2 (rs3218536), PCR-Restriction Fragment Length Polymorphism (RFLP) approach was applied to genotype. PCR product of 157 bp and 234 bp were obtained for RAD51 (rs1801320) and XRCC2 (rs3218536) SNPs respectively. PCR amplifications conditions are given in RAD51 (rs1801320) was dispatched with BstNI  by incubating at 60\u00b0 C for 4 hours which produced two fragments 86 bp and 71 bp in case of G/G allele while for C/C allele it produced only one fragment of 157 bp. Restriction enzyme Hph1  (37\u00b0 C overnight) bisected the T/T allele of XRCC2 (rs3218536) giving two fragments of 147 bp and 87 bp but didn\u2019t divide the C/C allele that is only one fragment 234 bp was observed. These DNA fragments were blemished with ethidium bromide and pictured on 2% agarose gel electrophoresis.Genomic DNA was separated from the blood specimens assembled from all patients by the help of DNA extraction mini kit, Favorgen, Taiwan. Genomic DNA amplification was executed using the predesigned forward and reverse primers. PCR was done by following the standard protocol mentioned in published method . In case of bothStatistical analysisStatistical analyses were carried out using the SPSS software package 13.0 . Mean age for cases and controls was evaluated by using Student\u2019s t-test. Odd ratios (ORs) and the corresponding 95% confidence intervals (CI) calculated by using logistic regression analysis were used to analyse the association between the polymorphic genotypes and CRC risk, based on heterozygous and homozygous comparison models with the wild type genotype served as the reference. Odds ratios of > 1.00 specified a positive risk association and vice versa. P values of < 0.05 were significant. Study populationRAD51 (rs1801320) and XRCC2(rs3218536) with a number of 200 controls. This study included 97 males (%) and 103 females (57.5%) colorectal cancer patients with an average age of 51 and the control group covered 87 males (43.5%) and 113 females (56.5%) with an average age of 47.The study was conducted through 200 patients of RAD51 (rs1801320) polymorphismRAD51 (rs1801320). This population based case-control study was conducted to survey the prevalence of RAD51 polymorphism in Bangladeshi population of CRC patients and normal controls. The genotype frequencies in cases and controls are presented in It was evident after gel electrophoresis that DNA fragment pattern of BstNI digestion of the PCR product was done to recognize the genetic variation at XRCC2 (rs3218536) polymorphismXRCC2 (rs3218536). This population based case-control study was conducted to investigate the prevalence of XRCC2 polymorphism in Bangladeshi population of CRC patients and normal controls. The genotype frequencies in cases and controls are presented in Digestion by Hph1 shows the mutation of RAD51 (rs1801320) and CRC with present study is shown in XRCC2 (rs3218536) and CRC with present study is given in A comparison of previous association studies between HRR) genes have an extremely immediate association with cancer threat. Both RAD51 and XRCC2 proteins are fundamental constituents of DNA double strand breaks (DSBs) reconstruction by HRR. Constructional at the same time functional correspondences are noted between RAD51 and XRCC2 gene . Genomic instability is demonstrated if cell deficient with any of RAD51 or XRCC2 genes products are defective in homologous recombination. The X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) gene plays an important role in the homologous recombination repair (HRR) pathway at the same time can be said a functional member for taking part in tumor progression . Improvement of unrepaired DNA destructions would be conducted by under expression of RAD51 gene. Replication blunders past these destructions would guide to the growth of mutations and cancer.Protein haploinsufficiency regulation by genetic polymorphisms in homologous recombination repair . Another Chinese case control study says that in CRC tissue, the expression of XRCC2 is inflated and notable interdependences are also found among positive XRCC2 expression, tumor size, Dukes\u2019 stage and TNM stage . In case of Australian population, a comparative consequence of the XRCC2 alteration to cancer threat is remarked for members of this family . Another case study on Polish population (Warsaw) also said that the feasible character of XRCC2 gene polymorphism is responsible for neoplastic diseases. Therefore, XRCC2 polymorphisms may take part dominant role in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors in Polish population . Similar relationship is also observed when studied on English population . The investigation on RAD51 and XRCC2 gene polymorphism was done by being encouraged with strong association between these genes and these gene polymorphisms may be used in several areas in colon cancer management, such as early detection of the carcinogenesis, prediction of tumor biologic behaviour and being a candidate therapeutic target for colon cancer. Evidence is yielded by this study that RAD51 and XRCC2 gene polymorphisms may be risk factors for colon cancer progress . A result of meta-analysis says that the RAD51 135 G/C polymorphism is responsible for increased risk of CRC in total using allele (OR=1.21) and recessive models (OR=1.62). However, XRCC2 rs3218536 A/G was not associated with the risk of CRC in total or in subgroups in that particular study. As claimed by the consequences of meta-analysis, the RAD51 135 G/C polymorphisms might influence colorectal cancer risk . Few reports are also made out regarding the impact of RAD51135G>C in spread of CRC in Asian populations. In a subgroup of population of Kashmir, RAD51135G>C has marked the association with CRC . On the other hand, in case of Iranian population RAD51 135G>C presumably does not impact on CRC susceptibility and other risk factors should be contemplated for furtherance of management potentials of the disease in Iran .Colon carcinoma can occur due to elevated-expression of RAD51 (rs1801320) and XRCC2 (rs3218536) genes have increased probability of colorectal cancer and both genes are significantly associated with colorectal cancer occurrence and further elucidate the relationship of multiple genotypes at the RAD51(rs1801320) and XRCC2 (rs3218536) locus with colorectal cancer occurrence. The outcomes found from our research are harmonious with various prior studies yet corresponding genotyping analysis in more racial communities is still necessary to confirm the association between SNPs and susceptibility to colorectal cancer. Our results confirmed that RAD51 (rs1801320) and XRCC2 (rs3218536) genes helps to recognize the malfunction of these proteins and can lead to successful therapies for colorectal cancer. In this study, it is observed that the risk factor of developing CRC is noticed in G/C, C/T heterozygote and GC+GG, CT+TT (heterozygote+ mutant) in RAD51 (rs1801320) and XRCC2 (rs3218536) respectively but no significance is found in case of G/G and T/T mutant. So, it can be said that a significant association between RAD51 (rs1801320) and XRCC2 (rs3218536) and colorectal cancer development is confirmed in our population. If the study can be conducted by using more samples from different areas, G/G and T/T mutant can also be found significant. However, it is the first study in Bangladesh and with a limited number of cases and controls. Therefore, RAD51(rs1801320) and XRCC2 (rs3218536) genes polymorphism and colorectal cancer risk is an important research area that needs much more attention as some statistically strong risk factors required to be excluded because of a small number of sample and control. It will also reduce the number of injuries or deaths resulting from incorrect or ineffective prescriptions prescribed for cancer patients and tend to integrate into personalized medicine.In summary, studying SNP in"}
+{"text": "The 4Ms of an Age-Friendly Health System start with What Matters to the older adult. A unique method for asking that question is through film. Schaalman Senior Voices (SSV) films older adults talking about What Matters to them, and uses the films to stimulate discussion about later life with older adults in the community (n=264), with health care professions students learning to listen to older adults (n=1250), and health system executives considering implementation of the Age-Friendly Health Systems (AFHS) initiative (n=100). SSV has completed longer professional films interviewing 12 older adults. Using a mobile platform, SSV has filmed 50 older adults in the community and at health events. Outcomes of film discussions will be presented, including inspiration for older adults having conversations with family and physicians about What Matters, health care students effectively using skills in asking What Matters to enhance the care they provide, and executives considering AFHS implementation."}
+{"text": "More than 19% of third-graders in Georgia had untreated dental caries (tooth decay) in 2016\u20132017 . The mosDental sealants , topicalWe developed a data visualization tool that maps county-level need for caries prevention and treatment programs and the distribution of dental safety-net programs in Georgia. This tool can be used by public health decision makers to 1) assess how well dental safety-net programs are currently allocated and 2) plan and target future programs.short). We obtained data on the prevalence of untreated tooth decay from a study that estimated this information for children aged 6 to 9 years , DeKalb (143 census tracts), Fulton (202 census tracts), and Gwinnett (113 census tracts). Level of need was based on the estimated prevalence of untreated tooth decay and the severity of a dental workforce shortage  as high Dshort areas  and census tracts below the median  as low Dshort areas.We used data from the Health Resources and Services Administration (HRSA)  on the sshort, 2) low prevalence of untreated tooth decay and high Dshort, 3) high prevalence of untreated tooth decay and low Dshort, and 4) high prevalence of untreated tooth decay and high Dshort. We designated counties in category 4 as having the greatest need for dental safety-net programs and counties in category 1 as having the least need. We designated counties in category 3 as having a greater need for dental safety-net programs than those in category 2 because of their higher prevalence of untreated tooth decay.We assigned counties to 1 of 4 categories: 1) low prevalence of untreated tooth decay and low DWe then overlaid information on current Georgia dental safety-net programs onto county need for such programs. Dental safety-net programs included 1) state-sponsored school sealant programs, 2) county-funded public health departments offering dental services, 3) federally qualified health centers offering dental services, and 4) dental hygiene programs providing community dental services. We obtained information on school sealant programs from the Georgia Department of Public Health Oral Health Program , informaOur visualization indicated good allocation of scarce dental public health resources. Of the 131 dental safety-net programs, 88 (67.2%) were in high-need counties, which is twice the number in low-need counties (43 or 32.8%). Many high-need counties, however, did not have dental safety-net programs. Among the 80 high-need counties, 52 had no programs . In high-need areas, programs were more common in the metropolitan Atlanta area than in the rest of the state. This information is important for planning purposes, although the state may not be able to immediately address the problem of dental shortages in nonmetropolitan counties because of resource constraints and the higher cost  of serving areas farther away from the State Oral Health Program, which is based in Atlanta.The maps also illustrate the importance of a granular visualization in areas with diverse populations, such as metropolitan areas. If only county levels are used, small pockets of need may be missed, as in Fulton County. Visualization at the census-tract level in Fulton County provides a better assessment of need and targeting.Our mapping technique provides decision makers in Georgia with a visual tool for assessing how well current dental safety-net programs are allocated across the state and identify gaps in resource allocation where needs could be addressed in future program planning. The data used to generate these maps are publicly available for states nationwide and thus, these maps could be replicated throughout the United States."}
+{"text": "We investigated the dimensional structure of mental health among aging Korean Veterans using latent profile analysis (LPA) on posttraumatic stress disorder symptoms (PTSD), late onset stress symptomology (LOSS), and psychosocial well-being (PWB). The Korean Vietnam War Veterans Study consists of 367 men . LPA identified five classes of mental health as best fitting the data. Most men were in the normal (38%) and moderate distress (31%) groups, while smaller proportions were in the low affect (13%) and severe distress (7%) groups. The resilient group (12%) had low PTSD, medium LOSS, and high PWB, and were highest on optimism, positive appraisals of military service, and social support. Negative and positive aspects of mental health outcomes were on separate dimensions rather than on a single bipolar dimension. Service providers should attempt to both reduce Veterans\u2019 negative psychological symptoms and increase psychosocial well-being. Part of a symposium sponsored by the Aging Veterans: Effects of Military Service across the Life Course Interest Group."}
+{"text": "Hackman G The latest guideline suggest adjuvant radiotherapy or observation following prostatectomy with adverse pathological findings , 2. ThisThe authors founded a 74% benefit of BCRFs in the adjuvant group, and the number needed to treat was 4. There were no difference in the overall survival and in cancer-specific survival, with more grade 1 and 2 adverse events in the adjuvant group.The first results of the RADICALS trial (NCT 005541047) recently presented at ESMO Congress 2019 did not show any benefit in BCRFs (secondary endpoint), supporting the use of early salvage radiotherapy."}
+{"text": "Bemisia tabaci poses a major threat to cassava production by small holder farmers in part due to their role as a vector of cassava mosaic begomoviruses (CMBs) and cassava brown streak ipomoviruses (CBSIs). In the present study untargeted metabolomics has been used as a tool to assess natural variation, similarities and attempts to identify trait differentiators among an East African cassava diversity panel that displayed tolerance/resistance to the effects of Bemisia tabaci infestation. The metabolome captured, was represented by 1529 unique chemical features per accession. Principal component analysis (PCA) identified a 23% variation across the panel, with geographical origin/adaption the most influential classification factors. Separation based on resistance and susceptible traits to Bemisia tabaci could also be observed within the data and was corroborated by genotyping data. Thus the metabolomics pipeline represented an effective metabotyping approach. Agglomerative Hierarchical Clustering Analysis (HCA) of both the metabolomics and genotyping data was performed and revealed a high level of similarity between accessions. Specific differentiating features/metabolites were identified, including those potentially conferring vigour to whitefly tolerance on a constitutive manner. The implications of using these cassava varieties as parental breeding material and the future potential of incorporating more exotic donor material is discussed.Cassava will have a vital role to play, if food security is to be achieved in Sub-Saharan Africa, especially Central and East Africa. The whitefly  Viral diseases like the cassava mosaic and cassava brown streak diseases (CMD and CBSD) constitute one of the major threats for cassava production in Sub-Saharan Africa (SSA)  of parent ions [M] were also excluded. The final data matrix contained 1530 unique chemical features . In order to reduce redundancy, chemical features corresponding to the isotopic species  and batch corrected contained 149 observations and 1529 variables  and was B. tabaci [To assess the overall biochemical variation of the Eastern African cassava elite varieties, unsupervised PCA was performed on the metabolite composition of leaf extracts. Score plot of components 1 and 2 explained 23% variation of the collection which was comprised of 26 varieties . Three m. tabaci  form a tGenetic similarity was evident when analysis of SNPs was carried out to assess the natural genetic variation of the diversity panel and compared to similarities found at chemical composition level. The Ward AHC dendrogram was constructed using the genetic similarities matrix obtained by running 96 highly informative SNP locus among the complete set of the 5CP collection, which includes 31 East African cassava genotypes . These AThe number of significant chemical features differentiating each sub-group of metabolome derived dendrogram  were calIn order to study whether the natural variation present in the collection can be utilised to define metabotypes representative of WF-R/WF-S phenotype and also to identify potential chemical markers linked to phenotype, a multivariate classification analysis was applied using the LC-MS untargeted data matrix as input.Supervised discriminant analysis like partial least squares (PLS) are often used for these purposes. In the present study an OPLS-DA model was chosen to incorporate both the orthogonal variation which is inherent of the metabolomics mass spectrometry data and the chemical variation of the different classes of phenotypes.Based on the whitefly abundance data available  OPLS-DA p-coumaric acid and caffeic acid and neochlorogenic acid  compared to the variation found in other cassavas\u2019 collections including both African and South American cultivars  where >5orted by . In effeHistorical breeding efforts of African cassava, documented since in the 1930s , 11, 13 The variability introduced by environmental adaptation factors has likely to have an impact in defining the preference of whitefly adults for certain varieties or the symptoms developed under virus infection and therefore hindering/misleading the identification of true-to-type phenotype classes. This hypothesis/concern also arises when the list of potential biomarkers generated from the classification model (ultimately based on observed phenotype) is investigated further. Pair-wise comparison of the WF-R variety Nase 18 (UG4) and the susceptible Sagonja (MAL5) revealed higher similarity between them than comparison between Sagonja (MAL5) and Kalawe (MAL6), despite both Malawian lines being phenotyped as the most susceptible. Varieties UG4 (Nase 18) and MAL5 (Sagonja) presented a significant number of phenotypic biochemical markers displaying a similar pattern of accumulation in both lines.p-coumaric acid malate esters among other unknown features. Malate esters of p-coumaric and caffeic acid were the most influential in the S-plot and present at lower levels in the resistant varieties UG4, TZ3 and TZ6 whilst neochlorogenic acid accumulated in the Tanzanian varieties resistant to whitefly and viral diseases CMD and CBSD Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Figth and 25th quartiles respectively.(A) Table of calculated coefficient of variation (%) within biological replicates per each variety. Columns indicate median values of CV of all variables  and the minimum and maximum CV values of each cassava variety. (B) Violin plot showing within subject coefficient of variation  for each variety. Median values indicated as straight lines and top and bottom dashed lines indicate 75(TIF)Click here for additional data file.S4 FigScore plot of components 1 and 2 displaying all biological replicates of each cassava variety as small symbols and median values as large symbols. Geographical origin is denoted with different colouring: Kenya (KE) as green, Malawi (MAL) as light blue, Mozambique (MOZ) as blue, Tanzania (TZ) as orange and Uganda (UG) as purple; and number of variety indicated as different symbols: (circle) variety 1, (box) variety 2, (triangle) variety 3, (diamond) variety 4, (pentagon) variety 5, (hexagon) variety 6, (4-point star) variety 7 and (5-point star) variety 8.(TIF)Click here for additional data file.S5 Fig(PDF)Click here for additional data file.S1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(PDF)Click here for additional data file."}
+{"text": "Family caregivers play an important role in the healthcare of older adults, but their circumstances, needs, and risks are often unknown to medical professionals. Standardizing how caregivers\u2019 needs are assessed in healthcare delivery can help clinicians design care plans that take caregivers\u2019 capabilities into account and provide targeted recommendations for caregiver support. Despite the potential of caregiver assessment, little is known about its use in primary care practice. The present study surveyed a national random sample of 1,000 U.S. primary care clinicians  to characterize current practices, barriers, and facilitators of caregiver assessment. A total of 231 completed responses were received. A minority of respondents (11%) reported that their practice or clinic had a standardized procedure for caregiver assessment; one in ten (10%) reported that they had personally conducted a caregiver assessment using a standardized instrument in the past year. The most common barriers to caregiver assessment were lack of time (65%), inability to have private discussions with caregivers (36%), lack of access to referral options (30%), inadequate reimbursement (30%), and reluctance of caregivers to discuss their needs (30%). The most frequently endorsed facilitators to aid future implementation included better availability of referral options (77%), easier referral mechanisms (67%), co-location of mental health specialists, care managers, or social workers (65%), and training in how to address caregiver issues (61%). Findings are discussed within the context of emerging healthcare policies and practice initiatives designed to promote caregiver assessment in health care settings."}
+{"text": "The University of New England College of Osteopathic Medicine (UNECOM) Geriatrics Education Mentor (GEM) Program is in its sixth year. It's a joint project between older community living adults and 2nd year medical students within the Osteopathic Clinical Skills course. The GEM program goal is to foster understanding and importance of the person/patient-provider relationship. Pairs of osteopathic medical students (N=87 +/- 5) were assigned to an older adult GEM (mentor) volunteer (N=87 +/-5) living within a 50 mile radius of UNECOM. Snowball sampling was used to recruit the GEMs; student participation is required. Four (4) home visits were conducted over 9 months with an assigned GEM; each visit included a new assignment. Students observed, summarized, and recorded experiences communicated by the GEM for each cumulative assignment. Data from assignments were \u201cgraded\u201d and content analyses of open ended evaluation/summary questions were conducted. This program is UNE IRB approved. Student pairs completed all assignments. Assignments analysis on Blackboard revealed that students developed respect and awareness of life and medical experiences of the GEM; expressed understanding of the GEM\u2019s life experiences and goals for what \u201cmatters most\u201d. Relationships with older adults were established while students maintained professionalism and succeeded in competent and confident interactions. Documentation review from the 4 assignments aided in building students\u2019 geriatrics knowledge, attitudes and skills. Pre-clinical medical education tends to be episodic; providing an opportunity to establish longitudinal assignments over the course of the academic year with the same older adult augments relationship skills and learning in geriatrics."}
+{"text": "The exposure of male individual to environmental toxicant is regarded as a channel that results in reduced sperm counts and infertility.This study investigated the ameliorative response of Sulforaphane (SFN) on Aluminum trichloride  were divided into four groups (n = 8/each). Group A) received distilled water orally as placebo; Group B) received 100 mg/kgbw AlCl The sperm parameters showed a significant difference within the AlCl The present study revealed the ameliorative response of SFN on AlCl The exposure of male individual to environmental toxicant is regarded as a channel that results in reduced sperm counts and infertility . Aluminum is considered as the most common metallic element detectable in natural waters, animal, and plant tissues (3) leading to a significant upsurge in both gastrointestinal absorption and urinary elimination of aluminum in exposed individuals (4). The affinity of aluminum to other elements stimulates free radical-mediated reproductive cytotoxicity causing impairment of testicular tissues to both humans and animals (5). Aluminum compounds are widely used as by-products for the manufacture of several household cooking utensils andpharmaceutical drugs  (6). Increase in the level of exposure to aluminum-containing products will boost the concentration of this metallic element in different organs thereby causing harmful effects to the well-being of humans (7).In addition, elevated concentrations of Aluminum in human sperm and seminal plasma were observed to decrease sperm viability and motility (8). Testicular Aluminum accumulations cause spermatocyte necrosis and trigger other reproductive toxicity through several mechanisms such as oxidative stress, which ultimately interferes with spermatogenesis and steroidogenesis, bloodtestis barrier, and endocrine disruption (9). The application of nutritional antioxidant supplements has increased over the years to tackle oxidative stress-induced tissue damage since they act as defense regulators and scavengers of reactive oxygen species. Sulforaphane (SFN) is the most active natural products found in crucifers such as broccoli sprout, cabbage, and kale with the potential of lowering the risk of cancer, oxidative stress-induced tissue injury, and age-related diseases (10). SFN possess antiproliferative activities and can effectively halt the initiation and progression of chemically induced tissue damage in animals (11). In addition, SFN has been suggested to have antidiabetic properties for normalizing changes in blood glucose and insulin sensitivity (12-14), and is used in cardiovascular and antihypertensive protection . It has been reported that SFN can promote elimination and detoxification of aflatoxin (17), acetaldehyde (18), methylmercury (19), acrolein (20), benzene, crotonaldehyde (21), and free radicals (22) through the Nrf2-mediated mechanism. Furthermore, some clinical studies have demonstrated the effectiveness of SFN supplements in the prevention and/or improvement of skin erythema (23), autism (24), insulin resistance (13), Helicobacter pylori-infection (25), and liver abnormality (26). SNF also has the ability to cause programmed cell death(apoptosis) and cell cycle arrest linked to their ability to regulate several proteins such as Bcl-2 and Bax family proteins, caspases, p21, cyclins, and cyclin-dependent kinases (27).This study was therefore designed to investigate the ameliorative response of SFN on the histomorphometric and enzymatic antioxidants on Aluminum chloride  were obtained from the animal house, Department of Human Anatomy, Ladoke Akintola University of Technology, Ogbomosho. The rats were collected in an isolated cages in the experimental house of the Department of Human Anatomy, Federal University of Technology, Akure. They were maintained under constant 12 hr light/dark cycle.The rats were divided into four groups (n = 8/each) Group A) represent control and received water as placebo. Group B) were administered  with 100 mg/kgbw AlClAll animals were observed for any behavioral anomalies, illness, and physical anomalies. The experimental procedures were conducted in accordance with the provided recommendations in the \u201cGuide for the Care and Use of Laboratory Animals\u201d prepared by the National Academy of Sciences. The rats were fed with standard rat chow and drinking water was supplied ad libitum. The weight of the animals was recorded at procurement, during acclimatization, at commencement of the experiment, and weekly throughout the experimental period using a CAMRY electronic scale .\u201cAfter the last administration, the rats were administered intraperitoneal pentobarbital sodium (40 mg/kg) and their abdominal region was opened and the testes of all the animals were immediately removed. The testicular weight of each rat were recorded. The rats were decapitated and blood samples were collected for analysis. The blood samples were centrifuged at 4\u00b0C for 10 min at 250\u201cThe spermatozoa from the cauda epididymis were obtained by cutting into 2 ml of medium (Hams F10) containing 0.5% bovine serum albumin (29). After 5 min of incubation at 37\u00b0C (with 5% COThe level of lipid peroxidation products were estimated in accordance with the method published by Adelakun and co-workers. (31). Nonenzymatic antioxidants such as reduced glutathione (GSH) and catalase (CAT) were estimated as described by Adelakun and co-workers. The SOD activity in the testes was also determined according to the method described by Adelakun and co-workers (31).\u201cThe hormonal levels of testosterone (TT), follicule-Stimulating Hormone (FSH), and Leutenizing Hormone (LH) were measured using available immunoassay (ELISA) kits  according to manufacturer's instructions\u201d.\u201cThe testes of the rats were harvested and fixed in Bouin's fluid for 24 hr before being transferred to 70% alcohol for dehydration. The tissues passed through 90% and absolute alcohol and xylene for different durations before being transferred into molten paraffin wax for 1 hr each in an oven at 65\u00b0C for infiltration. The tissues were embedded and serial sections cut on a rotary microtome set at 5 microns were performed. The tissues were picked up with albumenized slides and allowed to dry on hot plates for 2 min. The slides were dewaxed with xylene and passed through absolute alcohol (two changes), 70% alcohol, 50% alcohol, (in that order), and then in water for 5 min. The slides were then stained with Hematoxylin and Eosin, mounted in DPX, and photomicrographs were taken at a magnification of 100 \u201cMorphometric studies were carried out with modification of Akang and co-workers (32). Briefly, four sections per testis and six microscope fields per section were randomly chosen for analysis. Fields were sampled as images captured on a Leica DM750 bright field microscope (Germany) via LAZ software. Volume densities of testicular ingredients were determined by randomly superimposing a transparent grid comprising 35 test points arranged in a quadratic array. Test points falling on a given testis and its ingredients were summed over all fields from all sections. The total number of points hitting on a given ingredient (lumen (EL), epithelium (EE), interstitium (EI)), divided by the total number of points hitting on the testis sections (ET) multiplied by 100 provided an unbiased estimate of its percentage volume density/volume fraction. The estimation of the volumes of seminiferous tubule EE (seminiferous EE) and EI in the testes was done in accordance with Howard & Reed (33) and Baines and co-workers\u201d (34).\u201cThis was carried out according to the method described by Adelakun and co-workers (31). Briefly, quantitative evaluation of spermatogonia, preleptotene, pachytene spermatocytes, and round spermatid cells was performed using 50 round tubules per group selected in stage VII/VIII of the seminiferous tubule cycle at All animal handling procedure and research activities was approved by the Ethics Committee of the College of Medicine, University of Lagos, Nigeria (CM/ HREC/07/19/120).Where applicable, data obtained were analyzed statistically using one-way ANOVA, followed by Dunnett's comparison test. Data were expressed as Mean In addition, there was a significant decline in the relative weight of the testes in the rat that received AlClThere was a significant decrease in the body weight in the rats administered with AlClThe spermatozoa concentration showed a significant difference within the AlClIn addition, there was a significant decrease in sperm motility in the group administered with AlClFurthermore, the spermatozoa viability was significantly decreased after AlClThe AlClThere was a significant decline in the levels of serum TT, FSH, and LH in rats treated with AlClThe rats administered with AlClThe testicular histoarchitecture of the AlClThe volume density of the germinal of the AlClConcerning the EI, the AlClThe testicular germ cell count such as spermatogonia, preleptotene and pachytene spermatocytes, and round spermatids count in the seminiferous tubules showed a significant decrease in the counts compared to the control . Although, the germ cell count after the administration of SFN and AlClAn emerging pandemic global public health issue after cancer and cardiovascular diseases is infertility due to increase in testicular cancer (35) and based on the analysis on semen parameters such as reduction in sperm counts and qualities in various countries . The exposure of male individual to environmental toxicant is regarded as the channel that results in reduced sperm counts and infertility . Aluminum is considered as the most common metallic element detectable in natural waters, animal, and plant tissues (3). Compounds of Al due to its reactivity with other elements such as Sulphur and chloride are widely used in many products such as storage utensils, household cookware, food additives, toothpaste,and pharmaceuticals  (3). The enormous rate of exposure to Al increases the chances of health-related issues to human due to increase metallic concentration in various organs thereby damaging various tissue of the body including testicular tissues of animals and humans (38). Testicular weight is crucial in the evaluation of male fertility test due to its important association in sperm production (39). In our study, the decrease in body and testicular weights observed after AlClThe seminal fluid analysis  were significantly declined in the AlClThe process of spermatogenesis has been implicated to be under the regulation of reproductive hormones such as TT, FSH, and LH. In this present study, our results showed a decrease in this reproductive hormone after AlClThe antioxidant defense system prevents the cells of the body against the injurious effect of Reactive Oxygen Species (ROS) produced due to exposure to environmental toxicants, ultimately inducing toxicity to the reproductive system by perturbing the pro-oxidant and thereby leading to oxidative stress (53). Our study showed that exposure to AlClThe histomorphological features of the testis are critical and usually refer to as the endpoint in the evaluation of male fertility assessment and reproductive toxicity (56). In our study, histological observation of animals that received AlClThe present study revealed the ameliorative response of SFN on AlClThe authors declare that there is no conflict of interests regarding the publication of this paper."}
+{"text": "After this article  was publIn rnf-5(RNAi)) appear similar.In The authors noted that these panels were duplicated due to errors in figure preparation. An updated version of The following images have also been removed in the updated figure: the second panel in right column of As noted in the figure legend, the images shown in Raw data underlying all other results reported in the article are available.The authors apologize for the errors in the published article.S1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(XLSX)Click here for additional data file."}
+{"text": "Therefore, the serious ethical concerns regarding artificial intelligence are not related to the classification of massive photo data using simple/narrow artificial intelligence (ANI).Artificial intelligence (AI) is divided into 3 groups based on capability: 1) Weak/Narrow/Simple AI (ANI), 2) Strong/General AI (AGI), and 3) Artificial Super Intelligence (ASI).3Medicine is a prominent field that has witnessed a nanotechnological revolution. However, due to the current views in philosophy and ethics, this emerging technology can be considered inconsistent or conflicting with what most ethicists in the area of medicine hold to be true. Nanotechnology and neuroscience are raising unavoidable questions concerning the ethical justification of human enhancement and intervention.4The main ethical issues are related to the use of AI in general (AGI) and superintelligence (ASI) in particular. These two groups of AI need to be audited during their advancement, as they have the capacity to develop in a versatile and unpredictable direction. Providing safety measures to prevent any direct or indirect coercion can only be possible through continuous ethical evaluations and monitoring of technological development."}
+{"text": "Data comprised last year gamblers of three merged cross sectional Icelandic gambling surveys of 2007, 2011, and 2017 (N\u2009=\u20094422). For each of 15 game types (12-month time frame), a parallel multiple mediation model was applied to disaggregate bivariate associations of last year game type participation and problem gambling (Problem Gambling Severity Index) by six mediating mechanisms: (1) demographic problem gambling propensity, (2) number of game types played, (3) gambling frequency within the type, (4) maximum gambling frequency across all types beyond, (5) usual spending within the type, (6) maximum usual spending across all types beyond. Games showed two distinct profiles via which mediator they mostly impacted problem gambling: Electronic gaming machines offline, scratch cards offline, live betting online, and poker offline as well as online impacted problem gambling mostly via gambling frequency within, whereas all other types mostly impacted via the number of game types played. The applied mediation models answer the question by which mechanism game types impact problem gambling in a more exhaustive way than previous research.Bivariate associations of problem gambling with participation in particular game types often decrease when adjusting for demographics or consumption behavior . A summary of 14 peer-reviewed studies showed inconsistencies as well as conceptual and methodological challenges. The aim of this study was to expand previous research by a combination of (1) sophisticated feature-engineering, which disaggregates gambling intensity into facets  In general, it is a well known fact that problem gamblers tend to invest more time and money into gambling and usually participate in a larger number of games than non-problem gamblers  were applied. However, all of them were based on vastly different samples, ranging from the general population of Australia to patrons of two Las Vegas resort casinos Table\u00a0. In addiHowever, in spite of the methodological variations, the core idea of all data analyses was to examine the statistical association of participation in a specific game type and problem gambling. Therefore, participation in individual game types was applied as a predictor of problem gambling outcomes. This was done either in simultaneous model estimation with all game types and other covariates . They also underlined the importance of another construct of overall gambling intensity, the depth of involvement. Exemplary measures of depth of involvement include frequency of gambling across all game types during the last year combined . This further complicates the complex relationship between problem gambling, game types, context, individual predisposition, and behavior .In sum, the partially inconsistent empirical results of previous sophisticated regression-based studies document the complex relationship between gambling behavior and problem gambling as well as the challenges statistical modeling approaches of this relationship face. Hence, it is a major duty for further research (1) to disentangle the complexity of gambling problems and behavior as precisely as possible and (2) to provide a valid groundwork for evidence-based harm reduction measures referring to particular game types and overall gambling behavior in a given population. In a more practical sense, the inconsistent previous results also show that an unbiased evaluation of the impact of participating in particular game types on problem gambling behavior has to consider (1) demographic characteristics of the gambler and (2) his overall gambling behavior depth and breadth of involvement in regression-based models, however, not only results in the aforementioned empirical inconsistencies, but also in several methodological problems: First, the additionally inclusion of measures of overall gambling intensity (breadth or depth of involvement) in a bivariate model that predicts problem gambling by gambling participation in a specific game type only allows for indirect appraisals of the importance of the intensity measure. The extent of the decrease in statistical association of game type and outcome may be indicative for such an indirect appraisal  by which a predictor variable X  affects an outcome variable Y (problem gambling). In other words, mediation analyses answer the question how a predictor impacts an outcome and provide explicit point estimates and confidence intervals for specific mediating mechanisms of problem increasing gambling behaviors. Particularly this aspect qualifies parallel multiple mediation analysis to compare the importance of different plausible mechanisms within and beyond a game type, which may impact problem gambling.Against this background of empirical inconsistencies and methodological challenges, mediation analyses may solve some of the outlined problems. The core idea of mediation analyses Hayes  is to exIt is worth noting that the depicted previous linear-regression models in their current way of application are similar to an old-fashioned approach of mediation analyses, the so called \u201ccausal steps approach\u201d Hayes . The criMoreover, percentile bootstrap estimation of indirect effects and their confidence intervals is able to cope adequately with some bias caused by strongly correlated mediators like in the case of measures of gambling intensity. Neglecting correlated mediators can affect the standard errors of the association of mediator and the outcome of interest . This in turn affects statistical inference with normal-theory-tests for indirect effects  no explicit statistical information about the importance and confidence of specific mechanisms probably impacting problem gambling, (2) multicollinearity of gambling behaviors, (3) lack of conceptual clarity]. The proposed gambling consumption mediation model (GCMM) in the following analyses provides a novel analytical framework that includes (1) last year participation in particular game types as dichotomous predictor variable , (2) different proxy measures of gambling involvement (within and beyond the type of interest) as parallel mediators, and (3) a formative index of socio-demographic covariates that commonly increase the risk of problem gambling as another mediator that may pose an additional way via which particular game types impact an (4) outcome of problem gambling. The presented analytical approach of parallel multiple mediator models for each individual game type in the GCMM generates precise information by which specific indirect effect participation in a particular game type increases gambling problems. These empirically confirmed mechanisms can be addressed precisely by evidence-based harm reduction measures. Moreover, the applied mechanisms of the model (demographics or gambling behavior) are (1) founded in current research (Table\u00a0The aim of this study is to provide a new framework of  models  2012\u20132019 by Andrew F. Hayes), a syntax oriented supplementary tool for advanced mediation analyses in SPSS and SAS, based on ordinary least squares path analysis .A conceptual map of the applied parallel mediation models for each game type is illustrated in Fig.\u00a0p-level of 5% most game types showed statistically significant changes across the years of the surveys. Only scratch cards offline and sport betting offline showed no significant changes. However, the majority of changes were based only on minuscule effect sizes with Cramer\u2019s\u00a0V values below 0.1.Table\u00a0A small effect emerged for lotto offline with increasing participation from 2007 (75.6%) to 2011 (79.4%) and decreasing participation in 2017 (68.0%). A small effect also emerged for lotto online on an Icelandic website with an increasing participation from 8.7% in 2007 to 10.5% in 2011 and 19.5% in 2017. Moreover, participation in live betting online on Icelandic or foreign websites increased from 0.8% in 2007 to 4.6% in 2017. Also sport betting online on a foreign website increased from 0.2% in 2007 to 1.2% in 2011 and 5.3% in 2017. Poker offline increased from 7.4% in 2007 to 15.5% in 2011 and decreased again to 9.6% in 2017. Participation in bingo offline changed from 8.9% in 2007 to 15.2% in 2011 and 21.1% in 2017. Dividing participation rates of 2017 by rates of 2007 showed that the mean ratio for all 8 offline game types was 1.04 with largest growth values for bingo offline (2.36) and poker offline (1.29). In contrast, the ratio of 2017/2007 prevalence rates for the 7 online game types showed a mean growth rate of 7.06 with largest values for sport betting on foreign websites (24.89), poker online on a foreign website (7.15), live betting on an Icelandic or foreign website (5.85), and other online gambling on foreign websites (4.31).p\u2009\u2264\u20090.05) but minuscule effect sizes (Eta Square\u2009<\u20090.01) for the majority of inspected attributes . The only at least small effects (0.03\u2009\u2265\u2009squared eta\u2009\u2265\u20090.01) emerged for the following attributes: The number of game types involved in increased from a mean of 1.660 in 2007 to 1.921 in 2011 and 1.944 in 2017. Frequency within bingo offline, lotto online on an Icelandic website, sport betting online on foreign websites, and live betting online on Icelandic or foreign websites increased from 2007 to 2017. Usual spending within bingo, lotto online on Icelandic websites, sport betting online on foreign websites, live betting online on Icelandic or foreign websites, and poker offline increased from 2007 to 2017. Usual spending beyond a given game type increased for every game type from 2007 to 2017.Kruskal\u2013Wallis tests of the metric and ordinal variables across the years of the surveys also showed significant  within and beyond in many or even all game types. However, all relevant trends showed only small effect sizes between 2007 and 2017. Consequently, treating the entire dataset as one homogeneous population in the following analyses represents a justified step.Model estimates for unstandardized effects and 95%-percentile bootstrap confidence intervals of the parallel multiple mediation models are presented in Tables\u00a0total effects on problem gambling  of last year participation in 11 of the 15 game types were of statistical relevance  and 10 types were of problem increasing impact . Lotto offline was the only game type with a statistically relevant problem decreasing impact . For several game types the total impact on problem gambling was not statistically relevant: Lotto online on an Icelandic website, sport betting online on a foreign website, bingo offline, and other online gambling on foreign websites (not poker or betting).The Direct effects of game type participation on gambling problems  became non significant for 8 of the 15 game types. Statistically relevant problem increasing direct effects of last year participation when simultaneously considering all other mediating impacts were left only for lotto offline, sport betting online on a foreign website, and other online gambling on foreign websites (not poker or betting). Problem decreasing direct effects occurred for sport betting online on an Icelandic website, EGMs offline, scratch cards offline, and poker offline.specific indirect effects (a*b-paths) which provides an effect size and confidence intervals for each mediator, while considering the direct path and all other mediators (indirect paths) within the model simultaneously. The metric of the unstandardized effects is determined by the scales of the X  and Y variables (winsorized sum score of gambling problems), which both were similar across all analyzed game types. Hence, the size of the indirect effects is comparable across the mediators.However, total and direct effects are only of minor interest in the parallel mediation analyses at hand that try to answer the following question: By which mediator (gambling behaviors or demographic propensity) is last year participation in game type X impacting gambling problems most severely? This aspect can explicitly be tackled by the quantification of breadth or (2) mostly via frequency within.A close look at the specific indirect effects revealed two distinct profiles of decisive mediators impacting gambling problems within the different game types: (1) mostly via breadth (number of game types involved in). Breadth was the strongest mediating mechanism of gambling behavior on gambling problems for participating in:lotto offline,lotto online on an Icelandic website,betting on sport pools offline,betting on sport pools on an Icelandic website,sport betting offline,sport betting online on an Icelandic website,sport betting online on a foreign website,betting on skill games offline,bingo offline andother online gambling on foreign websites (not poker or betting).Table\u00a0frequency within. Frequency within was the strongest mediating mechanism of gambling behavior on gambling problems for participating in:EGMs offline,scratch cards offline,live betting online on an Icelandic or foreign website,poker offline andpoker online on a foreign website.Table\u00a0The decision about the most important mediating gambling behavior was unequivocal in almost all game types. For several game types there was only one relevant positive indirect effect like breadth for lotto offline or lotto online on an Icelandic website (positive a*b-path). All other mediating mechanisms did not show statistically relevant effects for these two game types or even showed problem decreasing effects such as propensity for lotto offline or online on an Icelandic website (negative a*b-path).But these negative effect sizes did not mean that the mediating path propensity was not associated with gambling problems for individuals that participated in lotto (positive b-path). Rather, the negative effect was the consequence of a negative association of gambling lotto offline and demographic problem gambling propensity (negative a-path). In other words: Individuals who participated in lotto showed a reduced level of demographic propensity for gambling problems . Consequently, the product of a*b for the mediator propensity among individuals participating in lotto offline showed negative effect sizes. Hence, this mediator could not be an important problem increasing mechanism for lotto offline, even if it was positively associated with gambling problems in general.problem reducing impacts were not plausible from a theoretical position . However, in all five depicted situations with statistically relevant negative single b-paths the products of a*b-paths were not statistically relevant. Hayes  in the following situations: (1) betting on sport pools online on an Icelandic website via spending within; (2) live betting online on a foreign or Icelandic website via spending within; (3) sport betting online on foreign websites via spending within; (4) other games online (not betting or poker) on a foreign website via frequency within; (5) other games online via usual spending within. These t. Hayes , p. 520 breadth of involvement (10 game types) or (2) via frequency of gambling within that type of interest (5 game types).A simple descriptive rule of thumb to determine the most important mediator among a game type is to divide the largest statistically relevant and positive effect by the second largest relevant and positive effect within a game type . In almost all game types, this ratio was between values of 3.96 (betting on sport pools on an Icelandic website) and 2.20 (live betting online on an Icelandic or foreign website), indicating distinct orders of most important mediating mechanisms (effect size of the most important mediator outperforming the second by at least factor 2 in 14 of 15 game types). The only exception from this order was betting on skill games offline, with a ratio of only 1.64 between the mediators breadth and propensity, indicating a more equivocal profile of most important mediators among this game type. Participation in any other analyzed game type was unequivocally most strongly mediated either via (1) However, the remarkable positions of the two mediators breadth and frequency within for some game types did not disqualify the other mediators in the GCMM as redundant. On the contrary: Propensity and frequency beyond both showed statistically relevant specific indirect effects in 14 of 15 game types, spending beyond in 13 of 15 game types, and spending within in 3 of 15 game types.The presented GCMM provides, for the first time, an analytical frame work to disentangle the complex network of (1) last year participation  in particular game types, (2) an outcome of problem gambling and different proxy measures of (3) socio-demographic problem gambling propensity, (4) overall gambling involvement , and (5) game type-specific gambling involvement . The chosen approach of parallel multiple mediation analyses allowed for explicit quantification of the behavioral or interpersonal mechanisms, by which participation in specific game types impacts the outcome of problem gambling. Cohort analyses of the three merged Icelandic surveys warranted treating the empirical dataset as homogeneous population even though the number of used game types increased slightly and online game types showed continuously increasing levels of participation.p-levels within the parallel mediation analyses at hand were not adjusted for multiple testing, in order to uphold statistical power of the first time application of the GCMM. Further research may apply a more confirmative approach of model testing, including model-fit-statistics, but the aim of this study was rather exploratory.A short summary of 14 peer-reviewed regression-based studies outlined inconclusive results as well as methodological and conceptual challenges that can partially be resolved by the chosen approach of parallel multiple mediation analyses for each particular game type with the proposed mediating mechanisms characterizing gambling behavior and demographic problem gambling propensity. The state-of-the-art percentile bootstrap procedure to estimate effects and confidence intervals of mediators is able to cope adequately with unspecified correlated error terms (multicollinearity of mediators), providing robust estimates of indirect effects with adequate errors of type I and II. Inconsistent results of former research may be partially caused by a lack of such robustness and statistical power of very complex models with many highly correlated predictors. Consequently, statistical mediators appears to be conceptually more convincing than the commonly applied regression-based models with many covariates, because gambling behavior in terms of regularity, diversity, and spent money or time may be part of the etiological process of developing gambling-related harms and problems\u2014not only a covariate one has to adjust for statistically.Treating different attributes of problem gambling behavior or propensity as Of course, mediation analyses are mathematically also regression-based, but the product-term a*b to quantify indirect effects provides additional information. Mediation analyses enabled us to quantify effects and confidence intervals to make precise evaluations of the most important mediating mechanisms by which behavior particular game types impact gambling problems. This information is of notable interest for testing competing models or theories Hayes  and for within and beyond as well as the number of game types a person was involved in. The applied maximum function to aggregate the beyond variables was chosen to curtail high correlations with the breadth variable, which occur by the alternative sum function across all game types. Further research is needed to make an informed choice about the most appropriate aggregation, because mean or median functions could also be useful proxies. However, the combination of (1) mediation analyses and (2) precise feature-engineering revealed explicit estimates and insights which were mostly concealed or at least only implicit in former research.The outlined analytical potential of mediation analyses was combined with a very elaborate process of feature-engineering for proxy measures of gambling behavior which distinguished mechanisms of demographic propensity, usual spending and frequency frequency within these types and not by the breadth of involvement or any other mediating variable of the model. Interestingly, results support findings of previous studies in which some of these types still showed explanatory power for gambling problems despite lots of other covariates in the models  see: Afifi et al. The empirical findings of the GCMM showed that last year participation in (1) EGMs offline, (2) scratch cards offline, (3) live betting online on Icelandic or foreign websites, (4) poker offline, or (5) poker online on foreign websites impacted gambling problems mostly via mechanisms of gambling To our knowledge, the GCMM represents the first analytical approach that provides explicit estimates of indirect effects and confidence intervals of the most important mediating mechanisms of a game type of interest impacting problem gambling. This data-driven information facilitates a valid evaluation of risk increasing mechanisms of game types and complements former evaluation tools  impacted gambling problems mostly in a qualitatively distinct way different from the breadth mechanism\u2014namely via gambling frequency within the type of interest. Furthermore, type-specific measures of gambling frequency within EGMs and poker. Obviously, the GCMM has the potential to conceptually support, model and specify a promising line of research on gambling consumption that tries (1) to explicate the dose\u2013response-relationship of gambling intensity and measures of gambling related harm and (2) to establish evidence based thresholds of low-risk gambling intensity by risk-curve- and receiver-operating-characteristic-curve-analyses , supply and access reductions may be effective due to the simple and convincing mechanisms of the total consumption model  of game type participation on gambling problems still showed stabile risk increasing or decreasing impacts. For instance, (1) lotto offline, (2) sport betting online on a foreign website, or (3) other online gambling (not betting or poker) on a foreign website showed direct problem increasing impacts. On the contrary, (4) sport betting online on an Icelandic website, (5) EGMs offline, or (6) scratch cards offline or (7) poker offline showed direct problem decreasing impacts (some kind of protective effect). Obviously, the applied mediators of the GCMM were not able to disentangle the complexity of gambling behavior exhaustively and other potential mediators may be at work that can additionally explain direct effects thoroughly. A mediation model which includes all relevant mechanisms will dissolve all direct effects (c\u2032-paths) completely. Hence, future research on mediating mechanisms on problem gambling should include additional variables, for instance psychological or psychiatric attributes or other operationalizations of propensity that include comorbidities or attributes of personality. For example, the problem increasing direct effect of lotto may be attributable to demographics and health related behavior  demographic propensity, of which information is available in most monitoring datasets, and via which game type participation may positively impact ascending levels of problem gambling. Therefore, the result section was mainly narrowed to the problem increasing mechanisms, mostly disregarding problem decreasing mechanisms. Further research is needed to elaborate potential beneficial mechanisms or protective factors. Further research should also specify the applied descriptive rule of thumb (ratio of largest and second largest positive indirect effect) to discriminate both emerging mediating profiles (mostly via breadth or via frequency within) by inferential statistics. Moreover, structural equation models could be applied to explicitly include correlated mediators into the statistical model.The focus of the current GCMM was on mechanisms of (1) The aggregation of demographic information into a mediating propensity score allows for precise comparison of the indirect effect sizes of demographics and behavior. However, in other situations applying demographics as covariates or moderators may be more adequate.The analyses at hand treated gambling problems as a continuously ascending scale. Treating gambling problems as a nominal attribute with different estimates for qualitatively different groups of low, medium and high risk gamblers may be a fruitful extension of the GCMM. Additionally, modeling outcomes of gambling-related harms (Delfabbro and King mode of access and (2) certain access configurations  could have remarkable impacts on the GCMM, but are currently not considered adequately . Therefore, the proposed way to distinguish game types statistically by their most important risk increasing mechanism was obviously unaffected by cursory classification in online or offline game types. At the same time, particularly for Internet gambling, it is worth noting that (1) the way or In general, the GCMM is in line with other recent research that sheds light on relevant gambling issues by advanced methods of statistical modeling . Therefore, future secondary data analyses on such datasets with the proposed modeling procedure of this study have the potential to replicate and extend the suggested blueprint at hand in different countries with diverse gambling products, contexts, and regulations.This study addressed several limitations in previous research on the complex interactions of participating in different game types, problem gambling, and individual gambling behavior or vulnerabilities. Taken together, the proposed GCMM overcomes current methodological challenges by (1) a parallel multiple mediation approach in combination with (2) sophisticated feature engineering of gambling behavior and provides explicit information about the mechanisms by which participation in specific game types mostly impacts problem gambling\u2014either mostly within or mostly beyond the type of interest."}
+{"text": "While eHealth programs equip survivors with tools at where and when they need, their benefit to and engagement patterns among older adults are less known. Data come from the Springboard Beyond Cancer RCT, a cancer survivor self-management program  and the corresponding qualitative evaluation/user testing (N=40). Younger survivors, but not older, preferred socially interactive and personalized long-in features which enable greater tailoring of the program. However, the older survivors who did enroll in the RCT were equally as likely as their younger counterparts to engage with one or more aspects of program. Health self-efficacy improvement from baseline to 3 months was significant among younger participants in the intervention (p<.05) but not the control arm (p=.54) (d=.20) and marginally significant among older survivors (age 60+) in intervention (p=.06) but not the control arm (p=.58) (d=.28). Results suggest that the program may benefit survivors regardless of age. Part of a symposium sponsored by the Cancer and Aging Interest Group."}
+{"text": "Esophageal cancer is the eighth most common cause of cancer mortality in Japan. More than 11,000 people had died from esophageal cancer in 2018. The Japan Esophageal Society has collected the data on patients' characteristics, performed treatment, and outcomes annually.We analyzed the data of patients who had first visited the participating hospitals in 2013. In 2019, the data collection method was changed from an electronic submission to a web-based data collection using the National Clinical Database (NCD). Japanese Classification of Esophageal Cancer 10th by the Japan Esophageal Society (JES) and UICC TNM Classification 7th were used for cancer stagingA total of 8019 cases were registered from 334 institutions in Japan. Squamous cell carcinoma and adenocarcinoma accounted for 87.8% and 6.3%, respectively. The 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, or esophagectomy were 88.3%, 32.4%, 24.4%, and 59.3%, respectively. Esophagectomy was performed in 4910 cases. The operative and the hospital mortality rates were 0.77% and 1.98%, respectively. The survival curves showed a good discriminatory ability both in the clinical and pathologic stages by the JES system. The 5-year survival rate of patients with pStage IV in the UICC classification that included patients with supraclavicular node metastasis was better than that of patients with pStage IVb in JES classification.We hope this report contributes to improving all aspects of the diagnosis and treatment of esophageal cancer in Japan. We deeply appreciate the great contributions of many physicians in the registry of esophageal cancer cases. The Comprehensive Registry of Esophageal Cancer in Japan, 2013, was published here. In 2019, the data collection method was changed from an electronic submission to a web-based data collection using the National Clinical Database (NCD). Personal information was replaced with individual management code inside each institute, and the NCD collected only anonymized information. The registry complies with the Act for the Protection of Personal Information.We briefly summarized the Comprehensive Registry of Esophageal Cancer in Japan, 2013. Japanese Classification of Esophageal Cancer 10th by the Japan Esophageal Society (JES) [We hope that this Comprehensive Registry of Esophageal Cancer in Japan for 2013 will help to improve all aspects of the diagnosis and treatment of esophageal cancer in Japan.I.Clinical factors of esophageal cancer patients treated in 2013Institution-registered cases in 2013Patient backgroundTableAge and genderTablePrimary treatmentTableTumor locationTableHistologic types of biopsy specimensTableDepth of tumor invasion, cT (UICC TNM 7th)TableLymph node metastasis, cN (UICC TNM 7th)TableDistant metastasis, cM (UICC TNM 7th)TableClinical stage (UICC TNM 7th)II.Results of endoscopically treated patients in 2013TableDetails of endoscopic treatment for curative intentTableComplications of EMR/ESDTablePathological depth of tumor invasion of EMR/ESD specimensFigureSurvival of patients treated with EMR/ESDFigureSurvival of patients treated with EMR/ESD according to the pathological depth of tumor invasion, pT (JES 10th)FigureSurvival of patients treated with EMR/ESD according to the lymphatic and venous invasionIII.Results in patients treated with chemotherapy and/or radiotherapy in 2013TableDose of irradiation TableDose of irradiation FigureSurvival of patients treated with chemotherapy and/or radiotherapyFigureSurvival of patients treated with definitive chemoradiotherapy according to clinical stage (UICC TNM 7th)FigureSurvival of patients underwent radiotherapy alone according to clinical stage (UICC TNM 7th)IV.Results in patients who underwent esophagectomy in 2013TableTreatment modalities of esophagectomyTableTumor locationTableApproaches to tumor resectionTableVideo-assisted surgeryTableFields of lymph node dissection according to the location of the tumorTableReconstruction routeTableOrgans used for reconstructionTableHistological classificationTableDepth of tumor invasion, pT (JES 10th)TablePathological grading of lymph node metastasis, pN (JES 10th)TablePathological findings of lymph node metastasis, pN (UICC TNM 7th)TablePathological findings of distant organ metastasis, pM (JES 10th)TableResidual tumorTableCauses of deathFigureSurvival of patients who underwent esophagectomyFigureSurvival of patients who underwent esophagectomy according to clinical stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to clinical stage (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to the depth of tumor invasion, pT (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to residual tumor (R)Institution-registered cases in 2013.Tables 8Tables Tables Tables 15"}
+{"text": "Bioscience Reports (2017) 37, https://doi.org/10.1042/BSR20170342) have realised that the vector-4 group image of The authors of the original article \u201cEffects of RNA interference-mediated gene silencing of VEGF on the ultrafiltration failure in a rat model of peritoneal dialysis\u201d (The correct The authors would like to express their apologies for any inconvenience caused to the readers of their published article by this error."}
+{"text": "Sus scrofa domesticus) is one of the important farm animal contributing 7% of the country\u2019s total animal protein sources in India. In the present study, random hexamer primer was used to amplify the complete mitochondrial genome of Central Indian domestic pig and resolved the complete mitochondrial sequence by shotgun sequencing followed by de novo assembly in MIRA version 4.0.5. The sequence assembly revealed to be 15,827\u2009bp mitogenome of pig (accession no. KT965278). The mitogenome in the present study has 99% homology with previously reported mitogenome of pigs from different parts of the world. The present study is the first report of complete sequence of mitogenome of pig from Indian subcontinent. Mitogenome analysis by MITOS web server revealed similarity of gene order, organization with the other pig breeds and vertebrates, comprising of 13 protein-coding genes, 22 tRNAs, 2 rRNAs and a control region. It was concluded that modified random hexamer can be successfully used for whole mitogenome sequencing using NGS without designing mitogenome-specific primer, thereby reducing cost and labor.Domestic pig ( Sus scrofa domesticus) is domesticated since 8000 years, yet the origin and evolution of domestic pigs of India has not been established. The introgression of exotic genome under state sponsored programs to upgrade the local population using semen or live animals of exotic breeds has diluted the gene pool of local breeds, thus breed specification of the local domestic pig remains questionable. Most studies on Indian domestic pig mitochondrial DNA (MtDNA) are restricted to capillary electrophoresis (CE)-derived short sequence fragments analysis of cytocgrome b, 12S rRNA  as out group using MEGA 6 . The 16,827\u2009bp length of the mitogenome of the CI domestic pig showed 99% homology with the available mitogenome sequences in the GenBank and genome annotation was performed using MITOS web server (Bernt et\u00a0al. Pig ("}
+{"text": "Sterna paradisaea) a species notable for undertaking the longest migrations of any species as well as breeding in sub-polar habitats and capable of enduring extreme altitude. The complete mitogenome was 16,708\u2009bp long and was typical of other avian mitogenomes in size and content. The phylogenetic position of the Arctic tern within Charadriiformes based on the coding region on the mtDNA corresponded closely to that based on nuclear loci. The sequence will provide a useful resource for investigations of metabolic adaptations of this remarkable species.The analysis of mitochondrial DNA (mtDNA) base composition, codon usage, and genome arrangement patterns can provide insight into metabolic pathways and evolutionary history. Here, we report on the complete mitochondrial genome (mitogenome) of Arctic tern ( Charadriiformes: Laridae: Sternini) are cosmopolitan core water birds closely related to the gulls, noddies, and skimmers. The life histories of 12 generally accepted genera of terns range from that of entirely sedentary to strongly migratory species (Cramp Sterna paradisaea) holds the record for the longest roundtrip animal migration ever recorded electronically  of Qiagen DNeasy  extracted DNA from mitochondrial-enriched DNA fraction obtained by differential centrifugation. The Illumina MiSeq run generated 8,468,804 paired-end reads that were mapped to complete Sterna hirundo genome . In total, 1.09% of the raw reads mapped to the Sterna hirundo mtDNA and yielded two \u223c12kb and \u223c3\u2009kb contigs that covered 95.62% of the reference genome. Sanger sequencing was used, to add the missing control region (CR) sequence (1158\u2009bp) and to confirm that no CR duplications  of Phylogenetic position of the newly assembled complete Arctic tern mitogenome coding sequence within the Charadriiformes was resolved in MEGA 7 (Kumar et\u00a0al."}
+{"text": "South Korea has included dementia care as part of their Long-Term Care (LTC) Insurance Program since 2014. Thus, LTC workers are increasingly engaged in dementia care. The purpose of this paper is to elucidate the role of the LTC workers\u2019 occupational identity in their consciousness of human rights as well as their practice of human rights protection. Data were collected in 2018 from 303 LTC workers employed by 12 LTC facilities who completed questionnaires. Their mean age was 53.6 years. We measured occupational identity with a 15-item scale (a=.772), consciousness of human rights for persons living with dementia (PLWD) with a 27-item scale (a=.916), and practice of human rights for PLWD with a 26-item scale (a=.956). Results show that occupational identity was positively associated with consciousness of human rights  and practice of human rights . The findings have implications for protecting the human rights of PLWD. Part of a symposium sponsored by the Aging Among Asians Interest Group."}
+{"text": "Does change in one lifestyle factor  help explain change in another factor or process ? The current modeling was a secondary analysis of a primary care feasibility study of individualized lifestyle (diet and exercise) treatment of metabolic syndrome  that achieved 19% reversal over one year. Diet quality was assessed by the Healthy Eating Index (HEI) (2005 Canada); while fitness was assessed by several measures . Three occasions  were examined using latent change score and latent growth curve models (in AMOS) to assess whether changes in one domain predicted changes in the remaining domains: (1) diet (measured by HEI or latent construct); (2) fitness (measured by VO2max percentiles or latent construct); and, (3) 10-year risk of cardiovascular disease (by Procam Risk score). Results showed significant improvement in all three domains separately during the intervention, with greater change between baseline and 3-month assessment and continued change between 3- and 12-months. Initial status variables on observed constructs were moderately positively correlated and change in dietary behavior was significantly related to change in fitness levels, but neither were significantly related to change in the 10-year risk of cardiovascular disease. In addition, the associations between change in diet and changes in fitness were inconsistent baseline to 3 months, and 3-12 months. These results offered new insight on relationships among interventions in a behavioural counselling program which can inform future programming."}
+{"text": "Treponema pallidum in an infant or fetus, acquired during pregnancy from a mother with untreated or inadequately treated syphilis. Congenital syphilis can cause miscarriage, stillbirth, or early infant death, and infected infants can experience lifelong physical and neurologic problems. Although timely identification and treatment of maternal syphilis during pregnancy can prevent congenital syphilis  a condition affecting stillbirths and infants born to mothers with untreated or inadequately treated syphilis regardless of signs in the infant or 2) a condition affecting an infant with clinical evidence of congenital syphilis including direct detection of Demographic and clinical characteristics of infants and their mothers were analyzed using Stata statistical software . On the basis of CDC\u2019s congenital syphilis prevention framework, each congenital syphilis case was assigned to one of four mutually exclusive missed opportunity categories based on the mother\u2019s prenatal care, testing, and treatment history: 1) lack of timely prenatal care with no timely syphilis testing; 2) lack of timely syphilis testing despite timely prenatal care; 3) lack of adequate maternal treatment despite a timely syphilis diagnosis;Among 1,306 congenital syphilis cases reported during 2018, 685 (52.5%) occurred in the South, 465 (35.6%) in the West, 103 (7.9%) in the Midwest, and 53 (4.1%) in the Northeast Census regions . NationaNationally, the most commonly missed prevention opportunity was a lack of adequate maternal treatment despite the timely diagnosis of syphilis during pregnancy (30.7%), followed closely by a lack of timely prenatal care (28.2%) . This naRacial/ethnic disparities existed within the highest morbidity regions. In the South, the most commonly missed prevention opportunity among white mothers of infants with congenital syphilis was lack of timely prenatal care (31.6%), whereas among black and Hispanic mothers, lack of adequate maternal treatment (37.0%) was the most common . In the Nationally, the most commonly missed opportunity for preventing congenital syphilis was lack of adequate maternal treatment, likely driven by the high numbers of cases in the South, where this missed opportunity was most prevalent. The most common missed opportunities for preventing congenital syphilis differed by geographic region. In the West, a lack of timely prenatal care was the most commonly missed opportunity, and in the Northeast, late identification of seroconversion was the most common. Regional clinical and demographic differences in mothers of infants with congenital syphilis indicate that different populations are at increased risk and might require different interventions. The high proportion of mothers with early syphilis in certain regions signals recent heterosexual transmission and the potential for future increases in congenital syphilis cases if no intervention occurs. The high proportions of symptomatic and stillborn infants in certain regions might be related to early syphilis among their mothers, given that higher rates of vertical transmission and worse infant outcomes are associated with early syphilis during pregnancy  and a lack of timely prenatal care (28%), followed by late identification of seroconversions (11%); prevalences of these missed opportunities differ regionally and by race/ethnicity.Halting continued increases in congenital syphilis requires understanding the missed prevention opportunities and implementing tailored interventions based on local experience."}
+{"text": "Dementia is arguably the most devastating condition of older adulthood with treatment options still elusive. Alzheimer\u2019s is the most prevalent form of dementia where cognitive deficits relate strongly to underlying brain pathology. However, there exist cases in which cognitive performance does not match the corresponding level of neuropathology. Attempts to explain this phenomenon often include the concept of cognitive reserve (CR), whereby greater CR  presumably results in less impairment relative to the extent of pathology early in disease progression but also greater impairment once cognitive symptoms manifest. We examined the influence of CR proxy variables (education and occupation) on the relationship between hippocampal volume and cognitive performance on tests of executive control and memory using data from the Czech Brain Aging Study (CBAS). Participants were cognitively normal/with subjective cognitive decline but without actual impairment =66.43; M(education)=15.90; 37 men) or had amnestic mild cognitive impairment =71.37; M(education)=14.92; 85 men). We found that hippocampal volume was significantly related to executive control  and memory  for participants with aMCI, but only memory  for CN participants. Occupational position moderated the association between memory and hippocampal volume in aMCI, with the result approaching significance (p=.07), whereby a greater link between memory problems and hippocampal atrophy was present in those previously in high occupational positions. No other moderations for occupational position or education emerged (ps>.25). We found evidence for the concept of CR using occupational position as proxy."}
+{"text": "Cognitive function is an important component of healthy aging and physical activities have been shown to support late life cognitive function. However, it is unclear whether non-traditional physical activities provide additional benefits for cognitive function above and beyond traditional leisure physical activities. This study examines the associations between movement therapy and cognitive function in the US population. We used data from the waves 1, 2 and 3 (1995-2014) of the Midlife in the United States (MIDUS) study. MIDUS included a national probability sample of community-living adults aged 25-75 years old in 1995 (wave 1) and added the wave 2 cognitive functioning tests of executive function and episodic memory. We applied multivariate linear regression models to estimate the effect of movement therapy (wave 2) on the cognitive episodic memory and executive function (wave 3) while controlling the covariates . A total of 2097 individuals aged 42-92 years  were included in the analysis. Movement therapy was independently associated with better episodic memory , but not with executive function , after including control variables. The results suggest that movement therapy may be an effective non-pharmacological intervention to attenuate age-related cognitive decline in middle-aged and older adults. Future research should test whether these findings can be replicated in similar populations and if confirmed, interventions should incorporate a wider range of physical activities in community-living older adults with the goal of maintaining and improving physical and cognitive health."}
+{"text": "Using comparative analysis of the permeability and sorption performance of the obtained PAA cryogels and earlier developed polyethyleneimine (PEI) cryogels, we have demonstrated the advantages and disadvantages of these polymers as sorbents of heavy metal ions (Cu(II), Zn(II), Cd(II), and Ni(II)) in fixed-bed applications and as supermacroporous matrices for the fabrication of composite cryogels containing copper ferrocyanide (CuFCN) for cesium ion sorption. Applying the rate constant distribution (RCD) model to the kinetic curves of Cu(II) ion sorption on PAA and PEI cryogels, we have elucidated the difference in sorption/desorption rates and affinity constants of these materials and showed that physical sorption contributed to the Cu(II) uptake by PAA, but not to that by PEI cryogels. It was shown that PAA cryogels had significantly higher selectivity for Cu(II) sorption in the presence of Zn(II) and Cd(II) ions in comparison with that of PEI cryogels, while irreversible sorption of Co(II) ions by PEI can be used for the separation of Ni(II) and Co(II) ions. Using IR and M\u00f6ssbauer spectroscopy, we have demonstrated that strong complexation of Cu(II) ions with PEI significantly affects the in situ formation of Cu(II) ferrocyanide nanosorbents leading to their inefficiency for Cs Taking into account the difference in affinities of PAA and PEI cryogels toward Cu(II) ions, we have investigated how a polymer matrix affects the efficiency of composite sorbents containing Cu(II) ferrocyanide for cesium ion removal. Transition metal ferrocyanides are the most efficient materials for selective uptake of cesium radionuclides from liquid radioactive wastes and natural waters; however, due to their small size and low mechanical strength, they cannot be used in columns without immobilization in organic or inorganic matrices, which can be realized under dynamic conditions ,45,46,474\u2212 anion ,50. We h4\u2212 anion , but PAAA composite formed in situ had homogeneous distribution of Cu and Fe on the surface, but CuFCN crystallites were not detectable with resolution of the SEM either on PEI or on PAA cryogels. XRD patterns of the composite formed in situ c did not6]4\u2212 complex due to the very high Lewis basicity of PEI. The latter possibility was demonstrated earlier for N-containing ligands and Fe(III) cyanide complexes [\u22121 typical for Fe(II) ferrocyanide (Fe-CN deformation mode) [6]4- complex ion in the CuFCN/PEI composite was also confirmed by the singlet in the M\u00f6ssbauer spectrum (Taking into account a difference in the color of CuFCN/PAA (reddish brown) and CuFCN/PEI (dark blue) composites formed in situ, one can suggest that the PEI matrix had a significant effect on formation of Cu(II) ferrocyanide in situ. There are two possible reasons for this: (i) very strong binding of Cu(II) ions by PEI; and (ii) dissociation of  solution was added dropwise under constant stirring, the obtained colloid solution of reddish brown color was fed through the column with 1 mL of PAA cryogel at a flow rate of 122 BV/h using a peristaltic pump (the stirring was continued). The CuFCN colloids were distributed over the full length of the column; iron and copper in outlet solutions were not detected by AAS. The column with the composite material (CuFCN/PAA (precipitation) cryogel) was washed with distilled water and used to investigate the dynamics of Cs+ ion sorption and Cs+ uptake in a batch. In situ formation of composites containing CuFCN was performed as follows: PAA and PEI cryogels were saturated with Cu(II) ions under dynamic conditions and washed with distilled water; in a week, 10 mL of 0.01 M K4[Fe(CN)6] solution was fed through the column at a flow rate of 8 BV/h. Finally, the composites were washed with 150 mL of distilled water, removed from the column, and air-dried for investigation of Cs+ uptake in a batch.Composite cryogels containing CuFCN were fabricated by (i) precipitation of ex situ formed CuFCN colloids on PAA-DGEBD 1:8 cryogel, and (ii) in situ formation of CuFCN in PAA-DGEBD 1:6 and PEI-DGEBD 1:4 cryogels. The composite formed by precipitation method was obtained as follows: 0.5 mL of 0.1 M Cu(NO+ ion uptake in a batch was determined as follows: 5 mg of the composite cryogel was shaken for 24 h with 5 mL of CsCl solution containing 20 mgCs/L (pH~6). The equilibrium content of cesium was determined by AAS. Dynamics of Cs+ ions sorption on CuFCN/PAA (precipitation) cryogel was studied by feeding CsCl solution containing 20 mgCs/L (pH~6) through 1 mL of monolith in insulin syringe at the flow rate of 84 BV/h using a peristaltic pump, the filtrate was collected every 5 mL and analyzed for cesium, copper, and iron content by AAS.The efficiency of CsMorphology investigations and elemental analysis of the freeze-dried composite cryogels were performed using a Hitachi TM3000 scanning electron microscope (SEM) equipped with a Bruker Quantax 70 energy dispersive X-ray (EDX) spectrometer at an accelerating voltage of 15 kV.X-ray powder diffraction analysis (XRD) of composite cryogels was carried out on a Dron-3 multipurpose diffractometer .Here we have investigated the reactivity of affordable and commercially available polyamine PAA  in cross-linking reaction with diglycidyl ether of 1,4-butandiol and showed that PAA cryogels were formed at lower molar ratios of cross-linker to polymer and had better stability under the flow conditions than did PEI cryogels. Both PEI and PAA cryogels were efficient for the removal of Cu(II) and Zn(II) ions in batch and fixed bed applications to the level set by the WHO for drinking water.3 solution.Although PAA cryogels had worse chelating properties than PEI cryogels, they provided high selectivity of Cu(II) recovery over Zn(II) and Cd(II) ions, and Zn(II) ions over Cd(II) ions under equilibrium sorption conditions. PEI cryogels can be used for Co(II) and Ni(II) recovery from two component solutions in fixed-bed and selective elution of Ni(II) ions with 0.1 M HNOWe have also demonstrated that formation of stable Cu(II)\u2013PEI complex hinders in situ formation of Cu(II) ferrocyanide that results in very poor sorption efficiency of this PEI-based composite in cesium ion uptake. In contrast, PAA cryogels are applicable for composite formation via loading of ex situ formed Cu(II) ferrocyanide colloids or the in situ formation of nanosorbent with preservation of the supermacroporous structure of the matrix."}
+{"text": "Using the Conservation of Resources Theory, this study examined how caregiver strain was influenced by care recipients\u2019 use of falls alert wearables. Online survey data from 486 unpaid caregivers for adults aged 50 and older were analyzed. Structural equation modeling was used to test the following hypotheses: (1) caregivers with fewer financial resources would engage in fewer resource conservation strategies ; (2) resource conservation strategy engagement would be associated less resource loss; and (3) the effect of resource conservation strategies on caregiver strain would be less salient than the effect of resources used on caregiving . The hypothesized model had a good model fit (CFI=.910), with SRMR (.060) and RMSEA (.062) being close to .05. All hypothesized paths were statistically-significant, except for the direct effect of using falls alert wearables on social support (p=.076) and caregiver strain (p=.135). As hypothesized, higher income was associated with greater likelihood of using falls alert wearables . Technology use was associated with less time spent on caregiving  and had statistically-significant indirect effects on caregiver strain . The total effect of using falls alert wearables  on caregiver strain was less powerful than the effect of time  or social support . Study findings suggest the benefits of using falls alert wearables to alleviate time-related burdens and downstream caregiver strain among unpaid caregivers. Future efforts should investigate the relative advantage of wearables for other caregiving purposes."}
+{"text": "This paper describes data of earthworm abundance and functional group diversity regulate plant litter decay and soil organic carbon (SOC) level in global terrestrial ecosystems. The data also describes the potential effect of vegetation types, litter quality, litterbag mesh size, soil C/N, soil aggregate size, experimental types and length of experimental time on earthworm induced plant litter and SOC decay. The data were collected from 69 studies published between 1985 and 2018, covering 340 observations. This data article is related to the paper \u201cEarthworm Abundance and Functional Group Diversity Regulate Plant Litter Decay and Soil Organic Carbon Level: A Global Meta-analysis\u201d [1]. Totally 340 observations from 69 studies were included. Detailed data are listed in 2A data set was compiled using literature search of peer-reviewed publications about the effects of earthworms on litter decomposition or SOC from the ISI-Web of Science and Google Scholar research database. We used three different combinations of keywords: earthworm and litter decomposition; earthworm and forest floor; earthworm and soil carbon. A total of 69 studies published between 1985 and 2018 were found , Table 5For To be included in the meta-analysis, the paper had to report the means, standard deviation (SDs) and replicate numbers of litter percent mass loss or SOC for the control treatment  and the experimental treatment . For studies that did not report SD or standard error (SE), we conservatively estimated SD values as 150% of the average variance across the dataset . To eval"}
+{"text": "Adult protective services and other community-based agencies respond to hundreds of thousands of elder abuse cases annually in the United States; however, few studies include elder abuse victims\u2019 voices. This study explored the most distressing aspects of elder abuse, as identified by victims themselves; to date, this is the first known study on this topic. Guided by a phenomenological qualitative methodology, this study conducted in-person, semi-structured interviews with a sample of elder abuse victims (n = 30) recruited from a community-based elder abuse social service program in New York City. To enhance trustworthiness, two researchers independently analyzed transcript data to identify key transcript codes/themes. Distressing aspects of elder abuse were identified across three key domains, related to feelings of loss (50% of codes), threats/negative consequences (55%), and client-needs/system incongruity (14%). Specifically, the first theme represented outcomes related to loss of relationships (19% of \u2018loss\u2019 codes), personhood (16%), credibility (19%), faith/trust in others (38%), and finances (8%). The second theme looked at threats to physical self (34% of \u2018threat\u2019 codes), psyche (39%), and others, including the perpetrator (27%). The third theme focused on mismatches in client/system goals (50% of \u2018incongruity\u2019 codes) and legal system involvement (50%). The findings in this study provide a comprehensive and conceptually organized range of aspects to serve as infrastructure for the development of meaningful interventions to address the needs of victims. This study represents one of the largest efforts to understand and integrate the perspectives and needs of victims into elder abuse intervention practice/research to date."}
+{"text": "Pseudomonas sp. strains isolated from marine sponges have shown potential quorum sensing inhibition (QSI) activity. We sequenced the draft genomes of the three strains with the goal of determining which genes or gene cluster(s) could be potentially involved in the QSI activity. Average nucleotide identity (ANI) and phylogenetic analysis classified the three strains as belonging to the Pseudomonas fluorescens species.Three  Pseudomonas sp. strains isolated from marine sponges have shown potential quorum sensing inhibition (QSI) activity. We sequenced the draft genomes of the three strains with the goal of determining which genes or gene cluster(s) could be potentially involved in the QSI activity. Average nucleotide identity (ANI) and phylogenetic analysis classified the three strains as belonging to the Pseudomonas fluorescens species.Three  Pseudomonas is a Gram-negative bacterial genus belonging to the Gammaproteobacteria class, whose members are known to colonize and survive in a wide range of diverse environments, mainly due to inherent broad metabolic diversity (Pseudomonas sp. strains in the inhibition of quorum sensing (QS) signaling systems has been reported  were isolated from 2 different marine sponges, belonging to the Hexactinellida class, that were collected off the west coast of Ireland as part of a marine biodiscovery cruise in May 2010. The isolation of these Pseudomonas sp. strains and their QS inhibition (QSI) activities were described previously . DNA libraries were prepared using a TruSeq exome library preparation kit. The draft genome sequencing was performed by the Beijing Genomics Institute (China) using the Illumina HiSeq 2000 sequencing platform with paired-end reads and a read length of 90\u2009bp for B98C39. The HiSeq 4000 platform, with paired-end reads and a read length of 150\u2009bp, was used for B98SK52 and B98SM8. In order to obtain high-quality reads for assembly, the FASTA/Q file manipulation tool readfq.v5 quiP (pvdThe draft genome sequences discussed in this work have been deposited at DDBJ/ENA/GenBank and the Sequence Read Archive (SRA). The corresponding accession numbers are listed in"}
+{"text": "A 63-year-old man presented to our hospital with 2 days history of right-sided earache and numbness followed by the development of vesicular rash involving the right side of the face. There was no history of headache, tinnitus, giddiness or hearing impairment. Neurological examination revealed right-sided mild lower motor neuron type facial palsy (A) and vesicular rash in the distribution of maxillary and mandibular branch of trigeminal nerve without any sensorineural deafness . Routine all laboratory examinations including retroviral screening were normal. A clinical diagnosis of the Ramsay Hunt syndrome (RHS) was considered based on earache, facial paralysis and typical dermatomal distribution of rash. He was started with oral valaciclovir 1gm three times daily (TDS) for 7 days and Tab prednisolone 60mg daily for 5 days. Two days after initiation of the treatment vesicular lesions disappeared but neurological examination revealed right-sided grade IV facial nerve palsy. Ramsay Hunt syndrome or Herpes Zoster Oticus is characterized by reactivation of latent varicella zoster virus in the geniculate ganglion and subsequent spread to cranial nerve. The diagnosis is mainly clinical. The facial paralysis seen in Ramsay Hunt syndrome is often more severe with the increased rate of late neural denervation and decrease the chance of complete recovery."}
+{"text": "This presentation reports an exploratory study evaluating the effect of Asian Care Training (ACT) Manual on Asian American (AA) caregivers\u2019 care capacity and knowledge growth. A total of 65 AA caregivers were recruited from community-based organizations in Los Angeles and passed the screening questionnaire, in which 44  completed the evaluation process. Participants were given autonomy to choose topics they desired to learn out of 25 topics in ACT manual and completed one-month learning. The data were collected via structured questionnaires before and after the self-learning and were analyzed with paired t-test on 5 questions about care capacity and 4 about caregiving knowledge. One-month self-learning of ACT manual enhanced participants\u2019 care capacity in 4 out of 5 sectors: confidence in caregiving ; ability to deal with emergency ; to solve concerns of the care recipients ; to communicate more smoothly . Improvements were found in 3 out of 4 sectors in knowledge: knowledge of Alzheimer\u2019s disease ; appropriated approach to displacing care recipients ; and information about caregiver support resources . This self-learning method of ACT manual was feasible for AA caregivers to broaden knowledge and care capacity while adapting with their intensive workload. This study constitutes an important step towards establishing culturally tailored self-training programs for Asian American caregivers for frail older adults via multiple platforms such as online curriculums and mHealth app."}
+{"text": "Control and treated animals (dams and offspring) were immunized ip with (0.5 ml) 20% sheep red blood cell (SRBC) suspension seven days before the end of experiments. At the end of exposure, ten dams and ten offspring from each group were used for assessment of cell-mediated immunity and a similar number of animals were sacrificed for evaluating the humoral immune response and serum protein profile. Aluminum chloride exposure of dams (G2 & G3) caused significant suppression of both cell mediated and humoral immune responses in the obtained offsprings compared to the control group (G1) without any significant effect on the immune responses of these dams. Moreover, the serum total globulins, albumin/ globulin (A/G) ratio and gamma globulin fraction were significantly decreased in the treated dam\u2019s offsprings compared to the corresponding controls while the serum total protein and all serum protein fractions showed non significant difference between the control and treated dams and between the two treated dam groups themselves. There were no histopatho-logical changes observed in thymus, spleen and liver of the control and treated dams. Thymus of treated dam\u2019s offsprings (G2) showed lymphoid depletion in both cortex and medulla. Their spleens showed lymphoid depletion in the white pulps and congestion with hemosiderosis in the red pulps. Liver of treated dam\u2019s offsprings showed dilation and congestion of its central vein with degenerative changes in the hepatocytes. These histopathological changes were more severe in G2 than in G3 offsprings. It can be concluded that gestational and/ or lactation exposure of pregnant dams to AI chloride caused suppression of both cellular and humoral immune responses of their offsprings.The present study was designed to explore the immunotoxic effects of orally administered aluminum (AI) on pregnant rats (n = 60) and their growing fetuses and consequently on the animal wealth. The animals were randomly allocated into three equal groups of 20 rats each. The first group has no treatment and kept as a control (G1). The second and third groups of pregnant rats were treated orally with aluminum chloride at 345 mg/Kg b.wt. The second group (G2) received the tested compound from the 6"}
+{"text": "The University of Chicago GWEP, SHARE Network , is located on the South Side of Chicago, an urban medically underserved community. SHARE Network partners with a variety of community based organizations (CBOs) to support Age Friendly care through an Age Friendly Community Education Curriculum. In a one year period, 28 events were held in 13 CBO sites. Each of these events addressed the 4Ms of Age Friendly care with a specific content focus on Mentation (5 events), Mobility (5), Medications (4), and What Matters (10), and 4 events focused on multiple domains. There were 458 attendees, 290 completed surveys (63% response rate). Eighty-eight percent of participants planned to make a healthy behavior change after participation. Age Friendly Community Education can complement health system transformation to lead to health behavior change for community-dwelling older adults in medically underserved communities."}
+{"text": "Research suggests that group music-making can improve well-being and cognitive function in people with dementia and their family carers. The importance of the music facilitator\u2019s role is recognised. However, empirical studies rarely capture their experiences and perspectives. Semi-structured interviews were conducted with three music therapists and three community musicians with specialisms in dementia care. The interviews sought to gain a detailed understanding of their work with people with dementia. Interpretative Phenomenological Analysis revealed eight super-ordinate themes: (1) benefits of music-making for people with dementia; (2) challenges of working with people with dementia; (3) involving family carers; (4) musical content; (5) impact of the facilitator; (6) developing field of Arts and Health; (7) work as a privilege; and (8) potential for misuse of music. This study provides a useful basis from which to further develop concepts for the amelioration of people living with dementia and their families."}
+{"text": "Korean immigrant older adults residing in areas without well-established Korean ethnic enclaves experience acculturative stress and depressive symptoms due to their lingual and cultural barriers. Expressive writing can be used as a culturally sensitive intervention to help those immigrants disclose their deepest thoughts and feelings related to their immigration and acculturation experiences. This study gathered qualitative data from the author\u2019s experimental study using expressive writing for first-generation Korean immigrant adults 60 to 88 years of age residing in Midwestern cities. Participants were instructed to write for 15-20 minutes per day in three consecutive days at their convenience in a comfortable and private setting and asked to return their writings by mail. A total of 22 participants returned their writings: 14 wrote about their past and current stressful experiences related to their immigration and acculturation, while eight wrote about their daily lives. Eight themes emerged from thematic coding processes guided by the grounded theory approach: (1) survival, resilience, hardiness, tenacity, pride; (2) lingual barriers; (3) religious faith; (4) gender difference in roles and values; (5) racial discrimination; (6) traditional strategies of acculturation; (7) family and intergenerational gap; and (8) aging. The themes illustrate the participants\u2019 lifelong efforts to shape their unique voices through heart-wrenching struggles, haunting wounds, and ethnic pride and resilience. The study findings suggest that culturally relevant programs and services are needed to facilitate social relationships and reduce lingual and cultural barriers for Korean immigrant older adults residing in non-ethnic enclaves."}
+{"text": "Scientific Reports 10.1038/s41598-020-58408-6, published online 30 January 2020Correction to: The original version of this Article contained a typographical error in the Abstract.\u201cWe focused on anlyse the functional trait patterns and functional diversity components of two main assemblages that were collected with window traps (WTs) and hollow emergence traps (HETs) respectively, between three protected areas of the Iberian Peninsula.\u201dnow reads:\u201cWe focused on analysing the functional trait patterns and functional diversity components of two main assemblages that were collected with window traps (WTs) and hollow emergence traps (HETs) respectively, between three protected areas of the Iberian Peninsula.\u201dThis has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "We read with interest the recent article by Liao et al. who concluded that patients in the endovascular cooling (EC) group had shorter intensive care unit (ICU) hospitalization and a better neurological prognosis than those in the surface cooling (SC) group . In thei"}
+{"text": "PKHD1 gene, 8 variants in the TMEM67 gene, 4 variants in the PKD1 gene, 2 variants in the HNF1B gene and 2 variants in BBS1 and NPHP1 genes, respectively. NGS is a valuable tool in the diagnostics of various forms of cystic kidney diseases. Its results changed the clinically based diagnoses in 16% (n = 5) of the children.Cystic kidney diseases are a very heterogeneous group of chronic kidney diseases. The diagnosis is usually based on clinical and ultrasound characteristics and the final diagnosis is often difficult to be made. Next-generation sequencing (NGS) may help the clinicians to find the correct final diagnosis. The aim of our study was to test the diagnostic yield of NGS and its ability to improve the diagnosis precision in a heterogeneous group of children with cystic kidney diseases. Next-generation sequencing of genes responsible for the formation of cystic kidneys was performed in 31 unrelated patients with various clinically diagnosed cystic kidney diseases gathered at the Department of Pediatrics of Motol University Hospital in Prague between 2013 and 2018. The underlying pathogenic variants were detected in 71% of patients (n = 22), no or only one  pathogenic variant was found in 29% of patients (n = 9). The result of NGS correlated with the clinical diagnosis made before the NGS in 55% of patients (n = 17), in the remaining 14 children (45%) the result of NGS revealed another type of cystic kidney disease that was suspected clinically before or did not find causal mutation in suspected genes. The most common unexpected findings were variants in nephronophthisis (NPHP) genes in children with clinically suspected autosomal recessive polycystic kidney disease . Overall, 24 pathogenic or probably pathogenic variants were detected in the  Cystic kidney diseases (CKD) are a very heterogeneous group of chronic kidney diseases that in pediatric patients comprise mostly inherited kidney diseases, such as autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis (NPHP), renal cysts and diabetes syndrome (RCAD) or autosomal dominant polycystic kidney disease (ADPKD) . In contIn the last decade, next-generation sequencing becomes the method of choice, allowing simultaneous mutational analysis of panel of genes that can be especially useful in genetic diagnosis of young patients with unclear or doubtful phenotype, in etiologically complex syndromes, or in differential diagnosis of phenotypically overlapping syndromes. In very rare cases a combination of mutations in two genes (digenic disease), can be found in children with severe neonatal clinical phenotype . TherefoThe aim of our study was to test the diagnostic yield of NGS and its ability to improve the diagnosis precision in a heterogeneous group of children with clinically diagnosed cystic kidney diseases.Altogether, there were 31 patients with clinical diagnosis of different cystic kidney diseases\u2013ARPKD, ADPKD, NPHP, RCAD syndrome and Bardet-Biedl syndrome. The group of patients was gathered at the Department of Pediatrics of Motol University Hospital in Prague between 2013 and 2018. The characterization of the group  is summarized in Clinical diagnosis of ARPKD was based on the fulfillment of established clinical criteria of ARPKD including 1) typical kidney involvement on ultrasound , with or without 2) liver involvement  and 3) normal renal US of both parents consistent with autosomal-recessive inheritance [Clinical diagnosis of ADPKD was based on the presence of one or more kidney cysts in one/both kidneys with or without positive family history of ADPKD and was mostly based on expert opinion as no consensus diagnostic criteria were stated for children under the age of 15. Retrospective evaluation shows that diagnosis of ADPKD in our patients followed the international consensus statement for radiological criteria for children and young people published in 2019 ,5, whereThe clinical diagnosis of nephronophthisis was based on the clinical finding of 1) polyuria/ polydipsia or 2) renal concentrating defect or 3) biopsy findings of chronic interstitial nephritis or US findings of normal sized hyperechogenic kidneys, all together with compatible autosomal recessive inheritance . NephronHNF1B nephropathy was mainly based on the presence of cystic kidney dysplasia with/without MODY and/or hypomagnesemia and/or pancreatic malformation, together with presence of other distinctive features described in detail in [Clinical diagnosis of renal cysts and diabetes syndrome (RCAD)\u2013etail in .Clinical diagnosis of Bardet-Biedl syndrome was in our group of patients (patient n.25) based on the presence of cystic kidney disease, obesity, polydactyly and cognitive impairment as described among other features in .th percentile [Hypertension was defined as blood pressure \u226595rcentile .All children with severe cystic kidney disease or systematic disease with presence of cysts treated in the Department of Pediatrics of Motol University Hospital between 2013 and 2018 were included in our group of patients. Cases of typical ADPKD phenotype with mild manifestation and positive family history of the disease, as well as patients whose parents/legal guardians did not give informed consent, were excluded from the study.Detailed clinical, laboratory and ultrasound information of patients are summarized in The study was approved by the Ethics Committee of General University Hospital in Prague and all patients/legal guardians were consulted by geneticist prior to molecular-genetic analysis and gave written informed consent for genetic testing.PKD1, library preparation from long-range PCR products was chosen for PKD1 library preparation  has been chosen. The full list of genes contained in the analyzed panel is in ribed by , PrimeSTThe bioinformatic analysis was provided by in-house bioinformatic pipeline. The analysis included detection of single-nucleotide polymorphisms (SNPs), small insertions and deletions and, in the case of panel sequencing, copy-number variants (CNV).PKD1 sequencing) and quality check of the reads and their trimming was provided by Trimmomatic 0.36 [https://github.com/lh3/bwa/tree/master/bwakit). The hs38DH genome provided by bwa.kit was used. Mapped reads were cleaned up and sorted using samtools fixmate and samtools sort, respectively . The PCR duplicates were then marked with picard MarkDuplicates 2.9.2-SNAPSHOT (Picard Toolkit by Broad Institute) and mapped reads indexed with samtools index (v1.6). For variant calling, freebayes v1.1.0-9-g09d4ecf was used [https://www.ncbi.nlm.nih.gov/snp/) and dbNSFP 3.2a (https://sites.google.com/site/jpopgen/dbNSFP).First, the quality of the FASTQ files created by MiSeq Reporter was evaluated using FastQC v0.11.5 (Babraham Institute). In the second step, cutting off the adapter (TruSeq3-PE-2) sequences (and PCR primers in case of tic 0.36 . The triwas used . The varwas used  and SnpSwas used  compilinThe variant prioritization was composed of automatic filtration (point 1 and 2) followed by evaluation by molecular geneticist in cooperation with nephrologist (points 3\u20135):The variant causes change on protein level (i.e. nonsynonymous sequence changes in exons) or the variant is in the intronic region in the donor  or acceptor  splite site.The variant has a population frequency (of European descend) lower than 0.1. 1000 Genome Project EUR population and Exome Aggregation Consortium (ExAC) was used for the assessment.in silico prediction by programs: SIFT [http://www.mutationtaster.org/), MutationAssessor [Evaluation of the variant based on ms: SIFT , PolyPhems: SIFT , LRT [18Assessor , FATHMM Assessor , PROVEANAssessor , CADD [2Assessor , ensemblAssessor , and conhttp://www.humgen.rwth-aachen.de/) and Autosomal Dominant Polycystic Kidney Disease Mutation Database: PKDB (https://pkdb.mayo.edu/).The consultation of variant with VarSome search engine  containiThe consultation with attending nephrologist regarding the possible pathogenic effect of detected variants with uncertain significance on patient phenotype.trans localization in the patient.If available, analysis of variant segregation in family members. In case of recessive inheritance, analysis of variation in proband\u2019s parents to determine The copy-number variant calling was done using CNVkit 0.8.6.dev0  in all sPKHD1 gene done within our previous project. These patients were either clinically suspected to have ARPKD or had neonatal/infantile onset of the disease. The sequencing method, data analysis and variant classification used in this project were in detail described previously [PKHD1 gene) of patients 3\u20135 and 7 were already published and discussed in [PKHD1 gene alone  have not been analyzed by panel or PKD1 sequencing . Patient 24 was analyzed in commercial laboratory. The complete list of patients and their respective genetic analysis are summarized in Patients 1\u201324 had had mutational analysis of the eviously . The defussed in . The patPKHD1 and HNF1B followed the genetic analysis of the PKHD1 gene in patients in whom no/one mutation in PKHD1 was found. The kits used for MLPA analysis were SALSA MLPA P341 PKHD1 mix 1, P342-PKHD1 mix 2 and SALSA MLPA P241 MODY Mix 1 (MRC Holland). The generated data were analyzed by Coffalyser.Net (MRC Holland).MLPA (Multiplex Ligation-dependent Probe Amplification) analysis was used for detection of large genome rearrangements. MLPA of NPHP1 gene found by panel sequencing. The kit used for the analysis was SALSA MLPA P387 NPHP1.The MLPA analysis was also applied in patient 29 to confirm the complete deletion of both alleles of PKHD1 confirmed the diagnosis in 10 (50%) of them. In the other 10 patients, the sequencing of PKD1 and panel of genes yielded the diagnosis in additional 5 of them . Four children harbored only one pathogenic mutation in the recessive PKHD1 gene, and the final diagnosis remained unknown.The group of 31 patients formed by patients from Motol University Hospital gathered between years 2013 and 2018 was analyzed within our project. The underlying pathogenic variants were detected in 71% of patients (n = 22), no or only one  pathogenic variant was found in 29% of patients (n = 9) . The resPKHD1 and those with childhood onset, without a clinical suspicion of ARPKD, a panel sequencing and sequencing of the PKD1 gene yielded the diagnosis in 57% patients (12 of 21). The most common unexpected findings were changes in nephronophthisis (NPHP) genes in children with clinically suspected ARPKD (n = 4). The most common incorrect clinical diagnosis was ARPKD (n = 10) with four patients having genetically proven NPHP, one ADPKD de novo and further five patients having no definitive genetic diagnosis.In patients without a yield by sequencing of PKHD1 gene (14 patients), 8 variants in the TMEM67 gene (4 patients), 4 variants in the PKD1 gene (4 patients), 1 variant in HNF1B (1 patient) and 2 variants in BBS1 (1 patient). Moreover, whole gene deletion was detected in heterozygous (HNF1B gene) and homozygous (NPHP1 gene) state in two patients.Overall, 24 pathogenic or probably pathogenic SNP variants were detected in the The molecular genetic data of patients are summarized in HFN1B and NPHP1 was detected. In both genes, whole gene deletions are the most common variants described in literature [Sequencing analysis performed in 31 pediatric patients with suspected cystic kidney diseases detected causal variant in 71% (n = 22) of patients. This roughly correlates with results presented by Bullich et al.  where taterature .TMEM67 variant), which was already described in 2009 by Otto et al. [NGS confirmed the clinical diagnosis in 55% (n = 17) patients and did not confirm or changed the clinical diagnosis in 45% (n = 14) of them. The most common clinical diagnosis that had to be changed thanks to the NGS results was ARPKD. Four children  with a clinical diagnosis of ARPKD was diagnosed as having genetically NPHP11 and one patient (28) de novo ADPKD. The clinical and ultrasound picture of ARPKD and NPHP can be similar making the differential diagnosis difficult mainly in children with non-neonatal manifestation in ARPKD and in absence of extra-renal/hepatic manifestation such as eyes or central nervous system abnormalities present in NPHP. The less severe NPHP phenotype in our patients was caused by the fact that all children carried the allele p.Cys615Arg  or had another clinical diagnosis discovered during follow-up . In three children (15%) with clinically diagnosed ARPKD only one pathogenic variant in the n et al. . Even thn et al.  suggestsNo or partial genetic findings in some patients could be caused by several reasons:DZIP1L [CEP83 [Mutations in other ciliopathic genes which were not in our NGS ciliopathy panel  covered by genetic analysis, e.g. regulatory regions in deep intronic sequences, untranslated regions of genes, first exons of genes or even promotor regions, that are especially important for genes coding transcription factors whose function strongly relates to expression level. Also, the causing variant could have been filtered out as variant of unknown significance (VUS) as its function is yet unknown or could have been missed by bioinformatic processing.Moreover, a combination of heterozygous mutations in two different ciliopathic recessive (or dominant) genes could theoretically cause a severe cystic kidney disease phenotype as an oligogenic inheritance where variants in different genes modify final phenotype  was already described in ciliopathies (reviewed in ), as welAnother possibility for the discrepancy between clinical and genetic diagnosis is that the cystic kidney disease in a given child is non-inherited  which is however very rare in pediatric patients especially if manifested in neonatal/infant age.Extra-renal manifestations, such as eye or CNS abnormalities were the best clues for the correct clinical diagnosis of patients with non-ADPKD cystic kidney diseases . NystagmThe strengths of our study are a very well clinical and ultrasound characterization of the patients, the long-term follow-up and the high number of ciliopathy genes in our panel. The genetic diagnosis consisted of several methods of sequencing and CNV detection and thus provided reliable results. We are aware of the limitations of our study\u2014the low number of patients, single-center study, lack of some non-ciliopathy genes in our panel and lack of whole-exome sequencing in the genetically unresolved patients.In conclusions, our study demonstrated that the next-generation sequencing method facilitates molecular analysis of different types of cystic kidney diseases and enables precise genetic diagnosis. Its results changed the clinical diagnosis in number of the children. The correct final genetic diagnoses enable better management of children with different forms of cystic kidney diseases and provide efficient genetic counseling.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table+, yes; -, no.(PDF)Click here for additional data file."}
+{"text": "We conducted a genome-wide association study of 1317 centenarians from the New England Centenarian Study and 2885 controls using >9M genetic variants. The most significantly associated variants were correlated to 4131 serum proteins in 224 study participants. The genetic and protein associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazy Jewish descent and a proteomic scan of approximately 1000 participants of the same study. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and underexpression of APOB in carriers of the APOE2 allele (p< 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2a/CDKN2B in chromosome 9). The analyses show that longevity variants correlate with proteome signatures that could be manipulated to discover healthy aging targets."}
+{"text": "Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract illness in infants and affects the elderly and the immune-compromised. RSV infection can cause pulmonary obstruction and disease, but the mechanisms contributing to these outcomes remain elusive. Despite the major health burden caused by infection, there is currently no licensed RSV vaccine and treatments are limited. The Special Issue on \u201cPathobiology of Respiratory Syncytial Virus (RSV)\u201d covers the attributes of disease pathogenesis, immunity, and vaccine development. In an article by Pedro Piedra, \u201cAntibody Response to the Furin Cleavable Twenty-Seven Amino Acid Peptide p27) of the Fusion Protein in Respiratory Syncytial Virus (RSV) Infected Adult Hematopoietic Cell Transplant (HCT) Recipients\u201d , the ant7 of the"}
+{"text": "The purpose of this study was to explore the relationship between nursing home volunteer programming and quality measures and increase the knowledge base of nursing home volunteer programming in various settings. Fifty-two nursing homes were surveyed using electronic surveys and personal interviews. Questions focused on the organization of the nursing home, characteristics of the volunteer program and volunteer activities. Of the 52 facilities surveyed, 19 were not part of a chain, 37 were in urban settings, and 24 were for-profit entities. Volunteers were used in 46 nursing homes with a mean number of volunteers of 51.7 onsite an average of 4.9 days per week. Bivariate analysis revealed statistically significant correlations (p<.05) between organizational and volunteer programming characteristics and six quality measures . Statistically significant (p<.05) inverse relationships were found between volunteers providing individualized activities  and the incidence of urinary tract infections and the use of psychotropic drugs. Multiple regression analysis revealed a statistically significant (p<.05) inverse relationship between personal volunteer services such as combing hair and doing nails and the use of hypnotic drugs and antipsychotic drugs. This study indicates a significant correlation between volunteer programming and quality measure scores. A larger study of these relationships is indicated."}
+{"text": "Semen samples were then cryopreserved in TEST-yolk buffer and stored in liquid nitrogen at -196\u00b0C.The identification of the differentially expressed proteins (DEPs) between the control and NSTC groups was con- ducted via Scaffold software. The criteria for the selection of DEPs for validation by Western blot (WB) included: 1) proteins involved in reproductive system development and function; 2) proteins involved in the top canonical pathways; 3) proteins with a higher difference of abundance between the experimental groups; 4) proteins with a well-described function in the literatureThe authos identified 189 differentially expressed proteins (DEPs) in the dataset, from which five DEPs related to sperm function and fertilization were selected for validation by Western blot. And they indentified that underexpression of the mitochondrial complex subunits NADH:Ubiquinone Oxidoreductase Core Subunit S1 (NDUFS1) and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2), as well as the underexpression of the testis-specific sodium/potassium-transporting ATPase subunit alpha-4 (ATP1A4) in the NSTC group.The results indicate that sperm mitochondrial dysfunction may explain the observed decrease in sperm concentration, total sperm count and total motile count in NSTC patients. The identified DEPs may serve as potential biomarkers for the pathophysiology of subfertility/infertility in patients with NSTC."}
+{"text": "Conventionally, (p)ppGpp collectively refers to two nucleotides, ppGpp, and pppGpp in the literature. Initially, (p)ppGpp has been discovered as a transcription regulatory molecule as it binds to RNA polymerase and regulates transcriptional gene regulation. During the past decade, several other target proteins of (p)ppGpp have been discovered and as of now, more than 30 proteins have been reported to be regulated by the binding of these two signaling nucleotides. The regulation of diverse biochemical activities by (p)ppGpp requires fine-tuned molecular interactions with various classes of proteins so that it can moderate varied functions. Here we report a structural dynamics of (p)ppGpp in the unbound state using well-defined computational tools and its interactions with target proteins to understand the differential regulation by (p)ppGpp at the molecular level. We carried out replica exchange molecular dynamics simulation studies to enhance sampling of conformations during (p)ppGpp simulation. The detailed comparative analysis of torsion angle conformation of ribose sugar of unbound (p)ppGpp and bound states of (p)ppGpp was carried out. The structural dynamics shows that two linear phosphate chains provide plasticity to (p)ppGpp nucleotides for the binding to diverse proteins. Moreover, the intermolecular interactions between (p)ppGpp and target proteins were characterized through various physicochemical parameters including, hydrogen bonds, van der Waal\u2019s interactions, aromatic stacking, and side chains of interacting residues of proteins. Surprisingly, we observed that interactions of (p)ppGpp to target protein have a consensus binding pattern for a particular functional class of enzymes. For example, the binding of (p)ppGpp to RNA polymerase is significantly different from the binding of (p)ppGpp to the proteins involved in the ribosome biogenesis pathway. Whereas, (p)ppGpp binding to enzymes involved in nucleotide metabolism facilitates the functional regulation through oligomerization. Analysis of these datasets revealed that guanine base-specific contacts are key determinants to discriminate functional class of protein. Altogether, our studies provide significant information to understand the differential interaction pattern of (p)ppGpp to its target and this information may be useful to design antibacterial compounds based on (p)ppGpp analogs. Escherichia coli culture. The concentration of these nucleotides was enhanced drastically in E coli cells during amino acid starvation and these nucleotides were inhibiting rRNA synthesis ppGpp is used for two nucleotides, guanosine 5\u2032-diphosphate-3\u2032-diphosphate (ppGpp) and guanosine 5\u2032-triphosphate-3\u2032-diphosphate (pppGpp). These nucleotides are synthesized by (p)ppGpp synthetase by transferring pyrophosphate groups from ATP to GDP/GTP to form ppGpp and pppGpp, respectively . There aThe molecular dynamics simulation studies provide structural dynamic information in the solution state of a molecule. Although, glycosidic bond and ribose sugar in the nucleotide structure exhibit conformational flexibility and classical molecular dynamics simulation on nucleotides is challenging because of energy barriers and sampling of conformations are limited. Therefore, Replica Exchange Molecular Dynamics (REMD) simulation was carried out on ppGpp and pppGpp nucleotides in solution states. In REMD, several identical replicas run in parallel at different temperatures and these allow enhanced sampling of high energy conformations. Moreover, these replicas are allowed to swap their states based on Boltzmann-weighted probability at neighboring temperature state. This process is repeated iteratively during the simulation and subsequently enhanced sampling of conformations is achieved at various temperatures.3 for both molecules and upon addition of buffer, the box volume was expanded to 145262 and 150766 \u00c53 for ppGpp and pppGpp, respectively. Negative charges, due to phosphates groups of (p)ppGpp molecule, were neutralized by the addition of 20 mM Mg2+ in the simulation system. The Optimized Potential for Liquid Simulations 3 enhanced (OPLS3e) force field was selected for the simulation ppGpp-protein complexes. The structural alignment was carried out in PyMol using an atom alignment algorithm. The distribution frequency of glycosidic bonds in unbound states of ppGpp and pppGpp were plotted at 300 K simulation pose in Schrodinger. The torsion angle and phase angle values were calculated from Pseudo-Rotational Online Service and Interactive Tool (PROSIT) , 2005.The structures of (p)ppGpp-protein complexes were downloaded from Protein Data Bank (PDB). The PDB ligand code G4P for ppGpp, 0o2, and C1Z for pppGpp was used as a search term to obtain structures of ppGpp-protein and pppGpp-protein complexes, respectively. As shown in Molecular dynamics simulation is one of the most commonly used approaches to understand structural dynamics of biomolecules in solution state . It has 2+ ions during the simulation, yet higher flexibility of phosphate atoms was observed in the RMSF plot. In contrast to (p)ppGpp, the phosphate groups in cyclic messenger nucleotides show lesser flexibility due to the unavailability of free phosphate chains (2 group of guanine ring of (p)ppGpp in REMD simulation. The detailed analysis of molecular properties shows the overall quality and conformational dynamics of (p)ppGpp during the simulation ppGpp were obtained by energy minimization in Maestro. The structural coordinates of bound (p)ppGpp were extracted from structures of (p)ppGpp-protein complexes. The structural alignment of unbound state and bound state of (p)ppGpp shows substantial similarity in the guanine ring region with RMSD of atoms less than one. However, the phosphate chain shows divergence upon structural alignment which is in agreement with our simulation RMSF plot.syn conformation, however, some occurrences were observed in anti conformation. Our results on the frequency distribution of glycosidic conformation in unbound states are similar to those observed in the bound states in the crystal structure. As most of the structures of (p)ppGpp-protein complexes have anti conformation of glycosidic bond except in few cases it was found in syn conformation such as nucleosidase (6GFM)  and maximum puckering amplitude (\u03bdmax) which show that ribose sugar adopts north conformation in both states ((p)ppGpp nucleotides exhibit a substantial extent of conformational flexibility because of various rotatable torsion angles present in the structure particularly a ribose ring . Therefoe (6GFM) , lysine e (6GFM) . The sugormation . Whereasd pppGpp . The fivse sugar . The ribse sugar . Additioh states . The com2+ ions. As seen by the hydrogen bonds histogram, the major interatomic polar interactions were observed in guanine ring and phosphate group atoms. The aromatic ring of guanine had\u03c0-\u03c0 base stacking interactions with the side chain of tyrosine in the structures of (p)ppGpp synthetases and nucleotide metabolic enzymes. The ribose moiety of (p)ppGpp makes comparatively fewer interactions with protein atoms which may be the consequence of the structural restrain of the ribose ring. Similarly, van der Waal\u2019s interactions were found majorly in the region of the guanine ring of (p)ppGpp ppGpp . The avaBacillus subtilis ppGpp synthetases are apparent (p)ppGpp binding proteins as these enzymes synthesize ppGpp and pppGpp from ATP and GDP/GTP, respectively. However, most of the structures determined so far are in complexes with substrate analogs as these complexes explain the catalytic mechanism. A brief structural review on (p)ppGpp synthetase proteins has been described previously  hence cusubtilis ; small as aureus  and one mophiles . The (p)2+ ions. Therefore, these interactions are considered as ionic interactions. The observed binding mode of (p)ppGpp to the nucleotide enzymes is similar due to an analogy of substrate nucleotide structure to the (p)ppGpp. As shown in the graph, the N1, N2, N7, and O6 atoms of the aromatic guanine ring of (p)ppGpp is a major contributor to hydrogen bond interaction with protein residues.There are six crystal structures of (p)ppGpp and nucleotide metabolic enzymes complexes available in the Protein Data Bank which includes Xanthine phosphoribosyltransferase (XPRT) , PyrimidThere are five crystal structures of GTP binding GTPase proteins in complex with (p)ppGpp available till now. These include Obg GTP binding protein , GTPase RNA polymerase was the first protein complex reported to regulate its activity by binding of (p)ppGpp . There aThere are several crystal structures of various other functional class of (p)ppGpp binding proteins reported including translation peptide chain release factor 3 (PDB: 3VR1) , acetylt2+) plays a significant role in the structural stability of nucleic acid and nucleotides by neutralizing highly negative charged phosphate groups (2+ ions assist in the specific interaction of (p)ppGpp to their target protein. As shown in the graph ppGpp synthetase, RelTt, it binds to only one chain of phosphate ppGpp but it also mediates interactions between (p)ppGpp and protein side chains. Each phosphate chain of (p)ppGpp is making interactions with one Mg2+ ion in the complex of RNA polymerase-(p)ppGpp. Altogether, we have observed Mg2+ ions in several other complexes of (p)ppGpp-protein structures except for few complexes which may be the limitation of electron density interpretation as discussed earlier ppGpp have linear phosphate chains that provide additional flexibility to adapt various conformations according to the stereochemistry of the binding site of a respective target protein. Overall, our results support the hypothesis that the conformation flexibility of glycosidic bond, ribose sugar puckering, and phosphate groups provide structural plasticity to the (p)ppGpp for binding to the various functional class of proteins. The structures of unbound ppGpp and pppGpp in solution states obtained by MD simulation are similar to that observed in the structures in bound form, hence, these structures resemble biologically active conformations of (p)ppGpp. The gyration conformation profile of glycosidic bond is in agreement with the conformation of (p)ppGpp observed in the bound state. The analysis of (p)ppGpp-protein interactions reveals that the binding pattern of these nucleotides governs the regulation for a particular class of target proteins.The original contributions presented in the study are included in the article/GK and NB conceptualized the study. GK and AP performed the study. All authors analyzed the data, wrote and edited the manuscript, and agreed on the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sarothrura ayresi was sequenced using next generation sequencing technology. The size of the genome is reported as 16,767\u2009bp and comprises 13 protein-coding genes, 2 rRNAs and 22 tRNAs. The organization of the genome is comparable to that of other bird species. A phylogenetic comparison mapped the relative relationship of Sarothrura ayresi with respect to other species in the order Gruiformes.The mitochondrial genome of  The Critically Endangered white-winged flufftail  forms part of the genus Sarothrura IUCN . The speTM \u2013 Tissue MiniPrep Kit (Zymo Research Corporation), library preparation and Illumina high-throughput sequencing . Sequences were assembled using the CLC Genomics platform . The mitogenome was assembled under the de novo option, using the standard parameters. Various kmer sizes were used during optimisation and the full mitochondrial genome for the WWFT was assembled using kmer size 31. The mitochondrial assembly constituted 8597 reads out of the 18,567,330 that remained after quality trimming and removal of contaminating adapters, using the Trimmomatic software  in January 2014 was selected for mitochondrial analysis. This was performed using standard extraction using the ZR Genomic DNAGallus gallus as reference  was performed using MITOS  and Heliornithidae (Heliornis fulica) than with members of the Gruidae (Anthropoides paradiseus) and Otidae (Otis tarda).The WWFT mitogenome constitutes the first whole mitochondrial genome entry within the Sarothruridae family. In order to evaluate its relative position within the order Gruiformes a phylogenetic tree (maximum-likelihood) was constructed to place the WWFT among species representing the Rallidae, Gruidae, Heliornithidae and Otididae Families using MEGA version 6 (Tamura et\u00a0al."}
+{"text": "Recent studies have reported ERp57 overexpression in various human cancers, and altered expression and aberrant functionality of ERp57 are associated with cancer growth and progression and changes in the chemosensitivity of cancers. ERp57 may become a potential biomarker and therapeutic target to combat cancer development and chemoresistance. Here, we summarize the available knowledge of the role of ERp57 in cancer and the underlying mechanisms.Endoplasmic reticulum resident protein 57 (ERp57) has a molecular weight of 57 kDa, belongs to the protein disulfide-isomerase (PDI) family, and is primarily located in the endoplasmic reticulum (ER). ERp57 functions in the quality control of nascent synthesized glycoproteins, participates in major histocompatibility complex (MHC) class I molecule assembly, regulates immune responses, maintains immunogenic cell death (ICD), regulates the unfolded protein response (UPR), functions as a 1,25-dihydroxy vitamin D With cancer incidence and mortality rates increasing rapidly, cancer has become a global problem and is expected to become the leading cause of death worldwide in the 21st century according to the Global Cancer Statistics 2018 report The PDI family includes more than 20 members that catalyze cysteine-based redox reactions and play critical roles in productive protein folding in vitro analyses and clinical trials support that ERp57 is overexpressed in a variety of cancers. ERp57 expression is significantly different between tumor tissues and normal tissues (P < 0.05) in a wide variety of cancers, including stomach adenocarcinoma, colon adenocarcinoma, liver hepatocellular carcinoma (HCC), breast invasive carcinoma, and prostate adenocarcinoma, as shown in Figure http://ualcan.path.uab.edu/analysis.html) Recent research from In vitro, knockdown of ERp57 in HeLa cells inhibits cancer invasiveness and metastasis Some studies have demonstrated that ERp57 is a primary cellular target that inhibits cancer cell proliferation + T cells is enhanced when ERp57 is knocked out in human CD8+ T cells because ERp57 knockout in CD8+ T cells regulates the expression of multiple immune regulators and effectors on the cell surface + T cells need to be explored in detail to expand the utility of ERp57 in cancer immunotherapy strategies.Calnexin (CNX) and calreticulin (CRT) predominantly act as lectins that specifically interact with nascently synthesized glycoproteins in the ER, and ERp57 forms complexes with these proteins to accomplish efficient folding and proper formation of intramolecular disulfide bonds in glycoproteins in vivo because CRT translocation is inhibited and immunogenic cell death is abolished Immunogenic cell death (ICD), a type of regulated cell death (RCD), induces adaptive immune responses to kill cells directly Due to its disulfide isomerase activity, ERp57 forms a complex with CNX and CRT to specifically modulate the folding of newly synthesized glycoproteins by facilitating the formation of native disulfide bonds Recent data suggest that ERp57 plays an important role in the DNA repair process. ERp57, accompanied by high mobility group proteins 1 and 2 (HMGB1 and HMGB2), acts as a component of a complex that detects damaged DNA, inactivates the mismatch repair system and decreases the sensitivity of cells to thiopurine treatment Taken together, the evidence indicates that ERp57 has a protective effect on the survival of tumor cells due to its contribution to the DNA repair process, which regulates the sensitivity of the tumor to DNA-modifying chemotherapy. Thus, it may become a biomarker to predict therapeutic failure and success. However, further studies are required to confirm these findings and identify potential antitumor targets.2D3 is the active form of vitamin D, and its analogs exert inhibitory effects on the proliferation and progression of multiple cancers, including melanoma 3-membrane-associated, rapid response to steroid binding  receptor, mainly located on the plasma membrane and Golgi/ER 2D3 to form a ligand-receptor complex to mediate several rapid signal transduction cascades; for example, it regulates STAT3 2+ release from lysosomes to activate autolysosomal degradation In vitro studies have revealed that knockdown of ERp57 inhibits HCC cell proliferation 1,25(OH)Mitomycin C (MMC) exerts anticancer effects by inducing DNA cross-linking in cancer cells Affymetrix microarray results suggest that cytoskeletal remodeling and the Wnt signaling pathway are the two of the top pathways disrupted by ERp57 silencing in HeLa cells 3-MARRS receptor ERp57 plays an important role in the natural history of cancer and the therapeutic process. As an ER chaperone, ERp57 is associated with CRT and CNX, participates in MHC class I molecule assembly"}
+{"text": "Cervical cancer is a common gynecologic malignancy worldwide. It is the fourth for both incidence and mortality. For cervical cancer, imaging and pathology assessments are incorporated in the revised 2018 Federation of Gynecology and Obstetrics (FIGO) staging system. Uses of imaging techniques for the pre-treatment work-up of cervical cancer have been increasing. Among imaging techniques for the evaluation of cervical cancer, ultrasound is cheaper, faster and widely available than other imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI). Advanced technique in ultrasound, such as three-dimension (3D) ultrasound and color Doppler, have improved the clinical application of ultrasound in cervical cancer. Ultrasound may provide highly accurate information on detecting tumor presence and evaluating local tumor extent if performed by ultrasound-trained gynecologists; the experience of readers is also critical for correct pretreatment staging and assessment of response to treatment. Sonographic images could be useful to predict response of neoadjuvant chemotherapy, radiotherapy, chemotherapy and concurrent chemoradiotherapy in patients with cervical cancer. This review article attempted to present the most updated specific applications of ultrasound in cervical cancer. Cervical cancer is a common gynecologic malignancy among women. It is the fourth for both incidence and mortality in Global cancer statistics 2018 Patient age, performance status, para-aortic lymph node status, tumor size, and pelvic lymph node status are significantly associated with progression-free interval Cervical cancer can spread by lymphatic or hematogenous dissemination or direct extension. Staging cervical cancer is critical for approaching the most effective treatment strategy and predicting the outcomes. Stage IA cancer can be treated with cervical conization procedure or simple hysterectomy, while later stages may require neoadjuvant chemotherapy, radical surgery, radiation, chemotherapy or a combination of therapies. It is valuable to evaluate the response to treatment in cervical cancer women.For cervical cancer, imaging and pathology assessments are incorporated in the revised 2018 F\u00e9d\u00e9ration internationale de gyn\u00e9cologie et d'obst\u00e9trique (FIGO) staging system Transvaginal and transrectal ultrasound (TVUS and TRUS) are typically performed by the gynecologist with the advantage of low cost and wide availability A study enrolled 52 patients, 13 were advanced-stage disease (stage \u2265IIb) and 39 were early-stage disease (stage \u2264IIa), to evaluate the combined use of transvaginal elastography (TVES) and high-resolution TVUS in comparison with the diagnostic performance of magnetic resonance imaging (MRI) in detecting parametrial invasion in cervical cancer. It could be promising and economic for pre-operative work-up of cervical cancer by a dedicated gynecologic radiologist using TVES combined with TVUS In the cases with negative paraaortic lymph nodes on computed tomography (CT) or positron emission tomography (PET-CT), it could be necessary to perform dissection of the paraaortic lymph node in surgical staging. Obtaining an ultrasound or CT-guided tru-cut biopsy in equivocal extrauterine lesion is recommended to reduce false positive findings by imaging methods Hence, uses of imaging techniques for the pre-treatment work-up of cervical cancer have been increasing Among imaging techniques for the evaluation of cervical cancer, ultrasound is faster, radiation-free, cheaper, noninvasive, no contrast medium required and more widely available than other imaging techniques The characteristics of the cervix blood flow in normal women and in women with precancerous lesions or invasive cancers were reported by using three-dimensional power Doppler ultrasound (3D PDU) indices, including the intensity of flow at the time of volume acquisition (FI), the number of vessels within the volume of interest (VI), and both blood flow and vascularization (VFI) TVCD combined with colposcopy was used to diagnose precancerous lesions and early stage cervical cancer A thorough evaluation to determine the extent of cervical cancer should be performed if the diagnosis has been identified. There were several studies involving detection of the extension of cervical cancer lesion Table .The role of ultrasound for staging cervical cancer was reported in early 90s The accuracies of staging with TRUS and clinical staging were 83% and 78%, respectively. The sensitivity, specificity and accuracy of TRUS for extent of parametrial involvement were 78%, 89% and 87%. TRUS could be helpful applied to routine pretreatment assessment of patients with cervical carcinoma In the assessment of parametrial infiltration in cervical cancer, a study included 29 patients using MRI and 2D and 3D ultrasound examination before treatment. The result showed that 2D and 3D ultrasound had similar moderate agreement with MRI. However, 2D and 3D ultrasound examinations are more available at low cost than MRI. Ultrasound could be considered as a method for preoperative work-up of cervical cancer The agreement of clinical examination, 3D and 2D sonography with MRI for local staging of cervical carcinoma was evaluated For evaluating the tumor's volume and intra-tumoral vascularization, the study enrolled 27 patients, with cervical cancer and stage 1B1 disease, who have an initial 2D ultrasound examination and followed by 3D volumes of the cervix. The Virtual Organ Computer Aided Analysis (VOCAL) program was used to calculate the tumor volume and vascularization A recent study reported the local staging of cervical cancer for 46 patients who underwent MRI of the pelvis and high\u2010resolution TVUS A previous prospect study, included 38 cervical cancer patients, involved the TRUS in the evaluation of cervical carcinoma and comparing with spiral computed tomography (SCT) and MRI For locally advanced cervical cancer, 3-dimensional transvaginal ultrasound (3D-TVUS) was used to diagnose the extent of invasive cervical cancer and compare to that of Magnetic resonance imaging For cervical primary tumor confined to the origin, the sonographic detection rate is high; transrectal or TVUS is a highly accurate modality in classifying early-stage tumors The diagnostic performance of TVUS and MRI for assessment of presence and extent of cervical cancer was investigated by a prospective study The diagnostic performance of TVUS examination with regard to local extent and tumor size of the disease of early stage cervical cancer was investigated Assessment of the extension of the lesion has been researched Furthermore, angiogenesis, the formation of new vessels in a specific area, is required for tumor growth and progression Transvaginal Color Doppler in cervical cancer allows non-invasive assessment of tumor angiogenesis Color Doppler findings associated with risk factors was reported by a study involving neoangiogenesis measured in early cervical cancer cases Angiogenic parameters, including subjective assessment of pulsatility index (PI) and the amount of vessels within the tumor (scanty-moderate or abundant), were evaluated by transvaginal color Doppler ultrasound for 27 early stage cervical cancer patients. The risk factors  were recorded. Tumors with abundant vasculization were significantly associated with parametrial involvement, lymph-vascular space involvement, pelvic lymph node metastases etc. Postoperative treatment was significantly more prevalent in patients with profuse vascularization The p53 protein expression in cervical cancer after RT correlated with transvaginal color Doppler ultrasound findings was reported by a recent study Several studies have evaluated the role of ultrasound for predicting the response to varied treatment in women with cervical cancer.The role of TVUS in early prediction of pathological response in a large series of locally advanced cervical cancer patients arranged neoadjuvant treatment followed by radical surgery was investigated by using 3D PDU Using Power Doppler vascularity index (PDVI) to predict the response to neoadjuvant chemotherapy (NACT) in bulky early stage cervical carcinoma was reported A prospective study involved 42 women with locally advanced cervical cancer referred for NACT Transvaginal Color Doppler sonography used to predict the response to chemotherapy in patients with advanced cervical cancer was reported The residual tumor in locally advanced cervical cancer patients receiving chemoradiation and radical surgery was assessed by 3D power Doppler, 2D ultrasound parameters, or contrast-enhanced indices Ttransvaginal color Doppler ultrasonography (TCD) used to predict response to preoperative chemoradiation for locally advanced cervical carcinoma patients was investigated Alterations in cervical intra-tumoral vascularization during and after radiotherapy investigated by 3D PDU was reported The evaluation of radiotherapy response of cervical cancer by suing gray scale and color Doppler ultrasonography was report It was reported that Transvaginal color Doppler sonography could be useful in predicting clinical response to concurrent chemoradiation for locally advanced cervical carcinoma The investigation of early response of locally advanced cervical cancer patients undergoing concurrent chemo-radiotherapy (CCRT) by ultrasound was reported The role of intraoperative ultrasound guidance in intracavitary brachytherapy of cervical cancer was investigated in a recent retrospectively study In a recent systematic review and meta-analysis, a decrease of uterine perforations by using ultrasound image-guided applicator insertion for cervical carcinoma patients underwent intracavitary brachytherapy was revealed TRUS guided high dose rate (HDR) interstitial brachytherapy for patients of cervical cancer was investigated For the ability of evaluating morphology and intensity of blood flow, ultrasound technique might be used to improve cervical cancer screening, and this need more studies to confirm the applications. Imaging during the primary diagnostic work-up is essential for accurately assessment of tumor extent and selecting the best therapeutic option for cervical cancer patients. Ultrasound may be a useful modality to evaluate local extent of disease in cervical cancer. This technique is limited for evaluating lymph node status. Tumor vascularization by Doppler ultrasound could be useful for monitoring and predict response to therapy."}
+{"text": "The Medication-Related Osteonecrosis of Jaws (MRONJ) diagnosis process and its prevention play a role of great and rising importance, not only on the Quality of Life (QoL) of patients, but also on the decision-making process by the majority of dentists and oral surgeons involved in MRONJ prevention (primary and secondary). The present paper reports the update of the conclusions from the Consensus Conference\u2014held at the Symposium of the Italian Society of Oral Pathology and Medicine (SIPMO) \u2014after the newest recommendations (2020) on MRONJ were published by two scientific societies , written on the inputs of the experts of the Italian Allied Committee on ONJ (IAC-ONJ). The conference focused on the topic of MRONJ, and in particular on the common practices at risk of inappropriateness in MRONJ diagnosis and therapy, as well as on MRONJ prevention and the dental management of patients at risk of MRONJ. It is a matter of cancer and osteometabolic patients that are at risk since being exposed to several drugs with antiresorptive  or, more recently, antiangiogenic activities. At the same time, the Conference traced for dentists and oral surgeons some easy applicable indications and procedures to reduce MRONJ onset risk and to diagnose it early. Continuous updating on these issues, so important for the patient community, is recommended. Medication-Related Osteonecrosis of Jaws (MRONJ) and its prevention play a role of great and rising importance, not only on the Quality of Life (QoL) of patients, but also on the decision-making process of the majority of dentists and oral surgeons, involved every day in MRONJ prevention (primary and secondary). The present report illustrates the update of conclusions adopted from the Consensus Conference held at the Symposium of the Italian Society of Oral Pathology and Medicine (SIPMO) on 20 October 2018, in Ancona (IT), when opinions were discussed and synthesized by 24 Italian experts. The Conference was the first national consensus to address the MRONJ disease and specific interventions , it sharThe present report was considered by the experts as convenient and worthwhile in the light of the new findings ,12,13 anThe updated Consensus Conference focused on the common practices still at risk of inappropriateness in MRONJ diagnosis and prevention, and on the dental management of patients exposed to ONJ. It is matter for the cancer  and osteometabolic patients, since they are exposed to an increasing number of drugs with antiresorptive  or antiangiogenic activities  ,16,17,18The experts focused on the topic of MRONJ using the following 6 main subcategories (issues): (1) clinical diagnosis; (2) radiologic diagnosis; (3) primary prevention (before and during drug intake); (4) dental management; (5) drug holiday (temporary suspension vs. therapeutic suspension); and (6) therapy.The IAC-ONJ planned that a recommended practice equivalent will be advised for any inappropriate practice, within these 6 issues.Assume that the Italian Consensus adopted the previously described definition of MRONJ ,5, as be(#1) Restricting the anamnestic interview only to the assumption of bisphosphonates for diagnosing MRONJ.(#2) Carrying out routine bone biopsies when suspecting an MRONJ.(#3) Considering the presence of exposed necrotic bone, in the oral cavity, as an essential (conditio sine qua non) sign to diagnose MRONJ.(#4) Judging the presence of pain as an essential symptom for diagnosing MRONJ.(#5) Believing that all MRONJ are preceded by dental invasive procedures.(#1) Evaluate not only the intake of bisphosphonate drugs (current or past), but also further pharmacological therapies  and perform a thorough physical examination and medical history, together with targeted radiologic examinations see  (confirm(#2) Perform jaw bone biopsies only if there is a suspicion of metastases in cancer patients (confirmed).(#3) Take into the account not only the presence of exposed necrotic bone but considering also other clinical signs and first/second-level imaging (confirmed).(#4) Consider that the symptom \u201cpain\u201d may not always be present in MRONJ cases, especially in the early stages (confirmed).(#5) Consider that some cases of MRONJ can arise from the presence of dental-periodontal diseases or spontaneously, without any relation to invasive dental procedures (confirmed).Radiologic imaging is assumed to be a fundamental tool for diagnostic completion, defining the extent of the disease at the skeletal level, staging and the correct therapeutic planning. Even if it is well known that no specific radiological signs of disease can be defined until now, an increasing volume of evidence recognizes some radiological characteristics that, although non-specific, are associated with MRONJ ,23,24,25(#1) Starting therapies at risk of ONJ without a radiologic assessment of dental arches, remarkably in cancer patients.(#2) Omitting the radiologic assessment for those patients at risk of MRONJ in the presence of dental/endo-periodontal diseases.(#3) Prescribing to everybody exposed to therapies at risk of ONJ all imaging techniques to rule out MRONJ.(#4) Requiring radiologic exams without a specific diagnostic hypothesis.(#5) Prescribing radiological exams for MRONJ only after onset of jawbone exposure.(#6) Diagnosing MRONJ only on the basis of the clinical signs, without radiologic assessment.(#7) Prescribing high-resolution imaging for soft tissue (with contrast medium) for diagnosis of MRONJ.(#8) Planning MRONJ treatment without second-level imaging exams for assessing jawbone disease extension and severity.(#9) Monitoring the extension of the MRONJ process only by investigations of first-level exams .(#1) Evaluate clinically and radiologically any local risk factors for MRONJ  for preventive dental screening in patients, remarkably cancer ones, who are candidates for therapies at higher risk of MRONJ; sometimes, MRONJ could manifest like a dental/endo-periodontal disease, or a worsening of a pre-existent disease (updated) .(#2) Perform radiological exams in all cases of dental/endo-periodontal diseases in patients at risk of MRONJ (confirmed).(#3) Reserve the indication for the execution of radiological exams of the second level  to patients at MRONJ risk only in the presence of ascertained clinical or radiologic signs compatible with MRONJ (confirmed) ,9,22.(#4) Specify always the diagnostic hypothesis when prescribing radiological exams of any level  in patients at MRONJ risk (confirmed).(#5) Do not delay in prescribing radiologic exams to investigate any clinical signs of possible MRONJ, independent of the presence of bone exposure or fistulas (updated).(#6) Integrate always the clinical check-up with the appropriate imaging exams for the diagnosis of MRONJ (confirmed).(#7) Prescribe radiologic exams for bone diseases without contrast medium for diagnosis of MRONJ (confirmed).(#8) Set up the MRONJ treatment after defining its extension and severity also by targeted imaging (confirmed).(#9) Use targeted imaging  to monitor MRONJ during follow-up after conservative and/or surgical treatment (updated).Assuming that recently it has been confirmed that MRONJ prevention means applying the correct protocols of (1) primary prevention for both pre-treatment and in-treatment patients, and (2) secondary prevention  , the ConPrimary prevention for MRONJ mainly means elimination/reduction of the oral and dental risk factors ,27,28,29A new emerging and huge aspect is that primary prevention should be performed not only prior to taking the MRONJ-related drugs but also during and after the treatment with antiresorptive agents (AR), in order to eliminate any infective outbreaks of MRONJ. It is the responsibility of the dentist to accurately assess the risk factors leading to the development of MRONJ and suggest a strategy to remove these factors or minimize the risk. The dentist must also stress the importance of maintaining effective dental hygiene , including regular check-ups, for the patient. Both are necessary to maintain oral health, reducing the outbreak of MRONJ and/or detecting possible signs of the early symptoms of this disease.Secondary prevention or early diagnosis is the second pillar in the strategy against MRONJ, since we know that MRONJ diagnosed at an early stage is more likely to be treated successfully. With respect to the diagnostic work-up, the main problem is the possible under-diagnosing of MRONJ cases without bone exposure (or fistula). A recent multicenter study ,30 has d(#1) Keeping teeth with endodontic and/or periodontal diseases at uncertain prognosis only to avoid extractive and invasive procedures, in patients at risk of MRONJ.(#2) Extracting teeth in partial or total inclusion for pure preventive purposes in patients that are candidates for treatment with drugs at risk of inducing MRONJ.(#3) Scheduling in cancer patients the first dental check-up only after diagnosis of bone metastases.(#4) Omitting in osteometabolic patients dental check-ups for oral health status assessment and relative preventive dentistry actions.(#5) Omitting periodic dental check-ups for edentulous patients or wearing removable prostheses, if they are at risk of MRONJ.(#6) Underestimating the usefulness of the imaging performed to evaluate cancer disease extension  with respect to MRONJ early diagnosis (and follow-up).(#1) Extract teeth with endodontic and/or periodontal diseases, in patients at risk of MRONJ, when a conservative approach is not possible and a good tooth prognosis is not guaranteed (confirmed).(#2) Maintain teeth in partial or total inclusion, if no sign and/or symptom is present  (confirmed).(#3) Schedule in cancer patients the first dental check-up as soon as possible, preferably during the tumor staging process (confirmed).(#4) Consider in osteometabolic patients  a potential gradient in MRONJ risk  (updated(a) Administration and duration of treatment with MRONJ-related drugs ,6,37,38;(b) Eventual presence of comorbidities and further medical therapies indirectly associated; assess, during the prescription of the MRONJ-associated drugs, the oral health status even by a questionnaire   39]; sc; sc39]; (#5) Schedule preventive dental check-ups even in patients at risk of MRONJ even if edentulous or wearing removable dentures, in order to intercept and correct any injury on the oral mucosa (confirmed).(#6) Research any sign of jawbone alterations in cancer patients, revising the pictures of the imaging investigations  already performed to stage the cancer disease, in order to potentially detect eventual early signs of MRONJ, before prescribing further specific imaging (updated).Assume that the Consensus Conference has now adopted the new protocols for dental management in patients at risk of MRONJ, published in the recommendations on MRONJ by the two scientific societies SICMF/SIPMO , in whic(#1) Building an implant rehabilitation in cancer patients who have to take or are taking MRONJ-associated drugs due to advanced cancer disease.(#2) Considering as contraindicated, in an absolute sense, implant rehabilitation in osteometabolic patients taking MRONJ-associated drugs (including cancer patients treated with antiresorptive agents for CTIBL).(#3) Prescribing antibiotic prophylaxis before non-invasive dental therapies.(#4) Performing extractive procedures without removing, even if necessary, the alveolar bone, and plan the healing as a second intention .(#1) Avoid in cancer patients implant rehabilitation and plan non-surgical rehabilitation (confirmed).(#2) Plan implant rehabilitation in osteometabolic patients taking into account the cumulative dose of the drug already taken, the periodontal status, lifestyle , comorbidities and other drugs. Share with the patient a hypothetical medium to long-term MRONJ risk due to \u201cimplant presence-triggers\u201d (such as peri-implantitis and micro-cracks), beside the lower probable short-term risk due to \u201cimplant surgery-triggers\u201d ,41,42,43(#3) Recommend always, in patients at MRONJ risk, antibiotic prophylaxis when surgical procedures involving the dento-alveolar process or maxillary bones are planned  (confirmed).(#4) Practice extractive or surgical procedures planning the healing as the first intention with the clot maintenance (confirmed).Assuming that a drug holiday is a controversial issue, involving both drug prescribers  and oral and dental specialists, it is important to clarify that \u201cDrug holiday\u201d can have at least two meanings in the medical literature when referred to MRONJ. It can mainly mean (1) the temporary and preventative suspension of drug therapy  in a patient at risk of MRONJ, before the necessary dental procedures (tooth extraction or jawbone surgery); or (2) the suspension of drug therapy  due to a diagnosis of MRONJ, hypothetically finalized to stop or to slow the osteonecrosis process (a practice with scarce literature as support). This document will afford only the first meaning of a \u201cdrug holiday\u201d.It is well known that suspension of drug therapy can create different cost\u2013benefit balances, according also to the type of molecule in those two patient populations.In cancer patients with advanced disease , suspension of antiresorptive drugs has to be decided on the basis of a difficult balance between a possible positive drug effect  and a potentially higher risk of a side effect anyway present . Clearly that balance could individually change on the basis of the moment along the patient cancer history and along the drug administration history: hypothetically, in the first months of drug administration for bone metastases or myeloma, the suspension is potentially more harmful for the (lack of reduction of) risk of SRE but less dangerous for the risk of triggering MRONJ; vice versa after two years of antiresorptive administration, for example, the suspension appears less dangerous for the risk of SRE (anyway present) whereas the risk of MRONJ (being higher with longer time and higher cumulative drug dose) might receive maximum benefit from the suspension.(a) -BPs have a long half-life and are able to accumulate in the bone tissue, potentially influencing the post-extractive bone tissue repair. Furthermore, for some largely used BPs , a possible antiangiogenic effect was described in the literature, potentially reducing the soft tissue repair process. Consequently, a precautionary and temporary suspension of the drug administration has been claimed by most of authors as potentially useful, even if no definitive data have been published;-\u00ae), a monoclonal human anti-RANKL inhibitor, is a drug with a short half-life and does not accumulate in the bone. A possible rebound effect on the bone turnover has been described after drug withdrawal, so that some authors advised against a (long) suspension.Denosumab , receive antiresorptive drugs at lower doses and less frequently . The fracture risk can be determined objectively and correctly by applying the DeFRA79 algorithm validated by AIFA, the Italian version of the FRAX algorithm [(b) lgorithm .-BPs  are synthetic analogues of pyrophosphates, which firmly bind to the hydroxyapatite and reduce bone metabolism/remodeling . The hal-\u00ae), a monoclonal human IgG2 antibody that highly binds the receptor activator of nuclear factor-kB ligand (RANK-L), blocks the osteoclast maturation, function and survival. Its half-life is 25\u201332 days and it does not amass in the bone with a peculiar regimen (1 dose s.c. of 60 mg every six months) [Denosumab (Prolia months) ,47,48. T months) ,50. Of nOn the basis of the two different antiresorptive agents, they are classified as follows:\u00ae) without agreeing any temporary suspension with the prescriber (oncologist/hematologist).(#1) Performing dental extraction or oral surgery in patients with active cancer and myeloma bone disease and in therapy with i.v. high-dose bisphosphonates or denosumab (Xgeva(#2) Suspending indiscriminately therapy with antiresorptive drugs  prescribed for osteoporosis (or its prevention), in case of necessity of extraction or programmed oral surgery, without agreeing with the prescribing physician.\u00ae) before and after the dental procedure. This combined assessment is mandatory in the absence of univocal data on the efficacy of the suspension of bisphosphonates or denosumab to reduce the risk of \u201cpost-extraction\u201d MRONJ, and in consideration of conflicting data about the possible anti-angiogenic effect of zoledronic acid ((#1) Plan, in cancer patients, combined assessment by the prescriber  and by the dentist  to determine whether or not there is the need for a precautionary suspension of i.v. high-dose bisphosphonate or denosumab  (updated). There are two different conditions ((#2) Plan, in osteometabolic patients, a balanced and combined assessment by the prescriber  and by the dentist  to assess whether or not you need precautionary suspension of BPs or postponing the denosumab (Prolianditions .(a) Patient under BPs, a drug suspension may be already considered useful one week before surgical procedures. BP administration can resume once the biological process of healing of the oral tissues is completed (at least 4\u20136 weeks after surgery) ,14;\u00ae); it is still possible to take advantage of the pharmacokinetic of Prolia\u00ae in order to define a time interval in those postponable and non-critical dental/periodontal conditions requiring invasive treatment and can theoretically take place without restrictions. This \u201cdelayed dosing window\u201d lasts about 2 months, starts ideally 5 months after the last dose of Prolia\u00ae and ends at the beginning of the 7th month. If the surgical dental procedure is assessed as urgent and not procrastinable, it is recommended to apply the suspension scheme of denosumab previously described for cancer patients [(b) Patient under denosumab  with respect to therapeutic strategies ,14; it f(#1) Forgetting the adoption of an adequate perioperative antibiotic regimen in case of surgical treatment of MRONJ.(#2) Performing a diagnostic bone biopsy, unless bone metastases are suspected.(#3) Applying of first-level imaging  only to plan surgical treatment.(#4) Awaiting the exfoliation (self-sequestration) of necrotic exposed bone via the use of non-surgical therapies, since this process is unpredictable over time.(#5) Neglecting shaving and smoothing of the bone surfaces as a mainstay of any surgical procedure.(#6) Banishing the surgical option for MRONJ cancer patients based on general statements of residual life expectancy.(#7) Merging BP-related and non-BP-related (anti-RankL and/or targeted therapies) MRONJ patients as a whole when considering temporary interruption of medications for surgical treatment.(#8) Adopting surgical treatment of MRONJ in symptomatic cases only.(#9) Relaying on systemic bone turnover markers to predict the success of surgical therapies in MRONJ patients.(#1) Prescribe a broad-spectrum antibiotic regimen as an integral part of surgical treatment: high-dose amoxicillin/clavulanic acid (1000 mg TID), plus high-dose Metronidazole (500 mg TID), from the day before surgery and up to the 10th post-operative day. Alternatives should be used in case of reported allergy to penicillin (confirmed).(#2) Perform a diagnostic bone biopsy in case of clinical and radiological suspicion of bone metastases to the jaw or myeloma area, in order to distinguish them from site of MRONJ disease, when clinically needed (confirmed).(#3) Use second-level imaging tools, mainly computed tomography (CT), to appropriately plan the extent of jawbone disease before surgery (confirmed).(#4) Anticipate surgical treatment, whenever indicated, to reduce the surgical burden for MRONJ patients and increase the likelihood of long-term healing (confirmed).(#5) Always perform the shaving and smoothing of bone surfaces as a mainstay of any surgical procedure to prevent further bone exposure (confirmed).(#6) Plan the surgical treatment of MRONJ on an individual basis, weighing the impact and the potential benefit of surgery on the general health status of patients (confirmed).(#7) Discuss and plan the temporary interruption of any given medication in agreement with the prescriber and based on its pharmacological properties, before initiating every MRONJ surgical treatment (confirmed).(#8) Adopt the early surgical treatment also in MRONJ asymptomatic patients (confirmed).(#9) Do not rely on systemic bone turnover markers to establish individual treatment algorithms for MRONJ, but carefully examine all potential factors that are likely to influence the long-term success of therapies, including the underlying disease (cancer or non-cancer) and the type of medication used (confirmed).MRONJ is a potentially severe complication of antiresorptive and/or antiangiogenic treatment in patients with skeletal events due to various cancers as well as osteometabolic diseases; MRONJ may lead to a reduced quality of life due to jawbone infections, chronic pain, tooth loss and compromised function. Although notable progress has been made, there remain a number of controversial aspects on MRONJ, especially regarding pathogenesis, diagnosis and treatment.The present paper updated conclusions from the Consensus Conference at the Symposium of Italian Society of Oral Pathology and Medicine (SIPMO) , after the newest recommendations on MRONJ were published in 2020 by two scientific societies , written on the inputs of the experts of Italian Allied Committee on ONJ (IAC-ONJ). Some recommendations were confirmed.We defined six issues of MRONJ and submitted for every issue the current knowledge and the appropriate best practices, in order to improve the management of patients.We highlighted the importance to disclose the appropriate information about MRONJ, and the statements and recommendations presented in this paper might represent a beneficial instrument both at a national and international level to better understand and manage this singular and severe disease.In the absence of clear knowledge on the etiology and given the continuous spread of the application of new target therapies, it will be fundamental to continue the research, to report any cases using new drugs and to clarify by evidence-based medicine all the controversial aspects of MRONJ."}
+{"text": "Radiotherapy is an important therapeutic approach to treating malignant tumors of different localization, including brain cancer. Glioblastoma multiforme (GBM) represents the most aggressive brain tumor, which develops relapsed disease during the 1st year after the surgical removal of the primary node, in spite of active adjuvant radiochemotherapy. More and more evidence suggests that the treatment's success might be determined by the balance of expected antitumor effects of the treatment and its non-targeted side effects on the surrounding brain tissue. Radiation-induced damage of the GBM microenvironment might create tumor-susceptible niche facilitating proliferation and invasion of the residual glioma cells and the disease relapse. Understanding of molecular mechanisms of radiation-induced changes in brain ECM might help to reconsider and improve conventional anti-glioblastoma radiotherapy, taking into account the balance between its antitumor and ECM-destructing activities. Although little is currently known about the radiation-induced changes in brain ECM, this review summarizes current knowledge about irradiation effects onto the main components of brain ECM such as proteoglycans, glycosaminoglycans, glycoproteins, and the enzymes responsible for their modification and degradation. Adjuvant chemoradiotherapy with temozolomide is a conventional protocol for the standard treatment for newly diagnosed glioblastoma multiforme (GBM) . Last deRadiotherapy (RT) represents an essential part of this post-surgery GBM treatment, and the current standard usually includes 30 X-ray fractions \u00d7 2 Gy, although multiple non-conventional RT sources and regimens are under active investigation .RT aims to destroy the residual GBM cells at the resection border and prevent the disease relapse, but it has wide biological effects on different molecular and physiological parameters in the irradiated brain tissue as well . NegativAlong with that, RT-induced lymphodepletion and subsequent suppression of immune response contribute to the insufficient efficiency of conventional RT and may be limiting the success of GBM treatment . Also, iAt present, more and more evidence is accumulating showing that TME is actively involved in the molecular fate of GBM tumor-initiating cells and tumor development, and significantly modifies the epigenetic landscape of GBM cells with unknown mechanism . IrradiaThe presented data demonstrate that different components of the GBM TME  actively respond to X-ray irradiation, whereas the contribution of extracellular matrix (ECM) to radiation-induced changes in both GBM tumor and normal brain tissue remain much less investigated. The available information on this issue is very scanty and fragmentary, but it may be useful to summarize it in order to outline possible directions for future research in this scientific field.Here, the effects of experimental and clinical irradiation onto key brain ECM components  in normal brain tissue and GBM cells/tumors will be reviewed.Proteoglycans (PGs) are the main components of brain ECM and play important roles in normal brain physiology and gliomagenesis . They reA major component of the brain ECM is chondroitin sulfate proteoglycans (CSPGs), which are actively involved in the organization of GBM TME and glioma invasion . The comThe few available data on radiation effects on CSPGs are quite controversial, although expression of CSPG-coding genes has a tendency to be down-regulated in non-tumor tissues and up-regulated in glioma cells or tissues upon X-ray irradiation . Cranial125I) seed results in an increase of NG2 content in the brain tissue. The U251 cells with activated NG2 expression (U251\u2013NG2) were significantly more resistant to 5 Gy irradiation compared to the NG2-negative U251 cells suggesting NG2 as an important prognostic factor for radiotherapy resistance  activates the expression of CD44 in these cells  is an integral component of any tissue, but it plays a particularly important role in the brain, where it represents a major component of intercellular space .Irradiation effects onto HA remain to be almost uninvestigated. The only study by Yoo et al. demonstrates that irradiation of GBM U87MG cells (2 Gy/day for 3 days) or U87MG orthotopic brain tumors (2.5 Gy/day for 3 days) results in a significant increase of HA content in GBM cell-conditioned medium and experimental tumors, respectively. The increase of HA content in tumor tissue affects the biomechanical tension in the GBM microenvironment and provides pro-invasive extracellular signaling cue due to binding with CD44 receptor and SRC activation sufficient for a mesenchymal shift of GBM cells. These findings suggest an explanation for the frequent brain tumor relapse after radiotherapy .Heparan sulfate proteoglycans (HSPGs) represent one of the main components of the neurogenic niche. Tight involvement of both the polysaccharide heparan sulfate (HS) chains and their degrading enzyme heparanase in the development of the nervous system and growth and invasion of glioma tumors are comprehensively described by Xiong et al. , 45. AmoThere is just fragmentary information on the irradiation effects onto these macromolecules.Experimental irradiation of normal mouse brain (7 Gy in a single dose) did not change expression levels of syndecan-1, glypican-1, and perlecan in short-term period (24\u201372 h) . HoweverDespite the common extracellular glycoproteins  not being much abundant in brain tissue, they are intrinsic components of brain ECM. Radiation-induced changes in their expression contribute to pathological brain ECM reorganization during radiotherapy.Whole-brain irradiation of experimental animals (a single dose of 10 Gy for rats or 8 fractions \u00d7 5 Gy for 4 weeks for mice) decreases collagen IV content in brain tissue by 24 h after irradiation, while no significant changes are shown at 4 or 8 h after irradiation. Simultaneous up-regulation of expression and enzymatic activity of MMP2 and MMP9 seems to be a molecular mechanism for irradiation-induces ECM degradation .Long-term effects (6 months) of irradiation of the whole brain of Rhesus macaques (age 6\u201311 years), which had received 40 Gy , increased expression of fibronectin 1 (FN1) in brain tissue at mRNA level  and protIrradiation of U87 GBM cells (2 Gy/day for 3 days) does not affect the expression of collagen type-I alpha 1 (COL1A1) and collagen type III alpha 1 (COL3A1) .Brain ECM structure is tightly determined by a complex interplay between the expression of ECM glycoproteins/PGs/GAGs and their proteolytic remodeling by matrix metalloproteinases (MMPs) and GAG-degrading enzymes , 48. RadX-ray irradiation of animal brain results in a quick (4\u201324 h) up-regulation of expression and enzymatic activity of MMPs: MMP2 and MMP9  and MMP2  . IrradiaIrradiation of U87MG GBM cells at 2\u20136 Gy doses increases expression and enzymatic activity of MMP2 in these cells and experimental orthotopic U87 tumors obtained from them . This reHeparanase (HPSE) is the main enzyme responsible for the degradation of polysaccharide chains of HS at the cell surface and ECM of all tissues. It involved in normal physiology and pathological reorganization of ECM into TME and cancer progression and metastasis , 45, 49.Gamma-irradiation of brain microvessel endothelial cells results in a significant increase in the release of heparanase, which degrades [35S]-labeled heparan sulfate from the subendothelial matrix. This was most pronounced at the 24 h after irradiation and can affect the interactions of tumor cells with endothelial cells and their microenvironment, which in turn facilitate the formation of metastasis in irradiated tissues . The relAccording to the presented data, X-ray radiation affects all key components of normal brain ECM  in different extent and directions .An interesting observation is that radiation has a much pronounced effect on normal brain tissue than on tumor cells. There is a common tendency to the increased expression of glycoproteins (collagen and fibronectin) and decreased expression of main proteoglycan components of brain ECM  indicating significant changes of normal structure of brain ECM . ReplaceOn the other side, GBM cells and tumors demonstrate more resistant phenotype to X-ray irradiation and completely different pattern of radiation-induced changes. Only three of fifteen ECM components  respond to irradiation by activation of their expression/content . The cooThese radiation-induced changes in brain ECM and the residual GBM cells cooperate to provide a favorable microenvironment for GBM progression. Moreover, multiple studies show that radiotherapy not only serves as a therapeutic mean to eliminate glioma cells but also activates proliferation and invasion of those cells which survived irradiation. This seems to occur due to the selection of radioresistant GBM clones and their active invasion in previously irradiated GBM tumor microenvironment .in vivo, possibly through the imbalance between MMP2 and TIMP2 and ECM degradation (Molecular mechanisms of negative side effects of irradiation are tightly related to GBM TME: subcurative irradiation of primary human GBM tumors in rat brain results in the increased proliferation (3-fold), migration, and invasion of the survived GBM cells associated with increased expression of CD44 and activation of MMP2 expression ; irradiaradation . Besidesradation .Radiation induces also significant changes in immune components of brain microenvironment, which contributes to poor efficacy of anti-GBM radiochemotherapy. Irradiation results in activation of the expression of immune-associated genes  in murine glioma and human glioma U87 cell line, leading to changes in immune microenvironment, glioma cells radioresistance, and treatment failure . Cranialin vivo, where the initial positive effect on inhibition of GBM tumor growth by 14 day is followed by the tumor relapse and higher mortality for the mice with a smaller tumor volume by 21 day (Thus, GBM radiotherapy possesses a double effect\u2014it directly affects brain ECM and induces GBM cells to modulate their microenvironment. The balance between these modalities might be responsible for the ambiguous functional effect y 21 day . OverallEG conceived the study, drafted, and edited the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Accidents, as the third important cause of mortality, are among main challenges of communities due their costs and irreversible damages. This study aimed to investigate the age distribution of people referred to the hospitals affiliated by Iran\u2019s ministry of health because of accidents.In a cross-sectional study, using a CDC checklist, data related to the injured people who referred to the hospitals affiliated by Iran\u2019s ministry of health in a one year period was gathered from hospital records, as well as interview and observation. The collected data was analyzed by descriptive and analytical statistics in SPSS11 software.The commonest age group involved in accidents during the year 1395 (2016) was middle-aged (37%) followed by youth (25%). The commonest accidents in children were: fall (23%), traffic accidents (19%), and burn (13%). In adolescents, the commonest accidents were: traffic accidents (32%), fall (16%), and violence and poisoning (5%). The commonest accidents in youth were: traffic accidents (35%), violence (9%), and poisoning (6%). In middle-aged group, the commonest accidents were: traffic accidents (30%), fall (12%), and violence and poisoning (7%). The commonest accidents in elderly were: fall and traffic accidents (25%), burn (4%), and violence and poisoning (3%).Making plan and policies to prevent accidents and injuries is a health priority and a key tool for improving the safety of the community. Also, informing the all age groups of the community about preventive actions is necessary.Road Traffic Injury, Trauma, Hospital"}
+{"text": "How have US clinicians planned for and responded to resource limitation during the coronavirus disease 2019 pandemic?This qualitative study included interviews with 61 clinicians across the United States. While institutions planned for an explicit and systematic approach to resource allocation in crisis settings, this approach did not address many challenges encountered by frontline clinicians, leaving them to struggle with what constituted acceptable standards of care and to make difficult allocation decisions.The findings of this study suggest that expanding the scope of institutional planning to address a broader spectrum of resource limitation may help to support clinicians, promote equity, and optimize care during the pandemic. This qualitative study describes the perspectives and experiences of clinicians involved in institutional planning for resource limitation and/or patient care during the coronavirus disease 2019 (COVID-19) pandemic. Little is known about how US clinicians have responded to resource limitation during the coronavirus disease 2019 (COVID-19) pandemic.To describe the perspectives and experiences of clinicians involved in institutional planning for resource limitation and/or patient care during the pandemic.This qualitative study used inductive thematic analysis of semistructured interviews conducted in April and May 2020 with a national group of clinicians  involved in institutional planning and/or clinical care during the COVID-19 pandemic across the United States.Emergent themes describing clinicians\u2019 experience providing care in settings of resource limitation.The 61 participants  included in this study were practicing in 15 US states and were more heavily sampled from areas with the highest rates of COVID-19 infection at the time of interviews . Most participants were White individuals (39 [65%]), were attending physicians (45 [75%]), and were practicing in large academic centers . Three overlapping and interrelated themes emerged from qualitative analysis, as follows: (1) planning for crisis capacity, (2) adapting to resource limitation, and (3) multiple unprecedented barriers to care delivery. Clinician leaders worked within their institutions to plan a systematic approach for fair allocation of limited resources in crisis settings so that frontline clinicians would not have to make rationing decisions at the bedside. However, even before a declaration of crisis capacity, clinicians encountered varied and sometimes unanticipated forms of resource limitation that could compromise care, require that they make difficult allocation decisions, and contribute to moral distress. Furthermore, unprecedented challenges to caring for patients during the pandemic, including the need to limit in-person interactions, the rapid pace of change, and the dearth of scientific evidence, added to the challenges of caring for patients and communicating with families.The findings of this qualitative study highlighted the complexity of providing high-quality care for patients during the COVID-19 pandemic. Expanding the scope of institutional planning to address resource limitation challenges that can arise long before declarations of crisis capacity may help to support frontline clinicians, promote equity, and optimize care as the pandemic evolves. Early reports from frontline clinicians in global epicenters describing extreme shortages and bedside rationing of ventilators and intensive care unit (ICU) beds2 prompted a national conversation about how to respond to similar challenges in the United States.3 Hospitals and health care systems drew on frameworks developed by the Institute of Medicine (IOM) and other national organizations to guide care in resource-limited emergency settings.7Since the first US case of coronavirus disease 2019 (COVID-19) was diagnosed in mid-January 2020,8 Under crisis standards of care, a specialized triage team becomes responsible for rationing scarce resources and making decisions about which patients will and will not receive potentially life-saving treatments.Under the IOM\u2019s framework, resource allocation is intentionally siloed from other aspects of clinical care to ensure a fair process and spare frontline clinicians from the responsibility of having to ration scarce resources at the bedside. The IOM recommends a phased adaptation to resource limitation. Institutions first shift from conventional to contingency capacity, in which resources are adapted, optimized, and redistributed to maintain a standard of care that is functionally equivalent to usual care. If resources become so limited that a functionally equivalent standard of care can no longer be sustained, institutions then shift to crisis capacity, and care is redirected to provide the greatest aggregate benefit to the population.10 and has been iteratively refined through ethical analysis8 and community deliberation,12 there have been few opportunities to test the framework in real-world clinical settings. Reports from past pandemics14 and from early global epicenters of the COVID-19 pandemic,15 press reports,17 and perspectives published in the scientific literature19 describe some of the challenges faced by frontline clinicians. However, there is little empirical work describing the experiences and perspectives of US clinicians pertaining to resource limitation and clinical care during the COVID-19 pandemic.21 To address this knowledge gap, we conducted a qualitative analysis of interviews with US clinicians during the pandemic.Although the IOM framework reflects lessons learned during earlier pandemicsCOREQ) reporting guideline  at our own institution (the University of Washington). We then expanded recruitment to include other groups of clinicians  and those practicing in other parts of the country. We used a snowballing recruitment strategy in which we asked participants to identify colleagues with relevant experience who might be interested in participating in the study. We did not exclude participants who had collegiate relationships with members of the research team. Interviews were conducted between April 9, 2020, and May 26, 2020. The University of Washington institutional review board approved this study and authorized verbal in lieu of written consent. Verbal consent was obtained from all participants. We report details of our methods using the Consolidated Criteria for Reporting Qualitative Research . All but 1 interview, which included 2 participants at their request, were conducted 1-on-1, and 2 interviews were spread over 2 sittings. A semistructured interview guide  independently reviewed and openly coded transcripts until reaching thematic saturation ,25 which occurred after reviewing 30 interview transcripts. One of us (C.R.B.) coded all remaining transcripts for concurrence. Throughout the analysis, the 2 investigators iteratively reviewed codes, collapsed codes into groups with related meanings and relationships, and developed larger thematic categories, returning frequently to the transcripts to ensure that emergent themes were well-grounded in the data.25 All coauthors  reviewed example quotations and themes and together developed the final thematic schema. We used Atlas.ti version 8 (Scientific Software Development GmbH) to organize and store text and codes.We conducted an inductive thematic analysis26 All but 1 participant completed the online survey. The mean (SD) age of participants was 46 (11) years, and most were White (39 [65%]), were attending physicians (45 [75%]), and were practicing in large academic hospitals . Participants were practicing in 15 states across the United States and had primary affiliations with 29 different hospitals or clinics, with greater sampling of clinicians practicing in states with the highest rates of COVID-19 infection at the time of the study .We approached a total of 97 clinicians by email, of whom 75 (77%) agreed to participate and 22 (23%) declined or did not respond to our inquiry. Among those who agreed to participate, we purposively sampled 61 clinicians to participate in interviews from April 9, 2020, to May 26, 2020 .26 All bThree overlapping and interrelated themes pertaining to resource limitation and clinical care during the COVID-19 pandemic emerged from qualitative analysis, as follows: (1) planning for crisis capacity, (2) adapting to resource limitation, and (3) multiple unprecedented barriers to care delivery. Exemplar quotations are referenced in parenthesis and listed in Institutional leaders who participated in planning for crisis capacity described the challenges of adapting and operationalizing existing guidelines as well as the substantial moral weight of the task. They were relieved when it became clear that these processes would likely not be needed at their institutions .Clinicians who were involved in institutional planning described strong institutional support for their work to develop protocols to guide care should their region reach crisis capacity (quotation 1). They believed that establishing protocols in advance would allow for a more carefully considered approach (quotation 2) and would be reassuring to staff (quotation 3).Their work involved developing actionable triage algorithms based on existing frameworks (quotation 4). Group deliberation focused on both big picture ethical questions (quotation 5) as well as more granular operational details (quotation 6). Several clinicians with whom we spoke were not formally involved in institutional planning efforts but had offered input and/or developed their own protocols when they identified gaps in planning or disagreed with institutional policies (quotations 7 and 8).To support fairness and avoid bias, the plan was for triage team members to receive very limited information about individual patients when making selection decisions (quotation 9). Some clinicians involved in planning were skeptical about the feasibility of making triage decisions in the absence of detailed clinical information (quotation 10). Others expressed uncertainty about whether and how triage protocols would address more ambiguous or dynamic types of resource limitation  (quotation 11). Clinicians could also be mindful of how their work might be viewed by other clinicians and the public (quotation 12) and were wary of sharing details about committee deliberations (quotation 13), plans (quotation 14), or team membership (quotation 15) with their colleagues and/or during the research interview.Clinicians who had been appointed to triage teams were usually respected leaders in intensive care, palliative care, or bioethics who were recognized for their ability to collaborate and communicate (quotation 16). Some of the intensivists and ethicists with whom we spoke saw the work of the triage team as an extension of their usual work (quotations 17 and 18), but many clinicians saw this experience as entirely new (quotation 19). Clinicians described being motivated to participate in the triage team out of a sense of duty and desire to contribute (quotation 20) but were also cognizant of the moral weight and emotional burden of the task before them (quotation 21).Clinicians involved in triage planning understood the processes they were developing to be intended exclusively for crisis settings (quotations 22 and 23) and saw the importance of optimizing resources under contingency capacity to avoid having to resort to crisis standards of care (quotation 24). While several clinicians described a period of intense planning early in the pandemic, by the time of our interviews, many were relieved to report that crisis standards of care were unlikely to be invoked at their institutions, and some had paused or disengaged from triage planning (quotations 25 and 26).Clinicians working during the pandemic were forced to grapple with multiple expected and unexpected forms of resource limitation that did not rise to the level of triggering crisis capacity. Nevertheless, these limitations could compromise care, require that they make difficult allocation decisions, and engender moral distress .Although none of the clinicians with whom we spoke reported a shift to crisis capacity at their institutions, they nevertheless described being faced with a range of expected and unexpected forms of resource limitation  (quotation 27) that could arise in a haphazard manner with little warning (quotation 28). Some expressed frustration that resource shortages they were seeing in practice were not acknowledged as such by hospital or regional leadership (quotations 29 and 30) or felt unsupported by colleagues at neighboring medical centers (quotation 31). When not available from their institutions, some clinicians resorted to obtaining health care equipment through personal contacts or even fabricated it themselves (quotations 32 and 33).Clinicians were strongly motivated to avoid situations in which they would have to categorically deny needed treatment to any patient (quotation 34) and went to great lengths to develop alternative treatment options (quotation 35). This might involve using unorthodox therapies or nontraditional approaches to care delivery that could be suboptimal or potentially harmful (quotations 36 and 37). For example, some nephrologists described triaging patients for hemodialysis based on immediate need (quotations 38 and 39), delaying dialysis until there was an emergent indication (quotation 40), and/or prescribing shorter treatment times. As 1 clinician explained, \u201ceveryone gets a little bit of bad care\u201d (quotation 41). Rarely, clinicians were able to draw a clear line between acceptable and unacceptable care (quotation 42), but most focused on doing the best they could under the circumstances (quotation 43).The notion of rationing generally had negative connotations (quotation 44), and some clinicians even described erring on the side of providing more intensive interventions to avoid the appearance of rationing (quotation 45). With rare exceptions (quotation 46), clinicians did not explicitly speak of having had to ration health care resources (quotation 47). Nonetheless, some clinicians did describe situations in which they had to make difficult choices about which patients would and would not receive life-saving therapies, typically on the basis of age and/or comorbidity. This was often seen as part of the spectrum of normal clinical decision-making (quotations 48 and 49) and within their scope of practice (quotation 50). Some clinicians did describe struggling to understand what constituted acceptable practice vs rationing (quotations 51 and 52) and expressed misgivings about the approach to selecting patients for life-saving treatments during the pandemic (quotations 53 and 54).Many clinicians were fearful of having to ration resources (quotation 55). Even in lower acuity and outpatient settings, some struggled with whether it was acceptable to provide suboptimal care (quotation 56) and worried about the potential harms of disrupted care practices (quotation 57). A sense of responsibility for poor outcomes could take a substantial emotional toll (quotation 58). Some clinicians felt that explicit guidelines would be helpful in limiting this moral distress (quotation 59), while others felt personally responsible for poor outcomes regardless of whether they were adhering to institutional recommendations or requirements (quotation 60).Clinicians described multiple barriers to care delivery during the pandemic. These challenges compounded and were difficult to disentangle from the effects of resource limitation .Policies and practices were modified to limit physical interaction between staff, patients, and family members with the dual goals of reducing viral spread and conserving personal protective equipment. While necessary, policies to limit contact with patients were seen as being detrimental to care and to the experiences of both patients and clinicians (quotations 61 and 62). Decisions about something as routine as whether to perform a physical examination could expose tensions around the conflicting goals of conserving scarce resources, protecting oneself, and caring for patients (quotations 63 and 64). Visitor restrictions could complicate and disrupt the process of engaging family members in decision-making (quotations 65 and 66).The rapid pace of change and limited scientific understanding of COVID-19 (quotations 67 and 68) led to substantial uncertainty in day-to-day practice. A sense of desperation and a desire to do everything possible to save lives might lead to more aggressive treatment practices and/or greater willingness to try unproven therapies (quotation 69), reluctance to engage palliative care specialists (quotation 70), and delays in end-of-life decision-making (quotation 71).Many clinicians commented that families and patients were often quite understanding of care disruption (quotation 72), and that they were surprised at how accepting some families could be when care was compromised by the need to conserve resources and/or protect clinicians (quotations 73 and 74). However, some clinicians did describe contentious interactions with family members (quotation 75) and patients (quotation 76) who felt that care was being inappropriately withheld. Other clinicians described deliberately avoiding mention of resource limitation when talking with families (quotation 77).30 the clinicians we interviewed described how, even in the absence of formal declarations of crisis capacity, a variety of expected and unexpected forms of resource limitations severely compromised care and required that they make difficult allocation decisions at the bedside.Our thematic analysis of interviews with US clinicians who were directly involved in patient care and/or strategic planning during the COVID-19 pandemic highlights the real-world complexity of adaptation to resource limitation. Clinicians described patterns of institutional planning that mirrored the IOM\u2019s phased approach, which assumes a common understanding about what constitutes usual standards of care with a plan for a coordinated regional response when these become untenable. However, consistent with prior anecdotal reports,31 and may not be supported by societal priorities for fairness in resource allocation.35Clinicians and clinical teams went to great lengths to develop alternative treatment options and to stretch existing resources to provide at least some care to all in need and avoid having to categorically deny treatment to any patient. However, this approach could mean providing care that fell far short of the IOM standard of functional equivalence to usual care. When substituting lower-quality or delayed treatments, clinicians and clinical teams were left to grapple with what constituted an acceptable standard of care, which could be a source of self-doubt and moral distress. While most clinicians did not feel that they had been in the position of having to ration scarce resources, some nevertheless described practices, such as selection by age or comorbidity, that may be subject to implicit biases7 represent an important step toward promoting fairness through transparent allocation processes.36 However, our results suggest that a narrow focus on crisis capacity may fail to address the full spectrum and complexity of challenges to providing high-quality care encountered by frontline clinicians during the COVID-19 pandemic .In this qualitative study, many clinicians described institutional planning for crisis capacity, but this did not always address real-world challenges to providing care when resources were limited. Expanding the scope of institutional planning beyond crisis capacity may be helpful in supporting clinicians and addressing moral distress, promoting equity, and optimizing care as the pandemic evolves."}
+{"text": "Shortening of the hospital stay in patients admitted with the diagnosis of acute myocardial infarction (AMI) has been observed within the last decades. Our center is the only cardiac center in the region providing tertiary care facility and hence receives all AMI patients deemed suitable for invasive assessment and management and this leads to huge required demand. Our aim is to assess feasibility and safety of the early discharge of selected proportion of AMI patients.P = 0.04) and treated more with primary percutaneous coronary intervention (PPCI) (P = 0.04). They had favorable coronary anatomy , better hospital course, and higher left ventricular ejection fraction compared to non-early discharged patients . Follow-up of those early discharged patients were promising as majority of them were asymptomatic (95%) and did well post-discharge.Out of 557 of patients presented with AMI and treated with percutaneous coronary intervention (PCI), 310 (56%) were discharged early. Men patients and pilgrims were more prevalent among the early discharge group. Early discharged patients had significantly less comorbidities compared to the other group of patients. Moreover, they presented mainly with ST-elevation myocardial infarction (Our study demonstrated data that support safety of early discharge in a carefully selected group of AMI patients. Early but safe discharge may have a huge impact on increasing bed availability, reducing hospital costs, and improving patient\u2019s satisfaction. Shortening of the hospital stay in patients admitted with the diagnosis of acute myocardial infarction (AMI) has been observed within the last decades \u20133.The current Guidelines of European Society of Cardiology for the management of acute myocardial infarction with ST-segment elevation, released in 2018, state that the selected patients may be considered (class of recommendation IIb) for early discharge (after approximately 72\u2009h), if adequate follow-up is arranged . This isHajj is a great event and it is one of the five Islamic pillars. Millions of pilgrims from different countries of the world come to the Kingdom of Saudi Arabia for performing hajj. The overcrowding, hot climate, and huge physical stress expose the pilgrims to many health hazards. Cardiovascular disease has recently emerged as the leading cause of death during hajj , 11. ThiOur tertiary center is the only cardiac center in the region providing tertiary care facility including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) and hence receives all AMI patients deemed suitable for invasive assessment and management and this leads to huge demand on cardiac services over the few weeks of hajj time. Reduced hospital stay has been proved to reduce the hospital burden and costs \u201315.The aim of our study is to assess feasibility and safety of the early discharge of selected proportion of AMI patients. This facilitates establishment and implementation of the successful and safe early discharge program to enhance bed\u2019s efficiency, improve occupancy rate and serve more patients during hajj crowdedness.This is a prospective, single-center study reviewing the clinical details of all AMI referred to our center for early revascularization and discharged during the two hajj seasons 2018 and 2019. It is designed to be a part of the standards of patient\u2019s care, to investigate and improve quality of AMI management and outcomes among a diverse population; general and cath consents were taken and has received approval of the ethics committee/institutional review board of our institution.As mentioned earlier, our center is the only cardiac center in Makkah with cath lab facilities, which provides invasive management of AMI, and we envisage capturing almost all AMI patients suitable for invasive management. Every year, our center receives about 1000 AMI patients; a quarter of them were admitted during the hot season in Makkah (2\u20133\u2009weeks of hajj). Our study population included residence and hajj patients . They were referred either from other primary, secondary, and Al-Mashaer hospitals or presented directly through our emergency department, and underwent coronary angiogram and PCI with drug eluting stents.All patients admitted with established diagnosis of AMI  during the few weeks of hajj seasons 2018 and 2019.Patients presenting with AMI where coronary angiography was not done because of preference of the patient or due to any other reason and AMI patients admitted outside hajj seasons were not included as well.Demographics. Age, gender, and status (residence/hajj)Risk factors. Diabetes (DM), hypertension (HTN), smoking, dyslipidemia, presence of chronic kidney disease, old cerebrovascular accidents (CVA), chronic obstructive lung disease (COPD), ischemic heart disease (IHD), and previous PCI/CABGClinical data. Type of AMI are as follows:ST-elevation myocardial infarction (STEMI) treated either with PPCI or with non-PPCIIHistory of pulmonary edemaIILeft ventricular ejection fraction (LVEF) in echocardiographyNon-ST-elevation myocardial infarction (NSTEMI) with high-risk features , which necessitate early revasculrizationCoronary procedure description and angiography findings. Access site , presence of left main disease (LM), single vessel disease (SVD), two or three vessel coronary artery disease (CAD), infarct-related artery (IAR), thrombus aspiration, and use of tirofiban/AggrastatThe following data for each patient were collected:AMI treated with successful PCI (TIMI flow III in infarct-related artery)Age \u2264 75\u2009yearsHemodynamic and rhythmic stabilityAbsence of comorbidities, which require continuation of hospitalizationAbsence of contraindication of dual anti-platelet treatmentSupposed cooperation, compliance, and adherence to medical treatment particularly DAPT Early discharge (24\u201372\u2009h) was planned for selected patients who were fulfilled those criteria:Alive/death with dateRecurrent symptoms of ischemiaAny bleedingRecurrent hospital admissionFollow-up of early discharged patients with telephone communications within 15\u2009days after discharge to check the safety of this strategy with collection of the following data:t test. Categorical data were given as a percentage and compared with a Chi-square test. A P value <\u20090.05 was considered statistically significant.Statistical analysis was performed by the use of the SPSS software package ; version 21.0. Continuous data were expressed as mean \u00b1 SD and compared using the Student Out of 1972 AMI consecutive patients, five hundred fifty seven were treated with PCI during their admission in our center within the two hajj seasons (2\u20133\u2009weeks of hajj) of the 2 consecutive years 2018 and 2019, respectively. Patients were distributed in to two groups: group I, 310 (56%) who were fulfilled the given early discharge criteria and discharged, and group II, 247 (44%) who were discharged late (after 72\u2009h). From the whole discharged AMI patients in the study period, 89 (16%) were discharged within 24\u2009h and 221 (40%) were discharged within 48\u201372\u2009h from admission. One hundred twenty patients (39%) were early discharged in the hajj season 2018 while 190 (61%) were early discharged in the hajj season 2019 . They also showed less prevalence of DM (161 (52%) vs 148 (60%)), HTN (181 (58%) vs 158 (64%)), history of ischemic heart disease (55 (17%) vs 53 (21%)), and previous coronary revasculrization (27 (9%) vs 34 (14%)) compared to group II patients  and 212 (68%) vs 87 (35%) and 146 (59%); P = 0.04). The early discharged patients had better hospital outcomes compared to the other group as they showed less prevalence of post myocardial infarction pulmonary edema (5 (2%) vs 15 (6%); P = 0.006) and higher LVEF . Otherwise, regarding the other treatment modalities, there were no detected significant differences between the two groups for the use of thrombolytic therapy and/or tirofiban post AMI treated with PCI.As shown in Table P = 0.003). Also, patients of group I with early discharge had favorable coronary artery disease anatomy as they showed less prevalence of both left main and three vessel disease in their coronary angiography compared to those of group II (7 (2%)and 55 (17%) vs 17 (7%) and 65 (26%); P = 0.01 and 0.02, respectively)  vs 171 (69%); Among 310 early discharged patients, only 187 (60%) could be contacted by phone (with help of many translators of different languages) for follow-up within 15\u2009days from the discharge date. They were questioned and found that 177 (95%) patients were totally asymptomatic, 6 (3%) had nonspecific chest pain which did not require any hospitalization, 2 (1%) had minor bleeding (epistaxis resolved spontaneously), and 2 (1%) re-admitted with heart failure symptoms. Those two patients re-admitted with heart failure had been found to have low ejection fractions with ischemic mild to moderate mitral regurge in their pre-discharge echocardiography and their follow-up echocardiography showed the same findings; however, they had mild chest infection, which predisposed to aggravation of heart failure  vs 6 (2%), respectively) Fig. . No recoThe overview of most of literature investigating the issue of safety and feasibility of early discharge in AMI patients shows variable methodology and this explains that guidelines for early discharge are based just on limited data derived from randomized trials. The issue of early discharge was investigated in PRAGUE 5 study, which after pilot phase randomized 56 low-risk probands with STEMI, discharged even the next day after successful PCI. It was the first study in which mean length of hospital stay was shorter than 72\u2009h . Most ofIt has been proven that substantial reduction in-hospital length of stay has been associated with reduction of in-hospital charge  with no Our center is the only cardiac center in the region providing tertiary care facilities and receives a huge number of AMI patients especially during the 2 to 3\u2009weeks of hajj seasons, subsequently this puts a big burden for the required provided service and hospital costs. The primary aim of our study is to create and implement successful safe early discharge program to improve bed\u2019s utilization efficiency and provide the best, safe, and maximum service for cardiac patients during over crowdedness of the hajj season. To the best of our knowledge, there are no similar studies conducted in our region concerned with this idea. We selected few weeks of each hajj season to conduct this study for many reasons: First, as previously mentioned, our cardiac center is the only center in the region of Makkah that has cath lab facilities and this required to provide tremendous tertiary care services to pilgrims and residents of Makkah during hajj season. Therefore, appropriate improvement of bed utilization is crucial with subsequent increase of hajj population in the successive years. Second, during this selected period, most of our AMI patients were pilgrims who had special ritual, religious emotions, and soul as most of them were doing their hajj for the first time having beliefs that longer hospital stay might reduce the opportunity to complete the hajj for which they were coming and persistently asking all the time for discharge. We believe that appropriate early post AMI discharge might grant their wishes provided it is totally safe. Third, during this short 2\u2009weeks of hajj season additional two millions of population increase within Makkah city from pilgrimage and this requires a huge health service demand. Many facilities provided by the Ministry of Health and Hajj Committee during hajj seasons to provide a tremendous 24\u2009h non-stop cardiac services included increasing manpower, raising number of working cath labs, improving working network, expanding all available services, and hence all that motivate the huge work and discharge of stable cases. We started implementation of early discharge program on hajj season 2018 and continued on 2019 to enlarge our sample size, which might help to gather more data and generalize our conclusion.Our results concluded that those early discharged patients had higher percentage of pilgrims who were in high need for early discharge to compete their hajj pillars with their groups and return back to the their home countries safely. They also showed to have low-risk AMI features including less prevalence of cardiovascular risk factors and comorbidities, which all might predict safe early discharge post revascularization. Early revascularization with PPCI with appropriate target for DBT  was recorded higher among those early discharged patients and this reflects higher quality of service provided by our center to AMI patients and could help in the process of early discharging them from the hospital. Clinical features and short-term outcome of AMI patients post event are crucial once decided the discharge process and these were followed carefully during our program implementation . Reassuringly, most of our early discharged patients had favorable coronary artery disease anatomy  and this encouraged their early discharge process.Follow-up data results were impressive as majority of our early discharged patients were totally asymptomatic (95%). Few percentages of those patients had non-serious symptoms and did not require any major intervention and this might reflect the early success of implementation of such program in our facility, which is considered the corner stone in the region.Finally, our current experience reflects many advantages: great compensation of the huge required hospitalization burden; provision of the best, safe, and maximum service for cardiac patients during over crisis periods; lower hospital cost; and improvement of patient\u2019s satisfaction.Our study is limited to a single center and relatively small population number (short period selected only two hajj seasons) corresponds to the conclusions of mentioned studies. There are many factors explaining limitation of our follow-up data (as 40% of our early discharged patients lost their follow-up): language barrier, wrong written contact number in our records, non-attending calls, and higher percentage of those patients were pilgrims who returned back to their countries immediately after hajj without any follow-up here. We tried to support our results with some previous randomized studies with such recommended strategies and shorter length of hospital stay.Suggested plan to establish proper educational program with help of the health promotion department supported with different language materials, which will be provided to those patients during their hospitalization regarding to their disease process, medication compliance and proper short-/long-term follow-upProper recording of correct contact numbers of the patients organized by our admission office and bed management departmentsMotivation of the primary and secondary hospitals in the regions to conduct similar programs and possible organization of better follow-up protocolsWe hope to reduce these limitations in future seasons by the following suggestions:Our results provide preliminary data to support safety of early discharge in a carefully selected group of AMI patients while providing them dedicated telephone support and follow-up. Early but safe discharge may have huge impact on increasing patient\u2019s satisfaction, bed availability  and reducing hospital costs. Furthermore, a larger multi-center study in the region has been encouraged to generalize our conclusion."}
+{"text": "The present study analyzes the drug-target-disease network and may prove to be a useful tool in gene-phenotype connectivity for genistein in HBV-related liver cancer. Our data also pave the way for further research on Grb2 during the development of chronic HBV infection in liver cancer.Genistein is a type of isoflavone, which has been widely described as an antitumor agent in many cancers. The present study aimed to provide information on the mechanisms of genistein's activity and thus enable a wider range of targeted therapies in hepatitis B virus (HBV)-related liver cancer. We searched the DrugBank database for direct targets of genistein, which were then analyzed through the STRING  database to predict their secondary protein targets. Thirteen primary protein targets of genistein and 209 secondary protein targets-associated genes were identified. The data were integrated into the network of protein targets-associated genes and visualized with the Cytoscape software. We further carried out GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Gene and Genome) pathway analysis using DAVID  tool. The top 14 KEGG pathways were further assessed, and 19 overlapping genes derived from pathways of hepatitis B and cancer were discovered. The overlapping targets were further mapped in the online tool UALCAN to evaluate the survival rate of hepatocellular carcinoma (HCC) patients. We found that the overexpression of Grb2 (growth factor receptor-binding protein 2) ( Worldwide, chronic infection due to hepatitis B virus (HBV) is recognized as a major reason for hepatocellular carcinoma (HCC), with a huge financial burden to the society  database, and generated 209 secondary protein targets-associated genes and constructed their protein\u2013protein interaction (PPI) network with the Cytoscape software. Primary target genes and the genes associated with them were further analyzed using DAVID  online tools for KEGG (Kyoto Encyclopedia of Genes and Genomes) biochemical pathways, and finally, the top 14 KEGG pathways were picked out. Nineteen overlapping genes derived from hepatitis B and pathways in cancer on the top 14 KEGG pathways were identified. At last, the expression level and overall survival (OS) of these hub genes were analyzed with UALCAN, which is a tool to facilitate the study of survival associations and gene expression variations across tumors based on exhaustive evaluation of TCGA (The Cancer Genome Atlas) gene expression data  enrichment analysis and KEGG pathway enrichment analysis were carried out using an online tool DAVID, which is an online database and analytic tool that provides information about a large list of genes or proteins and their potential functions  between normal and tumor samples and assess the effect of clinicopathologic features and level of gene expression on patient survival , prolactin signaling pathway (19 genes), pathways in cancer (37 genes), hepatitis B (23 genes), focal adhesion (26 genes), erbB signaling pathway (18 genes), PI3K/AKT signaling pathway (33 genes), proteoglycans in cancer (25 genes), estrogen signaling pathway (18 genes), colorectal cancer (15 genes), FoxO signaling pathway (20 genes), AMPK signaling pathway (19 genes), mTOR signaling pathway (14 genes), and HIF-1 signaling pathway (17 genes) . Moreovehttp://ualcan.path.uab.edu). We found that expression of GRB2 (p\u2009<\u20090.0001) followed by AKT1 (p\u2009=\u20090.0015) and PIK3CA (p\u2009=\u20090.0088) was linked to worse OS for liver HCC patients (The expression level and prognostic details of 19 selected genes are accessible online (patients . The UALInvestigations carried out in the past decades have shown that genistein demonstrates synergistic activities combined with chemo-drugs (Spagnuolo et al., A system biochemistry approach integrating multiple web-based tools was applied, and associations of HBV-related HCC and biological molecules with drug targets were evaluated. We obtained 13 primary and 209 secondary target genes/proteins in DrugBank and STRING. Nineteen overlapping genes from 2 of 14 enriched KEGG pathways related to genistein-altered genes were selected. The overexpression of AKT1, PIK3CA, and GRB2 in HCC was linked to decline in OS as per UALCAN. Therefore, we hypothesized that those three genes might be potential targets by genistein during the development of chronic HBV infection into liver cancer.The PI3K/AKT signaling pathway has been found abnormally activated in HCC and affects cell behavior, including proliferation, survival, metabolism, and tumorigenesis (Chen et al., In conclusion, with the increase in number of studies on genistein by traditional experimental techniques, more and more genistein targets will undoubtedly be identified. However, there is ambiguity in determining whether the specific biological effects on genistein can be definitively assigned to the individual or simultaneous modulation of their newly established or identified targets. This analysis enabled the interpretation of the inherent mechanisms of HBV-related cancer and genistein's target identification and would ultimately aid in future studies with rational experimental likelihood for detection and validation of logical hypotheses about the role of genistein in HBV-related liver cancers in the future."}
+{"text": "This talk explores the importance of a racially diverse graduate student interacting in an applied care setting with minority older adults in the Southeast relative to assessment of cognitive status and in the context of cultural mistrust and misdiagnosis. ~250 older adults (16% AA) in an applied care setting were administered a cognitive screener as part of a larger research battery. An independent samples t-test was conducted to assess differences in mean cognitive status. Non-Hispanic Whites (NHW) (M=76.8 years) were found to be more intact than AAs (M=73.27) on measures of cognitive status . Implications highlight that cognitive screeners have often been found to lack sensitivity in groups of marginalized older adults. Having an AA graduate student in these settings could be a way of mitigating the effects of culturally incompatible screening tools and bridging the gap between research and practice for AA older adults."}
+{"text": "We combined Medicare claims and nursing home (NH) administrative data to determine the mortality and morbidity effect of Hurricane Irma on nursing home residents. We utilized the Centers for Medicare and Medicaid Services (CMS) Standard Analytical Files (SAFs) combined with the Minimum Data Set (MDS) to create an exposure cohort of NH residents residing in Florida facilities immediately prior to Hurricane Irma\u2019s landfall on September 10, 2017. We created a control group of residents who resided in the same NHs over the same dates in 2015, a year when there were no hurricanes. Outcome variables included 30/90-day mortality and first hospitalizations post storm. Compared to the control, an additional 260 more NH deaths were identified at 30 days and 429 more deaths at 90 days. Long stay residents (\u2265100 days) were at particular risk for mortality compared to short stay residents (<100 days). Hospitalization was also markedly increased."}
+{"text": "Digital transformation creates new opportunities and is an important driver of novel and often disruptive innovation and value creation. Entrepreneurs are using digital technologies to finance innovation Opportunities and management of digital methods of funding innovation and entrepreneurship New value creation and platform innovation through digital technologiesCorporate entrepreneurship and startups within established organizations to approach opportunities and challenges of digital transformationExploitation of missing regulation of digital entrepreneurship Opportunities of Digital EntrepreneurshipThe following list of topics is neither exclusive nor exhaustive. We have structured them along three dimensions (Recker and von Briel Competence and team needs of (corporate) digital entrepreneursDigital entrepreneurial cultureThe role of universities and entrepreneurial ecosystems for digital entrepreneurshipImpacts of digital technologies on entrepreneurial decision makingUse of Social media or crowdsourcing resources by entrepreneursOrganization, organizational learning, and performance of digital startupsManagement of digital business model innovationInternationalization of digital startupsAlignment of digital capabilities and business modelsBehavior of startups in digital platform ecosystems Development and management of new digital ecosystems by startupsIndustry-specific classification schemes of startups or business models Changes in startup investment processes due to digitalizationProcesses, Organization, and Challenges of Digital EntrepreneurshipImpacts of Digital EntrepreneurshipImpacts of digital entrepreneurship on regions and countries Investments in digital innovation and their economic or societal pay-offsThe dark side of new digital business models Influences of digital entrepreneurial and innovative activities on government policy or regulationhttp://www.editorialmanager.com/buis/). Please observe the instructions regarding the format and size of contributions to Business & Information Systems Engineering (BISE). Papers should adhere to the submission general BISE author guidelines .Please submit papers by 1 March 2021 at the latest via the journal\u2019s online submission system (All papers will be reviewed anonymously (double-blind process) by at least two referees with regard to relevance, originality, and research quality. In addition to the editors of the journal, including those of this special focus, distinguished international scholars will be involved in the review process.https://www.fgf-ev.de/en/g-forum-conference-2020-karlsruhegermany/). In this paper development workshop, the special issue editors will provide feedback on early drafts or first paper versions. The submission to the G-Forum, however, is not a requirement for submitting to the special issue.\u00a0Please Note: We are closely monitoring the current situation with regards to\u00a0COVID-19\u00a0and the paper development workshop might therefore\u00a0be canceled or moved to a digital setting.There will be a special issue paper development workshop at the 24th Annual Interdisciplinary Conference on Entrepreneurship, Innovation and SMEs (G-Forum) which will take place at KIT Karlsruhe, Germany, from 30 September to 2 October 2020 (Deadline for submission: 1 March 2021Notification of the author 1: 3 May 2021Completion revision 1: 2 July 2021Notification of the author 2: 17 August 2021Completion Revision 2: 21 September 2021"}
+{"text": "A questionnaire-based survey was conducted among members of the European Society for Gynaecological Endoscopy (ESGE), with the aim of increasing awareness of the diagnosis and surgical treatment of tubal disease as an alternative to in-vitro fertiliszation (IVF). Seventeen participants (34%) occasionally used a test for prediction of the ovarian reserve before surgery, and the most commonly used test was anti-mullerian hormone assay . Laparoscopy was the preferred method for staging tubal disease .Thirty-seven (76%) participants always performed salpingectomy or tubal occlusion before the first IVF attempt. Thirty (60%) of the gynaecological surgeons considered the outcome with tubal surgery and IVF to be similar in mild tubal disease, whereas for severe disease, 31/50 (62%) felt that surgery had worse outcome. Among other factors to be considered in choosing a strategy for treating infertility, 20/50 (40%) of respondents listed the stage of disease. The findings of this survey suggest that first-line treatment for women younger than 35 years old with minor tubal pathology, is tubal surgery. IVF appears to be offered if there are other infertility factors, if the patient is >38 years old and if moderate to severe tubal disease is present. Tubal disease is responsible for 30-40% of cases of female infertility. Pathology of the fallopian tubes may vary from peritubal adhesions and distorted tubal anatomy or damaged fimbriae to hydrosalpinx or tubal blockage . Pelvic st to March 31st , 2019, ESGE members were invited by the ESGE Central Office to complete a 22-item online questionnaire, accessible through the ESGE website. For some questions, more than one answer was acceptable. The invited gynaecological surgeons were not specifically infertility specialists, but they had experience in laparoscopic treatment of tubal-factor infertility. The participants received three reminders during this period. Fifty 50 gynaecological surgeons participated in the survey.A questionnaire survey was conducted to assess the approaches of members of the European Society for Gynaecological Endoscopy (ESGE). From March 1Forty-eight (96%) of the participants were specialists and two (4%) were trainees. Sixty per cent of the participants were aged 35 to 54 years; 25(50%) were experts who performed more than 90 laparoscopic procedures per year; and 19 (38%) had over 16 years of practice in endoscopic operations. Eighteen (36%) of the participants performed more than 30 laparoscopic tubal operations per year and 22 (44%) performed 10 to 30 per year. Seventeen of the participants (34%) worked in a university teaching hospital and 25 (50%) worked in a national health service hospital.According to 43 (86%) of the surveyed gynaecological surgeons, the best method for staging tubal disease was laparoscopy. Salpingectomy was the operation preferred by 30 (60%) participants, salpingoneostomy by nine (18%), tubal anastomosis by six (12%) and tubal occlusion by two (4%). Twenty-nine (58%) of the participants preferred bipolar energy for electrocoagulation during surgical treatment for tubal disease. When there is an incidental finding of hydrosalpinx 21(42%) of the gynaecological surgeons reported treatment in all cases; 18 (36%) reported treatment depending on the case; six (12%) reported no treatment; and 4 (8%) reported treatment only in case of bilateral disease. When hydrosalpinx was an incidental finding, 43 respondents (86%) preferred to inform the patient first and perform second-look surgical treatment only when there is indication, such as pain or infertility.In treatment of asymptomatic hydrosalpinx 23 (46%) gynaecological surgeons reported using no routine antibiotic treatment, 18 (36%) reported using occasional antibiotic treatment; and five (10%) reported using antibiotic treatment in all cases. When antibiotics were used for this condition, 20(40%) of the gynaecological surgeons seemed to prefer a combination of doxycycline, cephalosporin and penicillin, whilst 25 (50%) seemed to prefer doxycycline or cephalosporin only.Twenty-two (44%) participants reported using a test for predicting ovarian reserve in all cases before tubal surgery for infertility, and 40 (80%) felt the most precise and reliable test for predicting ovarian reserve is the serum anti-Mullerian hormone assay. Twenty-four (48%) reported salpingectomy as the best method for surgical treatment of hydrosalpinx in case of infertility, while 17 (34%) prefer laparoscopic tubal occlusion, six (12%)prefer salpingostomy, and three (6%) prefer hysteroscopic tubal occlusion, with permanent micro inserts to cause fibrosis and irreversible tubal occlusion, which develop within three months of insertion.Thirty-seven (76%) participants always performed surgical treatment of hydrosalpinx before the first IVF attempt, and 40 (80%) supported salpingectomy as being the best operative method regarding the outcome of a following IVF attempt. For women with mild tubal disease, good ovarian reserve and no other infertility factors, the prognosis of tubal surgery versus IVF is similar according to 30(60%) respondents. For women with moderate tubal disease 19(38%) participants felt that surgery and IVF had similar outcomes, and 17 (34%) felt that surgery had worse outcomes. In the treatment of severe tubal disease, 31 (62%) gynaecological surgeons stated that tubal surgery has worse outcomes than IVF. Twenty-two (44%) of participants reported that the combination of both methods imposes higher cost. Finally, according to 20 (40%) of the surveyed gynaecological surgeons, the stage of tubal disease is the first factor to take into account when considering strategies for treating infertility, whereas 30 (60%) felt that age and other infertility factors are most important.The results of this survey of 50 members of the ESGE on surgical treatment of tubal-factor infertility are comparable to the published literature on this subject. Thirty-eight (76%) participants favoured laparoscopy as the ideal method for the evaluation of tubal patency and the diagnosis of tubal disease, which is in line with reported practice . Almost Based on the survey responses, first-line treatment for women less than 35 years old with minor tubal pathology seems to be tubal surgery. IVF appears to be offered when there are other infertility factors, if the patient is >38 years old, and when moderate- to-severe tubal disease is present. According to the surveyed laparoscopic surgeons, tubal surgery and assisted reproductive technology in most of the cases are not competitive techniques, but usually tubal surgery is a prerequisite for the success of the IVF. Optimizing pregnancy rates and reducing the risks associated with IVF or surgical treatment should always be the main goal. The outcome of our survey is especially meaningful because of the high level of expertise in laparoscopic surgery and the high level of expertise in the laparoscopic treatment of hydrosalpinx among the participating gynaecological surgeons. On the other hand, the insufficient number of participants is a drawback, which points out the need for a future survey, better designed and with more gynaecologists with experience in laparoscopic treatment of tubal-factor infertility. Such a survey would minimize bias and produce clear answers and recommendations."}
+{"text": "Family caregivers provide the majority of support for older adults and people with disabilities in the U.S. The onset of the COVID-19 pandemic forced radical changes in duties and relationships between family caregivers and care recipients. These changes can be attributed to fears of virus transmission as well as federal, state and local government mitigation strategies resulting in social distancing and quarantining limiting caregiving interactions. This qualitative investigation conducted 55 Zoom interviews over summer 2020 with family caregivers to explore their changing roles and duties during the pandemic. Researchers utilized a semi-structured interview guide to explore caregiver experiences with COVID-19. The average age of the caregiver participants was 59 and the average age of the care recipients for whom they provided care was 74. All participants provided unpaid care for family members. Interviews were conducted in English (n=40), Spanish (n=5), Somali (n=5) and Korean (n=5). Care recipients resided in a facility  (70%) with the caregiver (20%), and in a separate independent setting (10%). Data from each interview were coded into themes by two researchers. Themes that emerged from the analyses included concerns about care recipient mental and physical health deterioration, lack of communication from formal providers, change in relationships with other family members, and future concerns. Implications for additional research and practice are included."}
+{"text": "Home-based medical care (HBMC) is emerging in China, but research understanding the efficiency and effectiveness of this new care model is rare. In this study, researchers interviewed 17 Chinese homebound adults aged 45 and older  who have received HBMC, and collected detailed information regarding their experiences and attitudes toward HBMC. Participants were recruited from healthcare institutions in Shanghai, Jinan, and Zhangqiu of China. The evaluation of patients\u2019 experiences with HBMC yielded both positive and negative aspects. Positive experiences included 1) the delivery method was convenient for homebound patients; 2) health problems could be detected timely because doctors visited patients regularly; 3) home care providers had better bedside manners and professional skills than hospital-based providers; 4) the medical insurance covered the cost of home care services. Negative experiences related to the supply and quality of care, including 1) the scope of current HBMC services was too limited to meet the needs of homebound patients; 2) the visit time was too short; 3) healthcare providers\u2019 professional skills varied greatly. Findings from this study suggest that the HBMC model benefited Chinese older adults, primarily homebound adults, in terms of convenience and affordability. There are opportunities to expand the scope of home care services and improve the quality of care. Policymakers may consider providing more resources and incentives to enhance HBMC in China. Educational programs may be created to train more HBMC providers and improve their professional skills."}
+{"text": "Disease Models & Mechanisms (2019) 12, dmm040238 (doi:10.1242/dmm.040238).There was an error in The authors mistakenly used the wrong image for the FUS(1-359) vehicle panel in Both the online full-text and PDF versions have been updated and the authors apologise to readers for this error and any inconvenience it may have caused."}
+{"text": "Pakistan is a developing country with high number of road traffic injuries. High magnitude of road traffic injuries highlights deficiencies in road traffic laws which are not at par with current safety requirements resultantly fail to address important risk factors such as distracted driving, non-use of seat belt and helmet. Purpose: - To assess effect of deficient traffic laws related of distracted driving, seat belt and helmet usage in term of estimate prevalence of different types of distractions and use of helmet by motorcycle riders and pillion riders and seat belts by the drivers and the passengers on National Highway in Pakistan that can lead to road crashes and increasing the injuries.Roadside survey was carried on N-5 National Highway to estimate number of distracted drivers, use of helmet by riders and pillion riders and use of seat belt by drivers and passengers.Three types of distraction were observed i.e. Mobile Phone distraction (24%); Equipment related distraction (1%) and eating related distraction (1%) amounting to 29% of drivers distracted ;car drivers (29%), other vehicle drivers (6%), motorcyclists (3%) and trailer drivers (3%). Likewise; 64% drivers were found without seat belt, LTV drivers (85%), car drivers (74%) and truck drivers (69%). Similarly; 97% passengers were found without seat belt, LTV passengers (100%), truck passenger (99%), cars passenger (97%), Oil tanker and trailer passenger (90%). Helmet violation was high with 87.4% motorcycle riders and 100% pillion riders were found without helmet. Lack of enforcement due to deficient traffic laws result in RTIs in Pakistan. There is need to improve legislation on different forms of distractions, use of seat belt among passengers and helmet use by pillion riders; so that enforcement efforts can be made to address risk factors effectively to meet Decade of Action 2011-2020 targets.Seat belt, Helmet, Distraction, Pakistan"}
+{"text": "Dear Editor,We would like to thank Dr Arjun Srirampur for his interest in our work. Below please notice our replies:1. All of our diabetic patients were operated upon due to proliferative diabetic retinopathy (PDR) complications such as non-clearing vitreous hemorrhage and traction retinal detachment but there was no case of rhegmatogenous retinal detachment; therefore no tamponade was used during surgery.2. None of our patients had uncontrolled IOP during the short follow-up period (two weeks) after surgery in both groups. The corneal epithelial defect (CED) was improved in all eyes except three; and in those three eyes, lateral tarsorrhaphy and application of a lubricant ointment resulted in healing of the CED less than one month after surgery."}
+{"text": "Functional disability might be related to an increased risk of dementia or could represent a prodromal stage. We examined the occurrence of functional impairments over eight years follow-up and their association with dementia incidence in 1,666 participants aged 65+ from the English Longitudinal Study of Ageing. Growth models with distal outcome were used to examine whether different trajectories of functional abilities (activities of daily living (ADL); and instrumental activities of daily living (IADL)) between 2002/03 and 2010/11, were associated with dementia incidence four years later (2014/15). Participants with an increasing number of functional impairments (Class III), were more likely to be classified with subsequent dementia compared with those with no impairments (Class I). An increased risk was also observed for individuals with raised levels of impairments (Class II). We found IADLs more sensitive than ADLs, and this may imply a more comprehensive ascertainment during the prodromal stage of dementia."}
+{"text": "In 2020, the Center of Innovation for Veteran Centered and Value Driven Care (COIN) continued its monitoring and evaluation of the Veterans Administration (VA) Medical Foster Home (MFH) programs expansion into rural areas. Veterans in MFHs are provided 24/7 care by VA trained and supervised community caregivers and primary care by VA Home Based Primary Care (HBPC) teams. One year after the three-year (2017-2019) expansion funds stopped, COIN continued monitoring remaining programs. Objectives were to understand factors critical for program expansion and sustainability and the impact of COVID-19. Phone interviews were conducted with sixteen coordinators from seventeen programs. A thematic analysis approach was used to address the evaluation objectives using transcript data. Findings showed factors important to program sustainability were: 1) Program fit (finding caregivers in the community); and 2) Local VA facility support . COVID prompted losing some caregivers and prevented others from joining. Program staffing was not impacted as many program activities ceased. Recreational therapists (RTs) were significant to maintaining Veterans well-being and reducing social isolation through virtual activities. COVID required coordinators transition their supervision of MFHs to new virtual environments and HBPC to increase telehealth to new levels. Local leadership became important to monitoring local conditions and providing support to programs. The evaluation: 1) Found factors important to program sustainability were also critical to keeping programs operational during the pandemic; and 2) Stimulated future research on the suitability of MFH programs to meet challenges to resurgences of COVID or other national emergencies."}
+{"text": "The literature on the contribution of elastic fibre deposition to alcohol-related liver disease (ARLD) is limited. We studied: (1) 180 liver biopsies from ARLD patients; (2) 20 ARLD explant livers; (3) 213 liver biopsies with non-ARLD injury. Elastic fibres were assessed in terms of their distribution around hepatocytes [pericellular elastosis (PCE)] and within bridging fibrous septa  and scored using a semiquantitative system. We also investigated the composition of the elastic fibres  in 20 cases. PCE was associated with steatohepatitis in ARLD patients and with ARLD when compared to non-ARLD cases (p\u2009<\u20090.001). Oxytalan fibres were identified in PCE in ARLD biopsies and broken dense perisinusoidal mature elastic fibres in explanted livers. Septal elastosis increased from intermediate to advanced fibrosis stage. Early septal elastosis contained oxytalan fibres, whereas septal elastosis at more advanced stages contained mainly mature elastic fibres. PCE is a typical feature of steatohepatitis in ARLD and includes oxytalan fibres. Septal elastosis is a gradual process with a transition from oxytalan to mature elastic fibres usually present in explanted livers. There may be different dynamics in the assembly and reabsorption of pericellular and septal elastic fibres, and a potential role for stratification of patients with advanced stage ARLD. The spectrum of liver injury in alcohol-related liver disease (ARLD) ranges from simple steatosis to steatohepatitis and from minimal or no fibrosis to cirrhosis2. Elastic fibres are a component of the extracellular matrix (ECM) along with collagen, glycoproteins, glycosaminoglycans and proteoglycans3. The elastic fibres are composed of a core of elastin made of tropoelastin monomers encoded by ELN and a microfibrillar mantle composed of fibrillins, glycoproteins which in humans are present in three isoforms4. The relative proportion of tropoelastin and microfibrils divide elastic fibres into three main types: oxytalan, composed of microfibrils only with no elastin core; and elaunin and mature elastic fibres, both characterized by a central cross-linked core of elastin and a surrounding microfibrillar component. Elaunin fibres have a lower amount of elastin compared to mature elastic fibres5. Oxytalan fibres can be differentiated from both elaunin and mature elastic fibres by removing the oxidation step of histochemical elastic fibre staining methods such as the orcein stain or analogues9. Oxytalan fibres do not react with this modified protocol, whereas both elaunin and mature elastic fibres remain positive. Elastogenesis begins in the late stages of development and early after birth10 and is particularly active in those tissues in which elastic properties are essential for their function such as the aortic wall and lung parenchyma4. Elastogenesis is attenuated in normal adult tissues but reactivates in a wide spectrum of disease processes10 including wound healing12. Elastin has long been known to accumulate in fibrotic livers13. Little is known however about its role in the progression of ARLD and the literature on the contribution of elastic fibre deposition in ARLD injury is limited14. Porto et al.14 showed that in the early stage of alcoholic fibrosis there is deposition of oxytalan fibres in the space of Disse in the perivenular region. The internodular bridging fibrous septa of more advanced stages contained oxytalan and elaunin fibres. Our aim was to evaluate retrospectively a large series of liver biopsies from patients with ARLD focusing on the pattern, distribution and composition of elastic fibres.Worldwide alcohol-related mortality in 2016 was high at 38.8 per 100,000 people and half of cirrhosis related deaths were due, at least in part, to alcohol useOut of our initial cohort of 303 biopsies 180 fulfilled our selection criteria and were selected for our study.Seventy-three biopsies (40.6%) showed steatosis only (mild in 36 (49.3%), moderate in 28 (38.4%) and severe in 9 12.3%). Ninety-seven biopsies (53.9%) showed steatohepatitis. Ten (5.6%) biopsies were classified as NOS  of liver biopsies at the different disease stage were as follows: 0 (no fibrosis)\u2009=\u20094 (2.2%); 1 (early)\u2009=\u200984 (46.7%); 2 (intermediate)\u2009=\u200934 (18.9%); 3 (advanced stage cirrhotic transformation)\u2009=\u200913 (7.2%); 4 (advanced stage cirrhotic)\u2009=\u200945 (25%).For reference, examples of none and focal perihepatocytic elastic fibres, and PCE are demonstrated in Fig.\u00a0The correlation between pericellular elastic fibres and overall disease pattern is detailed in Supplementary Table PCE was identified in 58 32.2%) of the 180 cases studied. PCE was present in 7 (9.6%) of the 73 biopsies with steatosis, 47 (48.5%) of the 97 biopsies with steatohepatitis, and 4 (40%) of the 10 biopsies classified as NOS. When biopsies were divided into two groups according to presence or absence of steatohepatitis, PCE was significantly associated with steatohepatitis  with end stage ARLD. All patients had been abstinent at the time of transplantation for at least 6\u00a0months.Most cases showed a combination of grades 2, 3 and 4 of septal elastic fibres. Grade 0 was not observed in any of these 20 cases and grade 1 was present in three cases only. PCE was not identified in most cirrhotic nodules in 18 cases. It was present very focally in occasional cirrhotic nodules after extensive examination at high magnification in 4 cases, and was easily identified at low magnification in a few (7 cases) or several (7 cases) cirrhotic nodules. The pericellular elastic fibres were often in the form of broken dense strands or in a more perisinusoidal distribution. Examples are shown in Supplementary Figure In two other cases PCE was more prominent affecting approximately half of the cirrhotic nodules in the sample examined. There was no evidence of active steatohepatitis.We next correlated our findings with the immunohistochemistry for elastin and the repeat Victoria blue stain with and without the oxidation step to explore the proportion of oxytalan, elaunin and mature elastic fibres. , in all ten biopsies showing grade 1 or grade 2 septal elastosis with the conventional Victoria blue an appreciable reduction in elastic fibre stain with the modified Victoria blue method suggested the presence of a significant proportion of oxytalan.Grade 3 or 4 septal elastosis, consisted of elastin positive septa without reduction in stain with the modified Victoria blue stain indicating that the septa were composed mostly of mature elastic fibres.PCE appears to be composed of a significant proportion of oxytalan in most of the biopsy specimens and of mature elastin in the explanted livers . Further studies are needed to better understand whether the elastification process can be used to stratify patients with advanced stage ARLD and correlate with clinical outcome.Our study was based on four cohorts of specimens; (i) a series of 303 core needle biopsy specimens from patients with known ARLD clinically; (ii) a series of 20 livers removed at transplantation for ARLD; (iii) a control group of 213 core needle biopsy specimens with a variety of liver conditions other than ARLD characterized after clinico-pathological correlation; (iv) a selection of representative cases from cohorts (i) and (ii) to investigate in more details the elastic fibres morphology and composition in terms of oxytalan, elaunin and elastin content.16: steatosis, steatohepatitis, and not otherwise specified (NOS).Our review of the first cohort of biopsies included the assessment of the overall pattern of liver injury, fibrosis stage, and pattern of elastic fibre deposition. The biopsies were divided into the following categoriesFibrosis staging was carried out using a semiquantitative scoring system (0 no fibrosis identified); 1 or early; 2 or intermediate (bridging fibrosis); 3 or advanced stage with features of cirrhotic transformation; and 4 or advanced stage cirrhotic.We assessed the presence of elastic fibres in a pericellular/perivenular distribution and within fibrous septa.Pericellular elastic fibres were classified as absent, focal  and after extensive search), or pericellular elastosis (PCE) (perihepatocytic elastic strands obvious at 10\u2009\u00d7 or 20\u2009\u00d7 magnification).We classified septal elastosis into the following grades: grade 0: bridging fibrous septa with no elastic fibres; grade 1: bridging fibrous septa with delicate fibres visible only at high magnification; grade 2: elastic fibres visible at low magnification and clearly distinguishable from the residual portal or liver capsule elastic fibres, grade 3: strong elastic bundles well visible at low magnification and of similar density, blending with or indistinguishable from the to the residual portal normal or liver capsule elastic fibres; and grade 4: slender, regressive type dense elastic bundles visible at low magnification. Pericellular and septal elastosis were further investigated, in terms of their composition on a subseries of 20 cases using 6 serial sections. The sections were stained in the following sequential order with (i) anti-Elastin [BA4] antibody IHC (ab9519), (ii) Victoria blue with no oxidation step (demonstrating only mature elastin fibres and Elaunin), (iii) Victoria blue with oxidation and decolourisation step , (iv) (spare unstained back-up section), (v) Picrosirius red and (vi) Haematoxylin and Eosin. Reduction in stain between the Victoria blue with and without oxidation step was assessed as follows: minimal and focal ; partial ; marked . Septal elastin immunohistochemical stain was regarded as diffuse when present in most or all septa and patchy when approximately half of the septa were negative. Pericellular elastin stain was considered as diffuse (most hepatic plates), patchy , focal (identified at high magnification after extensive search) or absent.Details on the biopsy selection, histological categories, fibrosis scoring system staining protocols, statistical analysis and elastic fibres assessment are provided as supporting information. All methods were carried out in accordance with relevant guidelines and regulations, experimental protocols were approved by the Royal Free Hospital Ethics Committee (07/Q0501/50) and informed consent was obtained as appropriate.Supplementary Information."}
+{"text": "Loneliness and social isolation present emerging public health challenges for aging populations. To inform efforts against loneliness and social isolation, research is needed to evaluate impacts of these conditions on patterns of adverse aging outcomes. We used longitudinal, repeated measures data to isolate effects of loneliness and social isolation from effects of socioeconomic circumstances and psychological vulnerabilities, rule out reverse-causation, and test dose-response in associations with morbidity, disability, and mortality. We also explored the biological basis of relationships by testing associations with biological aging. We analyzed data from more than 12,000 adults aged 50-95 in the US Health and Retirement Study (HRS) who reported on symptoms of loneliness and social isolation at 2-3 time points during 2006-2014. We measured loneliness using the 3-item Revised UCLA Loneliness Scale and social isolation using a 6-item scale. We tested associations with chronic disease, disability, and biological aging in 2016 and with mortality through 2018. We found (1) associations of loneliness and social isolation with adverse aging outcomes are not fully explained by socioeconomic circumstances and psychological vulnerabilities; (2) the direction of relationships with disability indicates temporal precedence of loneliness and social isolation; (3) there is a dose-response in associations with loneliness; and (4) there is evidence of a biological mechanism explaining associations with loneliness and social isolation. Findings add to the emerging literature on health sequelae of loneliness and social isolation. Assessment of loneliness and social isolation in surveillance and intervention with older adults can enhance risk assessment for adverse aging outcomes."}
+{"text": "Digital methods are a way to engage marginalized populations, such as sexual and gender minority (SGM) adults. No study to date has leveraged these methods to engage SGM caregivers of people with dementia. We used digital methods to access SGM caregivers of people with dementia in our study of psychosocial measures of caregiving for recruitment and data collection. Posts on social media and online registries targeted SGM caregivers. The study landing page received 2201 views; 285 caregivers completed the survey. Participants learned of the study most frequently from Facebook (45%). The sample was 84% white, with gay (52%), lesbian (32%), bisexual (11%), and other sexual orientations (5%) and transgender (17%) caregivers represented. While we exceeded goals for inclusion of Latinx (26%) and Native American (4%) caregivers, the number of African American SGM caregivers was lower than projected (7%). Digital methods are effective for engaging SGM caregivers of people with dementia."}
+{"text": "Crops during their early growth stages are vulnerable to a wide range of environmental stressors; thus, earlier seed invigoration and seedling establishment are essential in crop production. As an alternative to synthetic chemical treatments, plasma technology could be one of the emerging technologies to enhance seed germination and seedling vigor by managing environmental stressors. Recent studies have shown its beneficial effects in various stress conditions, suggesting that plasma treatment can be used for early crop stress management. This paper reviewed the effects of different types of plasma treatments on plant responses in terms of the seed surface environment (seed scarification and pathogen inactivation) and physiological processes (an enhanced antioxidant system and activated defense response) during the early growth stages of plants. As a result, plasma treatment can enhance seed invigoration and seedling establishment by alleviating the adverse effects of environmental stressors such as drought, salinity, and pathogen infection. More information on plasma applications and their mechanisms against a broad range of stressors is required to establish a better plasma technology for early crop stress management. Rapid seed invigoration and seedling establishment during the early growth stages of crops are necessary to prevent crop yield loss due to unfavorable environments. Seed germination and early seedling growth are the most sensitive growth stages for a crop to a wide range of environmental stressors . Once thPlasma technology has been widely designated as an advanced oxidation process . It has However, no review has yet summarized plasma applications and their protective mechanisms against a broad range of stressors. The potential applications of plasma technology for early crop stress management are largely unknown. This review evaluated the effects of the different types of plasma treatments on plant responses in terms of the seed surface environment (seed scarification and pathogen inactivation) and physiological processes (an enhanced antioxidant system and activated defense response) during the early growth stages of plants. Recent information on plasma applications and their mechanisms against a broad range of stressors was reviewed from these two perspectives. Thus, this review proposes that plasma technology has potential uses for seed invigoration and seedling establishment under stressful conditions.The seed coat regulates seed germination through its thickness and permeability. Therefore, seeds with thick coats are incapable of water uptake rapidly unless it is scarified . In part6H5NH2) or cyclohexane (C6H12). However, RF discharge delayed the germination time of maize, radish, and some legumes such as soybeans, peas, and common beans when generated from carbon tetrafluoride (CF4) or octadecafluorodecalin (ODFD) otherwise known as perfluorodecalin (2H4)  .Dielectric barrier discharge (DBD) has been proven to be effective for seed germination and seedling vigor when generated under optimal conditions. DBD in air induced faster germination, leading to a better germination rate and early seedling growth of wheat, barley, and peas under laboratory conditions . A DBD wOther discharge plasmas, including corona, arc, glow, and microwave discharges, also have shown stimulating effects on seed invigoration of some crops although their maximum values differ depending on the treatment conditions of the plasma sources .These results suggest that plasma treatment can enhance the water absorption of seeds, thus leading to a better invigoration of crops. The beneficial effect of plasma treatment on seed invigoration is mainly associated with its power (W) and exposure time (min) , plasma treatments with DBD and arc discharge effectively inactivated its growth and thus reduced the fungal infection of rice by a maximum value of 51% under environmentally controlled conditions  radical into hydrogen peroxide (H2O2) and an ordinary molecular oxygen (O2). Finally, CAT in peroxisomes and PODs in the cytosol detoxify the hydrogen peroxide (H2O2) by catalyzing its reduction to water (H2O). Together with these enzymes, non-enzymatic antioxidants can provide cells with highly efficient machinery to detoxify the molecular species of active oxygen. After plasma treatment, the enhancement of these antioxidant systems has recently been reported in a few crops , catalase (CAT), and peroxidase (POD), in plant cells . The antCellular antioxidant systems are effectively enhanced by plasma treatments with a low power (W) and short exposure (min) see . SimilarDielectric barrier discharge has shown positive effects on the contents of the total phenolic compounds under laboratory conditions, although its effects depend on the types of feed gas. These results indicate that plasma treatments generated with a low power and short exposure time  can enhance cellular antioxidant systems  through H2O2-mediated signaling activating defense-related responses  and physiological processes  in seeds under stressful conditions such as drought, salinity, and pathogen infection (1) reduce infection with pathogenic microorganisms in germinating seeds or growing plants (2) regulate ROS homeostasis through the antioxidant machinery of plants (3) activate other defense-related responses in plant cells  and the seed surface, seed-borne pathogens, and cellular homeostasis, respectively. Although the plasma-induced effects are still poorly understood, their potential mechanisms for crop stress tolerance can be suggested based on the review of the literature on plasma-induced plant responses (Section 2). The ROS, RNS, and UV of plasma can change the physical and chemical properties of the seed surface before exposure to environmental stressors, thus enabling seeds to be more hydrophilic and permeable to water. Scanning electron microscopy studies have shown partial degradation of cellulose and formation of cracks on the surface of plasma-treated seeds . Additiog plants , 2) reguf plants , and 3) nt cells . Many stnt cells . AltogetSeed invigoration and seedling establishment under stressful conditions are highly variable depending on numerous factors, including biological  and environmental factors . There is little or no information for establishing crop stress management practices using plasma technology. To our knowledge, there are only a few studies under laboratory conditions on crop tolerance to disease , droughtPlasma applications have been widely used for seed scarification, pathogen inactivation, and antioxidant system activation with proven beneficial effects on seed invigoration and seedling establishment under laboratory and greenhouse conditions. Moreover, the optimal plasma exposure can enhance crop tolerance before stress events  by modulating the seed surface environment  and physiological processes  in seeds. This promising technology is potentially valuable for alleviating the adverse effects of environmental stressors on seed germination and seedling growth in crop production. However, information on plasma effects under stressful conditions is limited to a few crops under laboratory conditions. Further studies are necessary to fully understand the effectiveness of plasma applications to a broad range of stressors under field and greenhouse conditions. This review suggests that the power (W) and exposure time (min) are vital operating parameters of the plasma treatment that affect the phenomenon of the plasma. More experimental evidence is needed to adopt the use of the power (W) and the exposure time (min) as standardized values for the plasma treatment of various crops \u201d through the National Fusion Research Institute of Korea (NFRI) funded by government funds.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Chinese Center of Disease Control and Prevention (CDC) executed an intensive investigation program. WHO named this novel strain of coronavirus as sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) aka coronavirus disease 2019 (COVID 19). The sufferer of this virus predominantly and typically shows the symptoms of acute respiratory infections ranging from barely noticeable cough and dyspnea to need of mechanical ventilation in excessively compromised individuals but it typically causes pneumonia thus producing pneumonia like symptoms.th leading cause of death in USA.According to World Health Organization (WHO) the ailments caused by viruses have always emerged in the past and posed masses to life threatening medical conditions. Considering the last two decades, a number of viral infections emerged as epidemic including severe acute respiratory syndrome coronavirus (SARS-CoV), H1N1 influenza, Middle East respiratory syndrome coronavirus (MERS-CoV) and when the timeline approaches the present days there is an outbreak of coronavirus once again with drastic dissemination all across the globe but this time it is the novel one, having a new strain and originating from China in the city of Wuhan with its 1MMAA: Concept, design and accountable for all work.SQ: Drafting and revision.KK: Critical analysis and final approval."}
+{"text": "Purpose: To collect information on unintended drug exposure during pregnancy in early clinical drug development. Materials and methods: Questionnaire mailed in autumn 2015 to members of human pharmacology societies in Europe for anonymous responses via the online tool SurveyMonkey. Results: 53 of the ~ 700 addressees participated in the survey. 23 female trial participants and 11 female partners of male trial participants were exposed to investigational medicinal products during unintended pregnancies in a clinical trial. Most survey respondents confirmed adequate contraceptive methods by in/exclusion criteria and the use of pregnancy tests in female trial participants at screening and before the first dose. The last menstrual period was documented less frequently . A considerable proportion of respondents denied the routine use of compliance checks about the appropriate use of contraceptive methods, had no procedures in place if contraceptive methods failed, and did not train physicians in instructing trial participants about the appropriate use of contraceptive methods. Conclusion: The methods to avoid unintended pregnancies during participation in a clinical trial need improvement and should include (i) pregnancy tests, (ii) documentation of last menstrual period before the first dose, (iii) compliance checks of the appropriate use of contraceptive methods, and (iv) training of trial physicians. Procedures should be in place for what to do if contraceptive methods fail.  What is known about this subject Pregnancies in early clinical drug development must be avoided Appropriate methods to avoid unintended pregnancies are to be defined in the clinical trial protocol Guidance is provided in the ICH M3(R2) and the respective European Clinical Trial Facilitation Group recommendations (CTFG 2014) What this study adds This AGAH survey revealed that unintended pregnancies occur in early clinical drug development Regulatory recommendations are not fully implemented The methods to avoid unintended pregnancies during participation in a clinical trial need improvement A series of workshops related to early-phase clinical development has been hosted by the scientific society \u201cAssociation for Applied Human Pharmacology\u201d (AGAH e.V.) in Germany since 2012. In 2015, members from the pharmaceutical industry, contract research organizations, academia, ethics committees, and the German competent authority discussed unintended exposure to an investigational medicinal product (IMP) during pregnancy in clinical trials and its prevention [In early drug development, data on reproduction toxicity are in general not yet available. According to the ICH M3R2) Guidance [ Guidance\u201cMen can be included in Phase I and II trials before the conduct of the male fertility study since an evaluation of the male reproductive organs is performed in the repeated-dose toxicity studies\u201d \u201cFor women of childbearing potential (WOCBP) there is a high level of concern for the unintentional exposure of an embryo or foetus before information is available concerning the potential benefits versus potential risks\u201d If reproduction toxicity studies are not available, and WOCBP are planned to be included in a clinical trial, the guideline recommends limiting the risk by taking precautions to prevent pregnancy by (i) pregnancy testing , (ii) use of highly effective methods of birth control, and (iii) trial entry only after a confirmed menstrual period. To enable trial participation of WOCBP, the ICH M3R2) Guidance [ GuidanceInformed consent should be based on known risks to the embryo/fetus related to reproduction toxicity. A general assessment of potential toxicity of pharmaceuticals with related structures or pharmacological effects should be provided If no relevant reproductive information is available, the potential for unidentified risks to the embryo or fetus should be communicated as well Subjects should be instructed to use adequate contraceptive measures during the period of drug exposure which could exceed the length of the trial Pregnancy tests are required during the trial to ensure compliance with the contraceptive measures planned in the trial protocol In Europe, the Clinical Trials Facilitation Group (CTFG) has issued further recommendations related to contraception and pregnancy testing in clinical trials . They arA survey was conducted (i) to collect information on unintended pregnancies during clinical trials in early drug development and (ii) to learn from current experience whether applied precautionary measures are in line with current guidances , 3 and aDefinitions used are: Drug exposure via parent (DEVP) Unintended drug exposure during pregnancy in a clinical trial The survey addressed specialists working in early-phase drug development in Germany, Belgium, France, and the United Kingdom. The questionnaire  compriseThe questions covered the following topics (see questions (Q) provided in Characteristics of survey participants  Number and cause of unintended pregnancies in female participants and female partners of male trial participants in clinical trials combined in one protocol (Q3\u00a0\u2013\u00a0Q8) Age of women becoming accidentally pregnant in a clinical trial (Q9) Preventive measures (Q10\u00a0\u2013\u00a0Q13) It cannot be excluded that different participants belonging to the same organization referred to the same trial protocol(s). In consequence, a qualitative rather than quantitative interpretation of results is indicated. Not all survey participants answered all questions. For the respective questions, the total number of responses is given . A total of 53 of ~ 700 addressees answered the questionnaire. The majority came from contract research organizations (19), the pharmaceutical industry (15), but also from academia (8), independent consultants (8), biotechnology (2), or regulatory authority (1). Participants were from Germany (47), The Netherlands (3), Belgium (1), Luxembourg (1), and South Africa (1). 15 survey participants reported that 23 female clinical trial participants were unintentionally exposed to IMP during pregnancy in a clinical trial they sponsored or conducted during the past 10 years. 33 survey participants denied the occurrence of such pregnancies. A total of 10 survey participants reported that 11 female partners of male clinical trial participants were unintentionally exposed to IMP during pregnancy in a clinical trial they sponsored or conducted during the past 10 years. 36 survey participants denied the occurrence of such pregnancies. These included (i) non-compliance with trial-specific contraceptive methods (9), (ii) \u00a0failure of contraceptive methods (3), and (iii)\u00a0failure of the pregnancy test to detect pregnancy at screening or before first dose (1). The main outcome of this AGAH survey demonstrates that the occurrence of unintended pregnancies is a relevant issue in early drug development despite considerable effort to avoid them. Taking into account that 53 out of ~ 700 addressees responded, it may be assumed that the unintended exposure to IMPs in early pregnancy is higher than reported here. The number of participants is not a representative sample of all parties conducting clinical trials in Europe. Participants from the same organization may have referred to the same trials. To provide (i) data with respect to a topic with considerable lack of information, (ii) data on failure of/or compliance with contraceptive methods, (iii) data on training of physicians in instructing trial participants how to use the contraceptive methods as specified in the clinical trial protocol. Despite the advice provided in the ICH M3R2) guidance  guidance, 5, 6, 7If contraceptive methods fail in a clinical trial, the following procedures are useful in identifying the risk of having become or becoming pregnant and to estimate the usefulness of emergency contraception: Identification of exact kind and time point of contraceptive failure  Cycle history  Urine pregnancy test If possible, transvaginal ultrasound for determination of ovarian activity Blood sampling for determination of beta-human choriogonadotropin (\u03b2-HCG), estradiol, luteinizing hormone (LH), and progesterone There was agreement among participants of the workshop that good practices to avoid unintended pregnancies in early drug development comprise: Implementation of adequate contraceptive methods in the clinical trial protocol st dose, at appropriate time points thereafter, and upon completion of the clinical trial Pregnancy tests in female trial participants depending on the kinetics of the tested compound. At least screening before 1Written subject information concerning the adequate contraceptive methods to be used during the trial and the necessity avoiding DEVP as well as measures to be taken in case of possibly failed contraception before or during the trial Training of trial physicians on how to instruct trial participants about the appropriate use of adequate contraceptive methods as well as measures to be taken in case of possibly failed contraception  Routine compliance checks whether enrolled subjects are appropriately using the contraceptive methods as per protocol  Standard procedures in place regarding what to do if contraceptive methods failed  Decision on further measures to avoid unnecessary elective pregnancy terminations Compliance with measures indicated by the CTFG publication  Female clinical trial participants and female partners of male clinical trial participants must not become pregnant during early drug development; however, this AGAH survey shows that pregnancies did occur. According to the discussions during the workshop, the methods to mitigate the risk of unintended pregnancies need further improvement and should include (i) written information of the trial participants regarding contraceptive measures and the necessity of avoiding drug exposure via parent, (ii) repeated pregnancy tests, (iii) documentation of last menstrual period before the first dose, (iv) compliance checks of the appropriate use of contraceptive methods, (v) training of trial physicians. Procedures should be in place for what to do if contraceptive measures fail. Lessons learned from unintended pregnancies should result in appropriate modification of hitherto implemented procedures. This will mitigate the risk of DEVP in early-phase clinical trials. We thank Sam Welgemoed for her technical support . We thank all participants of the survey for their contributions. Survey: None. Open access provided by AGAH e.V. None. Supplemental material"}
+{"text": "Following these two introductory chapters, the monograph can then be divided into four main sections: (i) the technical overview of currently available commercial SGRT Systems (chapters 3\u20135), (ii) the commissioning of the systems described in part (i) (chapters 6\u20138), (iii) the clinical application of SGRT (chapters 9\u201319), and (iv) miscellaneous topics in surface image guidance (chapters 20\u201326). While the corresponding chapters in part (i) and (ii) can be read independently of each other, I personally would have found it more helpful if the technical overview of a particular surface image guidance technology would have been followed by the chapter on its commissioning. Having said that, each of the chapters in part (i) and (ii) strikes the right balance between technical detail and brevity, making them very useful both as a reference and an introduction to the technology and how to commission a given technology of surface image guidance. Part (iii) begins with an in depth look at the clinical application of this technology to breast cancer (chapters 9\u201311), while Chapters 12\u201314 consider Stereotactic Radiosurgery and Stereotactic Radiation Therapy in depth, including a very nice chapter on the risk analysis for SGRT\u2010based SRS/SRT. Part (iii) continues with a detailed description of respiratory motion management strategies employing surface image guidance in SBRT (chapter 15), including the use of surface image guidance for SBRT without respiratory gating (chapter 16). Chapters on the use of surface image guidance in the treatment of Head and Neck (chapter 17), extremities (chapter 18), and pediatric patients (chapter 19) conclude Part (iii). Chapters 20\u201326 round out the presentation with three perspectives on the clinical implementation of surface image guidance, one from the point of view of a physicist and two from the that of a radiation therapist (chapters 20\u201322); applications of surface image guidance to proton therapy (chapter 23); integration of surface image guidance into tomographic and bore type gantry systems (chapter 24); use of consumer grade cameras and alternate approaches to surface image guidance (chapter 25); and a final chapter discussing future directions for SGRT (chapter 26).In summary, this monograph presents a very readable account of the technical features of currently commercially available SGRT technologies, considers the commissioning of each in detail, and discusses in detail the clinical implementation and use of these systems for a number of important clinical sites, such as Breast, Stereotactic Body Radiation Therapy, Stereotactic Radiosurgery and Stereotactic Radiation Therapy, and Head and Neck. Regardless of career stage, professionals in either therapeutic medical physics or radiation oncology will find this monograph beneficial. The authors of this monograph balance technical detail with clinical information regarding the technology's implementation, and, hence, those interested in SGRT will find this monograph a valuable and welcome addition to their professional library. I have enjoyed reading through this monograph and found it a cogent reference and a thorough introduction to the topic.Wolfgang A. Tom\u00e9, Ph.D., FAAPM, FASTRO, is a Professor of Radiation Oncology and a Professor of Neurology at Albert Einstein College of Medicine  and the Chief of the Division of Therapeutic Medical Physics at Montefiore Medical Center ."}
+{"text": "Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis in skin and internal organs, progressive vascular obliteration, and the production of autoantibodies. Diagnostic imaging is irreplaceable in both diagnosing and monitoring patients suffering from systemic sclerosis. In addition to routinely used methods, such as comparative X-ray of the hands or a contrast-enhanced examination of the upper gastrointestinal tract or chest, there is an array of less widespread examinations, with an emphasis on magnetic resonance imaging (MRI) and ultrasonography, not only in the evaluation of the musculoskeletal system. This article will review the various imaging modalities available for SSc imaging and assessment, focusing on their utility as tissue-specific diagnosis and treatment monitoring. Systemic sclerosis  belongs to a wide spectrum of connective tissue diseases\u2014a diverse group of disorders characterised by chronic inflammation of connective tissue, usually of autoimmune origin . The mosSSc typically affects women (4:1 predilection), with the median onset at the age of 30\u201350 years. There is a higher morbidity within black patients than in other ethnical groups. A very high prevalence of SSc in Choctaw Native Americans suggests the possibility of a genetic factor in the pathogenesis of this disease. Reports of familial history of SSc or other autoimmune disorders in SSc patients have also shown support for the genetic grounds of SSc. The incidence rate seems stable over several decades in both Europe and the United States ,3,4,5. TThe diagnostic criteria for SSc are still not universal. The classification criteria of the American College of Rheumatology (ACR), presented in 1980 and updated by a collaboration of ACR and European League Against Rheumatism (EULAR) in 2013, are used most commonly. According to those criteria, skin thickening proximal to the metacarpophalangeal joints is sufficient proof of SSc. If it is not present, seven other signs should be evaluated: (1) skin thickening of the fingers (either sclerodactyly or puffy fingers); (2) fingertip lesions ; (3) telangiectasia; (4) abnormal nailfold capillaries; (5) pulmonary arterial hypertension (PAH) and/or interstitial lung disease; (6) Raynaud\u2019s phenomenon; and 7) SSc-related antibodies: anticentromere and/or anti-topoisomerase I (anti-Scl-70) and/or RNA polymerase III , al, al83], The prevalence of ischaemic heart disease related to vasospasm is increased in SSc patients. The vasospasm is often triggered by low temperature, and this symptom is sometimes labeled as the Raynaud phenomenon of the heart. It might be confirmed by visualising subendocardial hypoperfusion areas during an MRI examination .MRI \u2018wall tagging\u2019 and phase contrast techniques are useful to assess fibrosis and diastolic heart failure .Native and post-contrast T1 mapping combined with T2 mapping and LGE (late gadolinium enhancement) discriminate between several myocardial diseases and notably between myocardial fibrosis and edema. The number of studies regarding T1 and T2 mapping is rapidly increasing and the available data show that native T1 mapping detects left ventricular elevated T1 in 50% of patients with SSc while a third of them had normal conventional screening (including standard CMR). This proves that T1 mapping cardiac MRI imaging frequently detects subclinical diffuse myocardial fibrosis in systemic sclerosis patients .In patients without evidence of fibrosis (in LGE), T1 mapping parameters (extracellular volume fraction (ECV), gadolinium partition coefficient (\u03bb), pre-contrast T1, and post-contrast T1) correlated with the modified Rodnan skin score, indicating a correlation between SSc cardiac and skin fibrosis. .Moreover, T1-mapping offers incremental diagnostic value in the identification of patients with high risk of cardiovascular incidents and in addition to independently predict adverse outcomes at follow-up. Thus, CMR may be considered in cases where echocardiographic results are equivocal but the clinical picture warrants a higher index of suspicion, in order to identify high-risk patients early on and to institute prompt changes in the therapeutic management of SSc-related cardiac involvement .MRI allows to recognize one of the more common manifestations of the SSc in the GI tract\u2014lesions of the anus and rectum. Characteristic symptoms include ventral displacement of the anterior rectal wall, decreased thickness of the anal sphincter, and its reduced contrast enhancement caused by its fibrosis . In the A recent survey implies possible applications of MRI ultrafast echo-spin sequences in diagnosing interstitial pulmonary involvement\u2014a correlation between the results of MRI and HRCT was proven .In conclusion, SSc is associated with various radiological findings of specific organ and system manifestations of SSc, which may be apparent in its initial presentation and/or subsequent disease phases. This review may help clinicians and radiologists in the initial diagnosis and monitoring of progression of SSc."}
+{"text": "This cohort study examines the association of participation in a summer college academic enrichment program with diversity of students in medical school and intent to practice in underserved areas. As a strategy to increase diversity, many organizations and institutions sponsor premedical summer college academic enrichment programs (SCAEPs) that may address Liaison Committee for Medical Education Standard 3.3, Diversity/Pipeline Programs and Partnerships.2 and Graduation Questionnaire.3 The AAMC Human Subjects Office exempted the study from institutional board review because it did not constitute human participant research and used deidentified data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.This cohort study included US medical school matriculants from 2013 to 2015 who graduated through 2019 and voluntarily completed the Association of American Medical Colleges (AAMC) Matriculating Student Questionnaire5, by using program reports to the AAMC and other SCAEP participants (excluding those in SMDEP) by Matriculating Student Questionnaire self-report.2 We examined bivariate associations between SCAEP participation and sex, race/ethnicity, and first-generation college graduate (FGCG) identity and examined factors associated with sustained career intention (Matriculating Student Questionnaire and Graduation Questionnaire self-report) to practice in underserved areas by multilevel logistic regression. P values were 2-sided, and statistical significance was set at P\u2009<\u2009.05. Deidentified individual-level data linked via unique AAMC identifiers were analyzed using Stata, version 15 (StataCorp LLC).We identified SCAEP participants in the Robert Wood Johnson Foundation Summer Medical and Dental Education Program (SMDEP), which is a cost-free, 6-week national program to strengthen academic proficiency and career development of students underrepresented in health care professionsThe study sample included 29\u2009456 graduates . A total of 15\u2009050 (51%) were women, 4375 (15%) were graduates from racial/ethnic groups that are underrepresented in medicine, and 4255 (14%) were FGCGs . Among 25 of SCAEPs have shown an increase in the likelihood of application and matriculation to medical school associated with SCAEP attendance. We observed an association between SCAEPs and increased student diversity and that SMDEP participants were more likely to report sustained career intentions to practice in underserved areas. Because career intention to practice in underserved areas at graduation has established predictive validity,6 our findings may inform medical schools\u2019 investments in programs to recruit diverse students whose career goals align with national needs to increase access to care.Previous studiesOur study was limited by small numbers of American Indian or Alaska Native only and Native Hawaiian or other Pacific Islander only graduates, precluding their examination as discrete groups. In addition, we could not further disaggregate the other SCAEPs , which limits generalizability of observations for this group. In the context of the current coronavirus disease 2019 (COVID-19) pandemic and recent activism in response to anti-Black racism, SCAEPs such as SMDEP  may play a particular role in medical schools\u2019 efforts to recruit and educate a diverse physician workforce that will meet national health care needs."}
+{"text": "Hepatocellular carcinoma (HCC) and pancreatic cancer (PC) belong to the most lethal malignancies worldwide. Despite advances in surgical techniques and perioperative multidisciplinary management, the prognosis of both carcinoma entities remains poor mainly because of rapid tumor progression and early dissemination with diagnosis in advanced tumor stages with poor sensitivity to current therapy regimens. Both highly heterogeneous visceral carcinomas exhibit unique somatic alterations, but share common driver genes and mutations as well. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as non-invasive biomarker in early diagnosis and prognosis. CtDNA released from necrotic or apoptotic cells of primary tumors, metastasis, and circulating tumor cells can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. In this article, we focus on clinical impact of ctDNA as potential biomarker in patients with HCC and PC. Hepatocellular carcinoma (HCC) and pancreatic cancer (PC) represent two of the most challenging visceral malignancies in oncology with rising incidence and lack of reliable biomarkers for early diagnosis, prognosis, and therapy response. PC and HCC are estimated to become the second and third respective leading causes of cancer-related death in western countries by 2030 , Topoisomerase I inhibition by irinotecan, the DNA crosslinking agents oxaliplatin and cisplatin, and the tubulin inhibitor paclitaxel  1\u20133, platelet-derived growth factor receptor (PDGFR) beta, c-KIT, and RAF/mitogen-activated protein/MEK was the sole drug approved for the treatment of advanced HCC between 2007 and 2016 with a response rate of less than 5% and an extended median overall survival of 2.5 months  DNA originates from normal cells exported by exosomes as well as from apoptotic and necrotic cells with highly fragmented, double-stranded DNA of approximately 150\u2013180 base pair fragments in size being released into the bloodstream. In 1948, Mandel and Metais first reported the presence of cfDNA in human circulation followed by detection in urine, saliva, and other body fluids  DNA is becoming a research hotspot with high potential as liquid biopsy marker in cancer medicine  and digital droplet PCR (ddPCR) are the most promising methods for the detection of mutations in liquid biopsies. In general, plasma samples are used in preference over serum because of lower concentrations of wild-type DNA  in HCC patients Table . TERT pr. detected concurrent p15 and p16 methylation in 74% of ctDNA of 23 blood samples from 92% of HCC patients with tumor p15/p16 methylation , RASSF1A, and secreted frizzled-related protein 1 (SFRP1) resulted in an increased accuracy of 93% to differentiate between HCC and healthy controls    and therapy stratification in advanced non-small cell lung cancer patients (Zhang et al. Overall, ctDNA mapping of somatic driver mutations and specific epigenetic alterations has great potential in early detection and dynamic monitoring of hepatic or pancreatic carcinomas to achieve a significant decrease of mortality. However, low sensitivity of current ctDNA assays rest a major challenge.So far, ctDNA analysis in PC and HCC could reveal high frequency of common key mutations as TP53 and CDKN2A. CTNNB1 and TERT mutations and aberrant methylation of RASSF1A and CDKN2A were detected in ctDNA of HCC patients, whereas high frequency of KRAS mutations was characteristic for PC. Prospective trial data based on sufficient sample size and defined entry criteria regarding the blood draw procedure and pre-analytical variables as well as standardization of experimental techniques that demonstrate the clinical utility of ctDNA assays in PC and HCC are required."}
+{"text": "Pterocarya stenoptera is a common fast\u2010growing tree species often used in the ecological restoration of riverbanks and alpine forests in central and eastern China. Until now, the characteristics of the distribution of this species' habitat are poorly known as are the environmental factors that influence its preferred habitat. In the present study, the Maximum Entropy Modeling (Maxent) algorithm and the Genetic Algorithm for Ruleset Production (GARP) were used to establish the models for the potential distribution of this species by selecting 236 sites with known occurrences and 14 environmental variables. The results indicate that both models have good predictive power. Minimum temperature of coldest month (Bio6), mean temperature of warmest quarter (Bio10), annual precipitation (Bio12), and precipitation of driest month (Bio14) were important environmental variables influencing the prediction of the Maxent model. According to the models, the temperate and subtropical regions of eastern China had high environmental suitability for this species, where the species had been recorded. Under each climate change scenario, climatic suitability of the existing range of this species increased, and its climatic niche expanded geographically to the north and higher elevation. GARP predicted a more conservative expansion. The projected spatial and temporal patterns of P.\u00a0stenoptera can provide reference for the development of forest management and protection strategies.Climate change poses a serious threat to biodiversity. Predicting the effects of climate change on the distribution of a species' habitat can help humans address the potential threats which may change the scope and distribution of species.  Minimum temperature of coldest month (Bio6), mean temperature of warmest quarter (Bio10), annual precipitation (Bio12), and precipitation of driest month (Bio14) were important environmental variables influencing the prediction of the Maxent model. Under each climate change scenario, climatic suitability of the existing range of this species increased, and its climatic niche expanded geographically toward farther north and higher elevation. The GARP predicted a more conservative expansion. The results will allow researchers to identify the future suitable habitat and help in the use, management, and cultivation of P.\u00a0stenoptera.To determine the potential geographical distribution and the environmental variables influencing habitat suitability for this species, we used Maxent and GARP modeling to predict the future distribution of 22.1http://www.tropicos.org/), the Global Biodiversity Information Facility (http://www.gbif.org) and the Chinese Virtual Herbarium (http://v5.cvh.org.cn/) database; the latter holds the plant distribution records of the main herbaria of China. Some results from other field survey reports and scientific research literature   for 1984\u20131995 data.Soil variables are important factors controlling plant distribution; they change over relatively short timescales based on direct and indirect effects caused by anthropogenic climate change  2.6 and 8.5 proposed by the Intergovernmental Panel on Climate Change were used for the years 2050 and 2070. The BCC\u2010CSM1.1 is recommended for use in studies of operational short\u2010term climate prediction and studies of climate change in China [see Wu et al.  and refer|\u00a0>\u00a0.90) in each set was retained for further analysis. The variables in the final environmental dataset include precipitation of warmest quarter (Bio18), precipitation of wettest quarter (Bio16), precipitation seasonality (Bio15), precipitation of driest month (Bio14), precipitation of wettest month (Bio13), annual precipitation (Bio12), mean temperature of warmest quarter (Bio10), mean temperature of wettest quarter (Bio8), minimum temperature of coldest month (Bio6), temperature seasonality (Bio4), isothermality (Bio3), and mean diurnal temperature range (Bio2).Principal component analysis and correlation analyses (Pearson's correlation coefficient) were carried out to minimize the overfitting of the model and decrease the high collinearity. Only one of the highly correlated variables  , Bio10 (14.1% of variation), Bio12 (23.2% of variation) and Bio14 (29.2% of variation)  for those four most important variables in Maxent were generated to examine the climatic preference of a Figure\u00a0. Overall3.3P.\u00a0stenoptera  and modeling methods (GARP and Maxent), showing that the climatic suitability of the existing distribution range increased, and the suitable habitats of the species expanded geographically to the north and to higher elevations  , mean temperature of warmest quarter (Bio10), annual precipitation (Bio12), and precipitation of driest month (Bio14) were the most important environmental variables influencing the distribution of this species. The projected spatial and temporal patterns of P.\u00a0stenoptera can provide reference for the development of forest management and protection strategies.Under the climate change scenario, high\u2010quality distributional data play an important role in setting priorities and implementing effective protection actions. Our results indicate that the areas of suitable habitat for The authors declare no competing interest.Keliang Zhang: Formal analysis ; funding acquisition ; methodology ; writing \u2013 original draft . Huina Liu: Formal analysis ; writing \u2013 original draft ; writing \u2013 review and editing . Haolei Pan: Data curation ; investigation ; resources ; software . Yi Zhao: Data curation ; investigation ; resources ; software . Wenhao Shi: Data curation ; investigation ; resources ; software ; visualization . Silei Li: Data curation ; investigation ; resources ; visualization ; writing \u2013 original draft . Junchi Liu: Data curation ; investigation ; resources ; software ; visualization . Jun Tao: Conceptualization (lead); formal analysis ; project administration (lead); supervision (lead); writing \u2013 review and editing ."}
+{"text": "IGF2BP2 is known to affect both life span and energy expenditure. The positively selected mutations detected in IGF2BP2 likely affected the functionality of the encoded protein. IGF2BP2, which has been reported to simultaneously prolong life span and increase energy expenditure, could be responsible for the evolution of shortened MLS associated with the loss of flying ability.Acquisition or loss of flying ability is evolutionarily linked with maximum life span (MLS) in mammals and birds. Although ecological factors, such as extrinsic mortality, may lead to either shortened or extended life spans through natural selection, MLS is influenced by complex molecular and metabolic processes, and the genetic changes associated with flying ability that have led to either a longer or shorter MLS are unknown. Here, we examine the parallel evolution of flight in mammals and birds and investigate positively selected genes at branches where either the acquisition (in little brown bats and large flying foxes) or loss  of flight abilities occurred. Although we found no shared genes under selection among all the branches of interest, 7 genes were found to be positively selected in 2 of the branches. Among the 7 genes, only  Positively selected genes at the branches of interest. It has been proposed that species with lower extrinsic mortalities have longer life spans because they can invest in long\u2010term survival  receptors may have contributed to the evolution of their long life spans  and the little brown bat (Myotis lucifugus), as volant species with a longer MLS in mammals; and two penguins, the Ad\u00e9lie penguin (Pygoscelis adeliae) and the emperor penguin (Aptenodytes forsteri), and eight ratites, the common ostrich (Struthio camelus), the emu (Dromaius novaehollandiae), the great spotted kiwi (Apteryx haastii), the little spotted kiwi (Apteryx owenii), the okarito brown kiwi (Apteryx rowi), the greater rhea (Rhea americana), the lesser rhea (Rhea pennata), and the cassowary (Casuarius casuarius), as nonvolant birds with a shorter MLS. We then searched for positively selected genes among the different lineages to identify genes that evolved in parallel and are related to both flying and life span. Genes detected among multiple branches where changes in flying ability had occurred are discussed for their possible roles in energy expenditure and alteration in life spans.To shed light on the parallel evolution of either longer or shorter MLSs with that of either acquisition or loss of flight ability, it is necessary to examine candidate genes that have been subject to positive selection in multiple lineages of birds that have lost their flying ability in addition to those of mammals that have evolved the ability to fly. The purpose of our research was to detect positively selected genes at the branches where the acquisition or loss of flying ability occurred, using whole\u2010genome\u2010sequenced mammals and birds, and to explore the genes responsible for shorter or longer MLSs associated with the evolution of the loss or acquisition of flying ability. We chose two bats, the large flying fox (22.1Felis catus), cow (Bos taurus), dog (Canis lupus familiaris), elephant (Loxodonta africana), horse , human being (Homo sapiens), marmoset , mouse (Mus musculus), opossum (Monodelphis domestica), pig (Sus scrofa), platypus (Ornithorhynchus anatinus), rabbit (Oryctolagus cuniculus), rat (Rattus norvegicus), and sheep (Ovis aries) were selected as nonvolant species, and the large flying fox (Pteropus vampyrus) and little brown bat (Myotis lucifugus) were selected as volant species. All genome sequences were obtained from Ensembl 98 , emperor penguin (Aptenodytes forsteri), common ostrich (Struthio camelus), emu (Dromaius novaehollandiae), great spotted kiwi (Apteryx haastii), little spotted kiwi (Apteryx owenii), okarito brown kiwi (Apteryx rowi), greater rhea (Rhea americana), lesser rhea (Rhea pennata), and cassowary (Casuarius casuarius) were selected as nonvolant species, and the American crow (Corvus brachyrhynchos), Anna's hummingbird , bald eagle , mallard (Anas platyrhynchos), budgerigar (Melopsittacus undulatus), chimney swift (Chaetura pelagica), common cuckoo (Cuculus canorus), crested ibis (Nipponia nippon), downy woodpecker (Picoides pubescens), golden\u2010collared manakin (Manacus vitellinus), killdeer (Charadrius vociferus), little egret (Egretta garzetta), medium ground finch (Geospiza fortis), peregrine falcon , pigeon (Columba livia), and zebra finch (Taeniopygia guttata) were selected as volant species. Genomes of the zebra finch, emu, and the three kiwis were obtained from Ensembl 98 , reportedly the longest\u2010living bat, and the flightless brown kiwi  were not included in our analysis as their assembled genome sequences included many gaps and a sufficient number of orthologous genes was not available. Analyses for mammals and birds were conducted separately. We performed reciprocal basic local alignment search tool (BLAST) searches and obtained the highest score pairs of one\u2010to\u2010one orthologs using the BLASTp algorithm in National Center for Biotechnology Information\u00a0(NCBI) BLAST v.2.6.0+  or those that rarely fly (such as the tinamou or hoatzin). For mammals, the genome sequences of the cat . We focused on genes detected via both calculations with a gene tree and species tree, and the genes detected by both PAML and aBSREL analyses were considered candidates under positive selection. To evaluate parallel and/or convergent evolution between avian and mammalian species, we used one\u2010to\u2010one ortholog information between humans  and zebra finches (the reference species in birds) inferred by BLASTp  terms and pathways using the over\u2010representation test with Fisher's exact test and the Benjamini\u2013Hochberg procedure in PANTHER version 14.1  ; Visualization ; Writing\u2010original draft ; Writing\u2010review & editing . Daiki X. Sato: Formal analysis (supporting); Writing\u2010original draft (supporting); Writing\u2010review & editing (supporting). Takashi Makino: Formal analysis (supporting); Writing\u2010review & editing (supporting). Masakado Kawata: Conceptualization ; Supervision (lead); Writing\u2010original draft ; Writing\u2010review & editing (lead). Fig S1\u2010S19Click here for additional data file.Table S1\u2010S52Click here for additional data file."}
+{"text": "Oreolalax major was determined using polymerase chain reaction (PCR). It includes 13 protein-coding genes (PCGs), 2 ribosomal RNA (rRNA) genes and 19 transfer RNA (tRNA) genes (GenBank accession number KU310894). The features of O. major have one more tRNA gene (MettRNA) behind the original one before ND2 which is similar to Leptobrachium boringii. Phylogenetic analyses were based on the concatenated sequences of the 13 protein-encoding genes of O. major and other related species.In this study, the near complete mitogenome sequence  of  Oreolalax major (Liu & Hu 1960) belongs to family Megophryidae, genus Oreolalax. It is an endemic species of China, which is distributed in Hengduan Mountains of western Sichuan and southern Gansu Provinces  was collected from Wawushan Nature Reserve, Hongya , Sichuan, China in June, 2015. It was fixed in 75% ethanol and deposited in the Museum of Sichuan Agricultural University. The total DNA was extracted and purified from muscle tissue using the Ezup pillar genomic DNA extraction kit . We used twenty-three pairs of polymerase chain reaction (PCR) primers published by Zhang et\u00a0al. , 2 ribosomal RNA (rRNA) genes and 19 transfer RNA (tRNA) genes (GenBank accession number KU310894). The features of O. major have one more tRNA gene (MettRNA) behind the original one before ND2 which is similar to Leptobrachium boringii tRNA and GlutRNA genes. We regrettably did not sequence the region between 12S rRNA and Cyt b genes which contains 4 rRNA genes and 1 D-loop region because of difficult to amplify. There are two types of initiation codons used for 13 PCGs and most PCGs initiate from ATG, while others  start with GTG. In addition, 5 PCGs  terminate in incomplete stop codon T, the same number of PCGs  use complete stop codon TAA, and the rest of PCGs end with AGG. The 12S rRNA and 16S rRNA are determined to be 936\u2009bp and 1598\u2009bp long respectively and all the tRNA genes can constitute typical cloverleaf secondary structure exclude Ser(AGY)tRNA.The near complete mitochondrial genome of The NJ analysis of the combined data set indicates that all samples of Megophryidae form a strong supported  monophyletic group  and all"}
+{"text": "The purpose of this study was to describe the ocular findings, structural ocular complications, and vision impairment in a cohort of Lassa fever survivors in Kenema, Sierra Leone. A retrospective, uncontrolled, cross-sectional study of 31 Lassa fever survivors (62 eyes) who underwent an ophthalmic evaluation in January 2018 at the Kenema Government Hospital in Kenema, Sierra Leone was performed. Data collection included demographic information, ocular/systemic symptoms, visual acuity (VA), and ophthalmic examination findings. Main outcome measures included anterior and posterior segment ophthalmic manifestations and level of VA impairment in Lassa fever survivors. Anterior segment findings included cataract (18%) and pterygium (2%), while posterior segment manifestations consisted of glaucoma (6%), preretinal hemorrhage (2%), and lattice degeneration (2%). Findings suggestive of prior sequelae of uveitis included chorioretinal scarring (5%), retinal fibrosis (3%), and vitreous opacity (2%). Visual acuity was normal/mildly impaired in 53 eyes (85%), moderately impaired in 6 eyes (10%), and 3 eyes (5%) were considered blind by the World Health Organization (WHO) criteria. Median VA was worse in Lassa fever survivors with ophthalmic disease findings (p<0.0001) for both anterior segment (p<0.0001) and posterior segment disease (p<0.013). Untreated cataract was a significant cause of visual acuity impairment (p<0.0001). Lassa fever survivors in this cohort were found to have cataract and posterior segment findings that potentially represent sequelae of uveitis associated with visual impairment. Future studies are warranted to improve our understanding of the spectrum of ocular disease in this emerging infectious disease of public health consequence. Arenaviridae family. Lassa fever is endemic to the West Africa countries of Benin, Ghana, Liberia, Guinea, Mali, Sierra Leone and Nigeria, affecting 100,000 to 300,000 people annually, and causing approximately 5,000 deaths per year  19\u201350). The median time from the date of Lassa fever diagnosis to the date of ophthalmic examination was 10.03 years (IQR 6.0\u201312.0). Five patients (16.1%) reported eye symptoms including pain, redness, and blurry vision during the acute phase of Lassa fever. At the time of ophthalmic examination, Lassa fever survivors reported ocular symptoms including blurry vision (42%), itching (13%), pain (6%), redness (6%), tearing (6%), loss of near vision (3%), and floaters (3%) . Review Anterior segment findings included cataract (18%) and pterygium (2%). One patient had a traumatic cataract from penetrating corneal injury, which had self-sealed without surgical repair and showed evidence of uveitis with focal posterior synechiae . This siOphthalmic manifestations in the posterior segment included the presence of glaucomatous optic neuropathy (6%), chorioretinal scarring (5%), retinal fibrosis (3%), peripheral drusen (3%), preretinal hemorrhage (2%), lattice degeneration (2%), and vitreous opacity (2%) . There wVisual acuity was normal or mildly impaired in 53 eyes (85%), moderately impaired in 6 eyes (10%), and 3 eyes (5%) were considered blind according to the World Health Organization classification of visual impairment . The thrWe analyzed the impact of ocular structural complications on visual acuity, which are summarized in any ophthalmic abnormality by exam (p > 0.05). Individuals with any ocular abnormalities were likely to be older  compared to patients evaluated without ocular findings . Patients who were older tended to report blurred vision symptoms  than younger patients . Gender was not associated with the presence of ocular complications or blurred vision symptoms .A significant minority of Lassa fever survivors (42%) reported blurred vision and we thus assessed the relationship of this patient-reported symptom to visual acuity impairment and ophthalmic findings. No association was observed between individuals with reported blurred vision and at least moderate visual acuity impairment . In addition, no association was observed between blurred vision and evidence of Audiovestibular symptoms and joint pain have been reported in Lassa fever survivors and their relationship to ophthalmic disease was analyzed. Seven patients were found to have audiovestibular symptoms (23%) including 6 with hearing loss and 1 patient with tinnitus, which developed after acute Lassa fever. Hearing loss included bilateral disease (1), right ear (2), left ear (1) and unspecified (2). Hearing loss was not associated with patient-reported blurred vision or the presence of posterior segment or anterior segment disease findings . Joint pain was similarly unassociated with ocular findings (p > 0.05) in our series of patients, although like hearing loss, was observed in a modest proportion (26%) of patients evaluated.The ophthalmic sequelae of Lassa fever have not been well-characterized, and the aim of this study was to provide a preliminary investigation of the ophthalmic manifestations in Lassa fever survivors. Ocular involvement during the acute phase of Lassa fever has been reported to manifest as conjunctivitis, typically starting on day 7 of illness and lasting for a duration of 5 days . SubconjBlurry vision was a common visual complaint with over 40% of patients describing this symptom at the time of ophthalmic evaluation. The majority of patients (85%) had normal or mild vision impairment according to the WHO classification of visual impairment. While McCormick et al identified cases of uveitis with transient vision loss, we did not observe signs of active uveitis in our cohort of Lassa fever survivors who were evaluated . MoreoveThere are few reports in the literature documenting the prevalence and causes of visual impairment in the general population in West Africa. The Tema Eye Survey, a population-based cross-sectional study of 5,603 participants residing in an urban West African location, reported a 17.1% prevalence of visual impairment and 1.2% rate of blindness in Tema, Ghana, West Africa . RefractOther untreated ophthalmic conditions that were observed in our study of Lassa fever survivors included open globe trauma, cataract and advanced glaucoma. Specifically, cataract and end-stage glaucoma were identifiable causes of blindness (vision loss worse than 20/400) in three patients (9.7%). A dense mature cataract precluded view to the fundus in one of these patients, and thus it is unknown whether there were other posterior segment findings suggestive of cataract formation related to intraocular inflammation or if the cataract was merely age-related. The mechanism of glaucoma is unknown in the two patients with end-stage glaucoma and hand motions visual acuity; however, they did not have visible sequelae of prior ocular inflammation. In comparison, a retrospective study of a hospital population in Sierra Leone, West Africa conducted in 1989 and 1992 revealed that senile cataract was the major cause of blindness  followed by uveitis despite a significant decrease in blindness from onchocerciasis . BlindneLong-term systemic symptoms were also present at the time of ophthalmologic examination, including joint pain (26%), hearing loss (16%), and headache (16%). Hearing loss is a well-documented and potentially profound sequelae of Lassa fever, and a literature review of five hospital-based and population-based studies of Lassa fever survivors revealed that approximately one-third (4%-75%) of Lassa virus-infected patients developed sudden sensorineural hearing loss . Our limAnimal studies have been utilized to better understand the pathogenesis of LASV in the eye and to investigate the possibility of LASV persistence in this immune-privileged site , 21. WalArenaviridae family include accounts of similar descriptions of chorioretinal scarring in lymphocytic choriomeningitis virus (LCMV) [The few reports of ocular involvement in other members of the s (LCMV) \u201324. Thiss (LCMV) . In parts (LCMV) . In a res (LCMV) . Mets ets (LCMV) . LCMV ins (LCMV) .Ocular manifestations in viral hemorrhagic fever disease is not limited to Lassa fever and has been described previously with other hemorrhagic fevers including Ebola virus disease (EVD) and Marburg virus disease . A singlToxoplasma gondii. Selection bias was also a potential limitation, as patients may have presented for an ophthalmic examination primarily if they reported ocular symptoms. Future controlled, longitudinal studies with larger sample sizes are planned to characterize the prevalence of ocular disease and the spectrum of ophthalmic complications associated with Lassa fever.Limitations of our study include the cross-sectional, retrospective nature of the study. Because ophthalmic examination occurred at a single time point, the patient\u2019s baseline eye disease was unknown, and we were unable to ascertain whether the patients\u2019 cataract or chorioretinal scarring occurred as an immediate consequence of Lassa virus infection. Understanding the timing of the ocular findings following acute Lassa virus infection will allow clinicians and investigators to understand the potential relationship between the ocular findings identified and Lassa fever. It is currently unknown whether the etiology of chorioretinal scarring was from prior trauma or other infectious agents such as In summary, this cross-sectional, retrospective study highlights the first detailed characterization of ophthalmic manifestations in Lassa fever survivors. Evidence of cataract and prior sequelae of intermediate and posterior uveitis were present in this cohort of Lassa fever survivors. Moderate vision impairment was present in 10% of the patients in our study, highlighting the need for further investigation into ophthalmic complications of LASV infection during the acute phase of disease and convalescence. Future studies are warranted to improve our understanding of long-term ophthalmic sequelae and the spectrum of ocular disease in Lassa fever survivors, particularly given its high annual incidence in West Africa and our ophthalmology field\u2019s mandate to understand emerging infectious diseases of public and global health consequence.S1 Dataset(XLSX)Click here for additional data file."}
+{"text": "In contrast, in Li+-containing buffer, SERT showed only low force interactions. Conversely, the vestibular mutant SERT-G402H merely displayed the high force population. These observations provide physical evidence for the existence of two binding sites in SERT. The dissociation rate constant of both binding sites was extracted by varying the dynamics of the force-probing experiments. Competition experiments revealed that the two sites are allosterically coupled and exert reciprocal modulation.Crystal structures and experiments relying on the tools of molecular pharmacology reported conflicting results on ligand binding sites in neurotransmitter/sodium symporters (NSS). We explored the number and functionality of ligand binding sites of NSS in a physiological setting by designing novel tools for atomic force microscopy (AFM). These allow for directly measuring the interaction forces between the serotonin transporter (SERT) and the antidepressant S-citalopram (S-CIT) on the single molecule level: the AFM cantilever tips were functionalized with S-CIT via a flexible polyethylene glycol (PEG) linker. The tip chemistry was validated by specific force measurements and recognition imaging on CHO cells. Two distinct populations of characteristic binding strengths of S-CIT binding to SERT were revealed in Na Aa (Drosophila melanogaster dopamine transporter) (The serotonin transporter (SERT) is a member of the monoamine neurotransmitter sodium symporter (NSS) family . Its epoAa  and dDATsporter) , indicatsporter)  of NSS tsporter) .To date, a series of crosslinkers have been developed for covalent conjugation of functional molecules to atomic force microscopy (AFM) cantilever tips. Some conventional linkers are NHS-PEG-aldehyde , NHS-PEGForce measurements were conducted on living CHOK1 cells  stably eThe validity of the tip chemistry was also shown by topography and recognition imaging (TREC) . TREC isFrom a large amount of repeated force measurements using the same conditions, two populations with distinct unbinding forces  were obs3H]HT uptake was not detectable  and the width (xB) of prominent energy barriers of the interaction for the individual force populations by plotting the unbinding forces as a function of the force loading rate  for both S1 and S2  were in agreement with those determined for the S1 site by force spectroscopy (0.032 \u00b1 0.005 s\u20131) (We extracted the dissociation rate constant (k1 and S2 . We reli1 and S2  was empl005 s\u20131) .Dissociation of S-CIT at the central S1 site is delayed, if the vestibular S2 site is occupied by either S- or R-CIT . This obThe flexible PEG linker between the AFM tip and the CIT molecule provides the unique opportunity to explore the binding sites of different depths in transmembrane transporter. Force sensing in physiological conditions allowed for the extraction of dynamic information, thus unequivocally documenting the existence of two binding sites in SERT. Furthermore, our force experiments revealed a positive allosteric effect on the S2 site induced by the binding of S-CIT at S1 site. Given the importance of allosteric regulation in biology and pharmacology, SMFS provides a unique approach to explore transient binding sites in clinically relevant membrane transporters for addressing the modulation of interaction forces between ligands and allosterically coupled binding sites.Indeed, such an allosterically enhanced binding strength of S-CIT at the S2 site could be a critical contribution for the capture of the S2 site by X-ray crystallography. The X-ray structure of SERT bound with S-CIT  verifiedWe notice that the only common amino acid residue of S2 site revealed by the crystal structure and previous studies is the arginine R104. The involvement of R104 in S2 site is partially supported by the experiment of recognition imaging . The bloFurther developed AFM techniques have provided the possibility to measure the depth of ATP binding site in mitochondrial uncoupling protein 1 (UCP1)  or to reAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Globally, wetlands are in decline due to anthropogenic modification and climate change. Knowledge about the spatial distribution of biodiversity and biological processes within wetlands provides essential baseline data for predicting and mitigating the effects of present and future environmental change on these critical ecosystems. To explore the potential for environmental DNA (eDNA) to provide such insights, we used 16S rRNA metabarcoding to characterise prokaryote communities and predict the distribution of prokaryote metabolic pathways in peats and sediments up to 4m below the surface across seven New Zealand wetlands. Our results reveal distinct vertical structuring of prokaryote communities and metabolic pathways in these wetlands. We also find evidence for differences in the relative abundance of certain metabolic pathways that may correspond to the degree of anthropogenic modification the wetlands have experienced. These patterns, specifically those for pathways related to aerobic respiration and the carbon cycle, can be explained predominantly by the expected effects of wetland drainage. Our study demonstrates that eDNA has the potential to be an important new tool for the assessment and monitoring of wetland health. These aspects include: 1) identification of sensitive indicators  for discriminating different types of anthropogenic disturbance ; 2) demonstrating consistency of indicator responses across different wetlands and wetland types; and 3) using temporal sampling to show whether reverse trends in indicators of anthropogenic disturbance are detectable in wetlands undergoing restoration.S1 FigFilled circles represent sample depths.(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "Dear Editor,JAK2 V617F mutation, insertion and/or deletion (indel) mutations of CALR exon 9 are the second most common driver mutations in the myeloproliferative neoplasms (MPN) of essential thrombocythemia and primary myelofibrosis and their detection is considered a major diagnostic criterion for these malignancies. It is becoming increasingly apparent that MPNs harboring CALR mutations  may occur in patients with BCR-ABL1-positive chronic myeloid leukemia (CML) as evidenced by a wave of recently reported cases. The CALR-positive MPN and CML may appear concurrently with composite morphology or sequentially with either malignancy revealed as a consequence of specific treatment for one of the malignancies (Table 1CALR-mutated MPN in the remaining 12/24 (50 %) cases. Evidence exists for molecular abnormalities occurring within a single clone and in distinct clonal populations.After the JAK2 V617F mutation in all newly presenting CML cases (McCarron et al., 2012[CALR and MPL mutations in all likelihood would show a similar redundancy. Given the low incidence but increasing awareness of co-existing CML and MPN, testing for the relevant rearrangement should therefore be implemented when there is clinical, hematological or morphological evidence.While co-existence of CML and another MPN has clinical relevance with respect to selection and timing of tyrosine kinase inhibitor therapy, there is currently insufficient follow-up data to ascertain overall survival of such cases. There is limited value in assessing the The author declares no conflicts of interest."}
+{"text": "Older adults\u2019 behavioral stage of change for adopting fall prevention interventions, and their use of evidence-based interventions are not well understood. A survey was administered to older adults (65 years+) (n=1063) to understand their stage of change and fall prevention behaviors. Descriptive statistics were calculated and logistic regression conducted to determine factors most related to stage. The distribution of subjects by stage was precontemplation (17%), contemplation (2%), preparation (5%), action (15%), and maintenance (61%). The strongest variable related to being in an action stage  was screening positively for fall risk . The most common preventive actions for those in an action stage were taking Vitamin D (37%), and having vision tested (30%). Older adults at risk for a fall are ready to take action to prevent falls; health promotion should focus on increasing knowledge and use of different evidence-based interventions."}
+{"text": "Alternative splicing generates multiple protein isoforms from one primary transcript and represents one of the major drivers of proteomic diversity in human cells . AlternaAlthough significant progress has been made in recent years, important questions still remain to be addressed. In particular, we need to determine (i) the role(s) of the majority of the splicing isoforms during physiological  processes, (ii) the factors involved in their production, and (iii) how splicing is integrated with other gene expression regulatory programs.RAD6B gene and their association with melanoma pathogenesis [SMN2 gene [moso bamboo (an important forest species) by supporting the translation of a fraction of transcript isoforms targeted by nonsense-mediated mRNA decay (NMD) pathway [Trichophyton rubrum (a dermatophytic fungus) suggesting strategies employed by dermatophytes in response to antifungal therapy [This special issue collects recent insights addressing the above interrogatives. More specifically, Palombo and colleagues illustrate the function of two splicing factors (hnRNPM and SRSF3) in regulating DHX9 poison exon, with potential implications in Ewing sarcoma proliferation and sensitivity to chemotherapy , whereasogenesis , while Mogenesis , which mMN2 gene . In thei pathway . Taking  therapy .This special issue also includes four reviews. In particular, Biamonti and colleagues discuss the key role played by alternative splicing in cancer cell plasticity and tumor heterogeneity . The posWe hope that the articles and reviews included in this special issue will illuminate new progresses in the field of alternative splicing and its function(s) in physiological and pathological conditions."}
+{"text": "Needs during and following end-of-life (EOL) experiences are distinctive for sexual and gender minority (SGM) people and, in particular, older lesbian, gay, and bisexual women (LGB) women; however, access to supportive services is limited. This poster presents findings from a qualitative study of older (60+) LGB women who have lost a spouse or partner. This work draws on queer gerontological theory, addressing issues of individual agency, systemic silence, and marginalization by invisibility of older SGM women in order to illuminate specific areas in which policy may be changed and improved. The study analyzed participants\u2019 (n = 16) reflections on their experiences of losing a loved one, including how they sought out and received essential grief support and the type of support they would have preferred and from whom, particularly immediately following their spouse or partner\u2019s death. Thematic analysis revealed three main findings: 1) having a women-identifying support presence at the time of death for both themselves and their spouse or partner; 2) needing LGB women  during EOL for support; and 3) preferring grief groups comprised of other LGB women  based on their feelings of difference from gay men and heterosexual/non-SGM women and men. Findings reveal the need for a better understanding among healthcare and social work support professionals regarding LGB women\u2019s grief needs and preferences; grief options  grief groups); and how to implement policy changes reflecting these needs and preferences."}
+{"text": "The Saint Louis University GWEP partners with a rural Missouri critical access hospital and an urban Federally Qualified Health Center to support their transformations into an Age-Friendly Health System in their community. With an emphasis on the 4Ms, programmatic innovations include development and training of: 1) electronic health records integration of the Rapid Geriatric Assessment (RGA) for patients 65+ years old; 2) RGA-based protocol for Medicare Annual Wellness Visits (MAWV); 3) Interprofessional health care team approach; 4) Evidence-based or Evidence-Informed treatment interventions, including Cognitive Stimulation Therapy (CST), exercise and strengthening program, caregiver support, and Circle of Friends, an intervention for loneliness and social isolation. Outcomes will be presented which suggest increased assessment practices and improvement in functional and cognitive status. Successes and lessons learned regarding strategies to develop an Age-Friendly Health System in two different primary care settings will be discussed."}
+{"text": "This article has been corrected: The authors requested replacement of Figure 4h (upper panel). Originally, to represent the morphology of brown adipose tissue (BAT) in the Middle-Aged group, the authors used the same image in Figure 3c (lower panel) and Figure 4h (upper panel). To avoid misinterpretation, they have replaced the Middle-Aged, Rest panel  with a representative image from the original set of experiments. This alteration does not affect the results or conclusions drawn in this work."}
+{"text": "Recombinant human insulin plays an important role in the gut maturation of preterm infants. This meta-analysis was carried out to assess the efficacy and safety of enteral recombinant human insulin in decreasing the time to full enteral feeding in preterm infants. The pooling of data from four clinical trials yielded a significant decrease in the time to full enteral feeding in preterm infants under both low  and high doses of insulin . These findings require confirmation by further large trials that evaluate the efficacy and safety of enteral insulin, especially at supraphysiological doses. A preterm birth is categorized as the birth of a baby before 37 weeks of gestation . Around Studies on animal models suggest that maternal milk contains factors that stimulate the development of the gastrointestinal tract . These iSome clinical trials have been conducted on this topic, but they have not been systematically evaluated. In this study, we aim to evaluate the efficacy and safety of enteral human recombinant insulin in reducing the time to full enteral feeding in preterm infants. Our meta-analysis will help to determine if this intervention can prevent feeding intolerance and associated complications in this vulnerable population.This meta-analysis was conducted according to the guidelines of the Preferred Reporting Items for Systematic Review (PRISMA) . The PRIWe initially screened articles based on titles and abstracts and then screened them by reading the full text of the research articles. Two separate authors (FQ and MA) conducted the screening, and any conflicts and discrepancies were resolved through discussion with the third author (MA). We included controlled clinical trials that enrolled preterm infants and compared the efficacy of recombinant human insulin concentration with placebo or no treatment. Our outcomes of interest were the reduction in the time to full enteral feeding and the incidence of serious adverse events.2 statistic. We evaluated the efficacy of enteral insulin in two doses: (a) the physiological dose (400 \u00b5IU/mL milk) present in human colostrum (low dose) and (b) a supraphysiological dose (2000 \u00b5IU/mL milk) (high dose) [We pooled the data using RevMan 5.4 software under a random-effects model using mean differences (MDs) and risk ratios (RRs) with their 95% confidence intervals (CIs). Heterogeneity was assessed by the Igh dose) .The screening process identified four trials meeting the inclusion criteria that contributed five comparisons to the meta-analysis with a total of 388 participants  ,14,15,16The quality assessment of RCTs was carried out using the revised Cochrane Risk of Bias (RoB 2.0) tool . One tri2 = 48%; 2 = 0%; The results of our meta-analysis show that the use of enteral recombinant human insulin significantly decreased the time to full enteral feeding in preterm infants at both low  should be evaluated."}
+{"text": "Anemia in patients with chronic kidney disease (CKD) is associated with increased morbidity and mortality, decreased quality of life, and substantial health care costs. Iron therapy is recommended, usually in combination with an erythropoiesis-stimulating agent (ESA), in many CKD patients with anemia and low iron levels to raise hemoglobin levels to a range of 10 to 12 grams per deciliter; iron deficiency is defined by a ferritin score less than 100 micrograms (mcg) per liter and transferrin saturation (TSAT) less than 20%.To examine the use of intravenous (IV) iron and it's associated economic and clinical outcomes in Medicare beneficiaries with stage 3 or stage 4 CKD and anemia.This was a retrospective cohort analysis using 2006 and 2007 Medicare 5% Standard Analytic Files (SAF). Use of therapy with IV iron and/or ESAs was identified among patients diagnosed with CKD and anemia. The study index quarter was the first quarter in 2006 during which the patient had primary or secondary diagnoses of both CKD and anemia. Based on the receipt of IV iron or ESA treatment in the index quarter, patients were classified into 1 of 4 treatment groups: IV iron and ESA; IV iron without ESA; ESA without IV iron; neither IV iron nor ESA. Therapy with oral iron was not measurable with this database. Clinical and economic outcomes, including the progression to advanced CKD stages, development of anemia, mortality, hospitalization, and net Medicare reimbursement  for all-cause health care services, were examined for 1 year following the index quarter. Between-group differences were tested using Pearson chi-square for categorical variables and the Kruskal-Wallis nonparametric test for reimbursement. Multivariate logistic regression models were estimated to assess the associations of mortality, inpatient hospitalization, skilled nursing facility (SNF) admission, and hospice care with treatment regimen, controlling for patient demographic and clinical characteristics.Of the 4,310 study patients with both CKD and anemia, 2,913 (67.6%) received neither IV iron nor ESA; 984 (22.8%) received ESA without IV iron; 277 (6.4%) received IV iron and ESA; and 136 (3.2%) received IV iron without ESA in the index quarter. Logistic regression analyses showed that patients receiving neither IV iron nor ESA (reference group) were at increased risk of death compared with patients receiving both IV iron and ESA . Additionally, patients receiving neither IV iron nor ESA were more likely to be hospitalized compared with patients receiving both IV iron and ESA , IV iron without ESA , and ESA without IV iron . Further, patients not receiving IV iron or ESA were more likely to be admitted to an SNF than patients receiving both IV iron and ESA , IV iron without ESA , and ESA without IV iron . Patients receiving neither IV iron nor ESA in the index quarter had the highest mean [SD] total Medicare reimbursement per patient in the subsequent year  compared with patients receiving IV iron without ESA , IV iron and ESA , or ESA without IV iron .Use rates of IV iron and ESA in a sample of Medicare enrollees with CKD and anemia in 2006 suggest that anemia management therapies may be underutilized; however, oral iron therapy use was not measurable with the study database, and therapies initiated after the index quarter were not measured. Patients not treated with IV iron or ESA had significantly higher rates of hospitalization and SNF admission than patients treated with either IV iron or ESA. Further, mortality was significantly higher in patients receiving neither IV iron nor ESA than in patients who received IV iron and ESA. Additionally, total all-cause health care costs were higher among patients receiving neither IV iron nor ESA treatment compared with patients treated with IV iron and/or ESA."}
+{"text": "Due to a production error, the funder University of Bern was erroneously omitted. Statement to be added, \u201cOpen access funding by University of Bern.\u201d The corrected Funding statement appears below:\u201cData collection and publication was supported financially by the canton of Aargau. Internal funding of research time. JJ work in tobacco prevention is funded by a career development award (CDA) funded by Swiss Academy of Medical Sciences (SAMS) (YTCR-34/19). Open access funding by University of Bern.\u201dThe publisher apologizes for this mistake. The original article has been updated."}
+{"text": "Arabidopsis thaliana), neighbor cues reduce the activity of the photosensory receptors phytochrome B (phyB) and cryptochrome 1, releasing photoreceptor repression imposed on PHYTOCHROME INTERACTING FACTORs (PIFs) and leading to transcriptional reprogramming. The phyB-PIF hub is at the core of all shade-avoidance responses, whilst other photosensory receptors and transcription factors contribute in a context-specific manner. CONSTITUTIVELY PHOTOMORPHOGENIC1 is a master regulator of this hub, indirectly stabilizing PIFs and targeting negative regulators of shade avoidance for degradation. Warm temperatures reduce the activity of phyB, which operates as a temperature sensor and further increases the activities of PIF4 and PIF7 by independent temperature sensing mechanisms. The signaling network controlling shade avoidance is not buffered against climate change; rather, it integrates information about shade, temperature, salinity, drought, and likely flooding. We, therefore, predict that climate change will exacerbate shade-induced growth responses in some regions of the planet while limiting the growth potential in others.When exposed to changes in the light environment caused by neighboring vegetation, shade-avoiding plants modify their growth and/or developmental patterns to access more sunlight. In Arabidopsis ( The signaling network involved in shade avoidance responses integrates information from environmental variables such as temperature, water availability, and salinity. Shade avoidance responses are changes in plant growth and/or developmental patterns elicited by modifications of the light environment caused by neighboring vegetation. Their function is to increase access to sunlight and reduce the risk of future shade .There are four strategies  to achieve these goals: (a) To overtop neighbors, elevating the foliage above vegetation shade; (b) to move the position of the foliage on the horizontal plane away from the shade of neighbors; (c) to reduce the proportion of the foliage placed at the shaded base of the canopy; and (d) to modify the phenology to elude the time when deep shade is present.The growth and developmental responses inherent to each one of these strategies, respectively, include (a) enhanced elongation of the stem or petioles and the shift of leaves to a more erect position (enhanced leaf hyponasty); (b) asymmetric growth of the stem or the leaves (the phototropic response of light-grown seedlings can be included within this class of shade avoidance responses) and asymmetric branching; (c) the inhibition of branching at the base of the plant, the reduction of expansion of shaded leaves and the advanced senescence of basal leaves; and (d) the accelerated transition to reproduction (flowering) to complete the life cycle before shade becomes too deep and the delayed seed germination until shade disappears.Glycine max) (Helianthus annuus) (Triticum aestivum) (Hordeum vulgare) (Sorghum bicolor) (Zea mays)  and sunflower   and sunf annuus) , reduce estivum) , barley vulgare) , and sorbicolor) , and enhbicolor)  and orieea mays)  and sunfea mays) . Enhanceunflower . The widArabidopsis thaliana) for which the molecular events are best understood. We propose that the output of this network integrates different light, temperature, salinity, drought, and likely flooding cues and is, therefore, affected by climate change.Different species may show selected components of the shade-avoidance syndrome and shade avoidance is actually weak in shade-tolerant plants adapted to the understory of tree canopies . This reThe presence of neighbors modifies diverse features of the physical and chemical environment, including mechanical cues , which cCompared with isolated plants, the intensity of neighbor cues shows three phases of progressive strength with closer proximity to these neighbors and increased size particularly of their green organs . First, A. thaliana, sunlight activates phyB and cry1 to repress shade avoidance responses. The loss-of-function mutants of these photosensory receptors show shade avoidance responses under full sunlight  shows enhanced expression of the PHYA gene and phyA accumulation, which combined with a higher specific intrinsic activity of phyA and enhanced activation of inhibitors of shade avoidance prevents hypocotyl elongation in far-red rich environments  (BES1 to reduce cotyledon expansion under shade (Some of the downstream targets of PIFs are transcription factors themselves . A consp (ATHB2) , which m (ATHB2)  and ARFs (ATHB2) . Also, Per shade .PIF gene expression levels. For instance, prolonged exposure to low blue light enhances the expression of PIF4  targets IAAs to degradation in the proteasome  and shadHFR1  to SPA4 form a complex that acts as an E3 ubiquitin ligase substrate recognition module . In the Cardamine hirsuta, which is, therefore, more stable and helps reduce shade avoidance in this shade-tolerant species , YUC5, YUC8, and YUC9 are shade induced within 15 min in cotyledons  mutant deficient in auxin synthesis  gene subfamily occurs 15\u201345 min after the beginning of neighbor cues, even in the pin3 pin4 pin7 and yuc2 yuc5 yuc8 yuc9 mutants  shows that both conditions elicit similar hypocotyl elongation but very different reprogramming of gene expression  of leaves (9-CIS-EPOXICAROTENOID DIOXIGENASE 3 and 5 (NCED3/5) expression (a rate-limiting enzyme) and higher abscisic acid (ABA) levels  levels . Gene ex) levels . Whether) levels . Intrigu) levels .Medicago sp.) or sunflower which perform heliotropism to continuously reposition their leaves according to the solar position  and hence of the AN3 targets GROWTH REGULATING FACTOR1 (GRF1), GRF3, and GRF5 involved in cell proliferation (CYTOKININ OXIDASE 6 (CKX6) gene involved in the breakdown of cytokinin, a response proposed to be mediated by enhanced auxin levels in leaf primordia  (HOMEOBOX PROTEIN 21 (HB21), HB40, and HB53 genes and these transcription factors, together with BRC1, increase the expression of NCED3   a known 1 (BRC1) . In turnof NCED3   (FLOWERING LOCUS T (FT) and its paralog TWEEN SISTERS OF FT (TSF)  . The AraFT (TSF) . As FT eed ratio . In rapied ratio   by direct binding to its promoter (ORE1 expression indirectly by binding to and enhancing the expression of ABA INSENSITIVE 5 (ABI5), ENHANCED EM LEVEL (EEL) and ETHYLENE INSENSITIVE 3 (EIN3) followed by direct activation of ORE1 by these transcription factors  and REPRESSOR OF ga1-3 (RGA) (ABI5 (SOM)  , ABI5 (OA) (ABI5  and the I5 (SOM) , all of I5 (SOM) . Active I5 (SOM) . In addiromoters .In many areas of the planet, plants are experiencing a temperature increase that is so fast that it jeopardizes their ability to adapt. Moreover, global temperatures will continue to rise to an extent that will depend on the adoption of strong climate actions . In paraPIF4 gene (PIF4 (PIF4 promoter (PIF7 transcript (a third temperature sensor), increasing its rate of translation and hence PIF7 protein abundance , whereas warmth has little effect on expression and increases protein stability , necessary for BES1 activity , transcriptional regulators (ARFs and BES1/BZR1), and post-transcriptional regulators  fulfill crucial organ- and/or environment-specific functions.The importance of shade avoidance of liquid\u2013liquid phase separation, chromatin remodeling, and carbon allocation is beginning to emerge.The activity of key components of the shade avoidance network responds not only to neighbor cues but also to temperature, water availability, salinity, and/or oxygen availability, acting as cellular integrators of above- and belowground information.To what extent is the signaling network involved in shade avoidance responses in Arabidopsis conserved in other species?What is the specific function of the negative regulators of shade-avoidance responses that increase their expression in response to neighbor cues?Which genes provide organ specificity to core shade-avoidance proteins such as PIFs or COP1?What are the patterns and mechanisms of integration of the auxin and sugar signals moving from the cotyledons to the growing hypocotyl? Is a similar convergence observed for other interorgan communication processes such as control of bud outgrowth?Is there deep signaling integration between soil resources-sensing mechanisms affected by climate change  and the perception of neighbor cues by aerial organs?Can shade avoidance responses modify the impact of climate change on plants?"}
+{"text": "Central line-associated bloodstream infections (CLABSI) are associated with increased morbidity, mortality, and healthcare costs. Many CLABSIs can be prevented using evidence-based care. To make this information more accessible and actionable, we developed interactive dashboards that translate data on CLABSI-related metrics and prevention efforts into visual formats that can be easily understood by healthcare professionals.A multidisciplinary work group of data analysts, infectious diseases physicians, and infection preventionists determined the content and layout of the dashboards. A query was written to extract necessary data elements from the Electronic Medical Record and NHSN. Data was then exported and used to build the dashboards using Tableau\u00ae software. The dashboard can be filtered at the facility level or at the unit level., one intensive care unit (ICU) , and one cardiovascular ICU (CVICU) . The central line standard utilization ratio (SUR) was higher for the CVICU ( >1.5), followed by the ICU (\u22481), and the general ward (< 1). Blood culture intensity (number of blood cultures collected/patient-days) was less for the general ward (< 5%), variable for the ICU (8-14%), and persistently higher for the CVICU (11%). Compliance with daily chlorhexidine bathing was higher for both the CVICU (80%) and the ICU (75%) compared to the general ward (40-60%). The CLABSI rate per 1,000 central line-days has been downtrending for the CVICU and uptrending for the ICU. Besides lower compliance with daily chlorhexidine bathing, the examined ICU has also recently shown a higher proportion of long-term devices (40%), calculated as proportion of central lines \u2265 7 days/all central lines, compared to the CVICU (25%).We present the dashboard of one general ward Dashboards should contain meaningful outcomes and standardized process metrics that are mapped to strategic goals and be timely to support prompt identification of deviations. Our CLABSI dashboards are effective tools for communicating and tracking performance data. Filtering at the unit level allows us to identify unique unit characteristics, or \u201cfingerprints,\u201d and recognize specific areas for improvement. This enables us to develop targeted interventions for each unit.All Authors: No reported disclosures"}
+{"text": "Despite evidence suggesting a decline in the physical activity of middle-aged adults, 40\u201364-year-olds participation in group exercise is actually increasing. One potential reason for this increase in activity is the increase in a range of different online group exercise formats and contexts. Recent research suggests that people join, participate, and stay involved in, exercise groups that reflect who they are - a process of social identification. The purpose of this research is to qualitatively explore participants\u2019 experiences and facilitators of social identification related to the online group exercise platform known as Zwift.Zwift participants (n\u2009=\u200917) aged between 40-64 (midlife)  were recruited into the study for three stages of data collection: (stage 1) an initial semi-structured interview exploring participant exercise history and use of Zwift, (stage 2) completing a two-week post exercise diary to capture their experiences of social identification after participation, (stage 3) a follow up final interview to explore topics raised over the first two data collection steps. This generated 23\u2009hours of interviews, that were then transcribed and combined with the participant diaries resulting in 468 pages of data.Reflexive thematic analysis was used to identify themes from the data. The results from this analysis indicate the following themes from the data: (1) Online exercise as an enabling facilitator of exercise identity; (2). Online exercise provides exercise identity continuity or exercise identity creation depending on the exercisers, exercise history; (3) Online exercise identification via communities goes through phases of identification; (4) Two-way communication contributes to perceptions of identification phases of identification; and (5) Social identity leadership is demonstrated by online exercisers norms, behaviours and beliefsOverall, this research highlights three key suggestions for mid-life physical activity promotion: (1) That facilitators and processes of social identification may be context specific; (2) That social identification processes should be considered in the design of online exercise; and (3) That online exercise that enables social identification should be considered as a vehicle of maintaining/ increasing exercise participationThe study was funded by the researcher."}
+{"text": "Coccinella undecimpunctata Linnaeus (1758) (Coleoptera: Coccinellidae). Tens of individuals of both sexes were discovered at a single location, indicating that the species may already be established on South Georgia. Transport connectivity with this site suggests that the species most likely arrived recently from the Falkland Islands as a stowaway on a ship. We discuss the implications of our discovery for the continued development of South Atlantic biosecurity.Biological invasions represent a growing threat to islands and their biodiversity across the world. The isolated sub\u2010Antarctic island of South Georgia in the South Atlantic Ocean is a highly protected area that relies on effective biosecurity including prevention, surveillance and eradication to limit the risk of biological invasions. Based on an opportunistic field discovery, we provide the first report of an introduced ladybird beetle on South Georgia. All specimens discovered belong to the Eurasian species  Coccinella undecimpunctata. The species may already be established and reproducing on the island and likely arrived from the Falkland Islands as a stowaway on a ship. This discovery has implications for the continued optimisation of South Atlantic biosecurity and global island conservation.During a scientific expedition in South Georgia, we incidentally discovered the presence of the introduced ladybird beetle  The entCoccinella undecimpunctata is established in North America  (Coleoptera: Coccinellidae) on South Georgia.Among the approximately 6000 described species , sex determination relied on the sexual dimorphism of the 8th abdominal segment: males have a \u201cnotch\u201d on the posterior margin of the sternite . Cutting through the posterior tip of the abdomen to expose the reproductive system enabled determination of the sex of most individuals. For a few specimens that were kept intact (2.3t\u2010tests were used to investigate if the widths of the pronotum and of the head differed between sexes. Maps of South Georgia were based on topographic data from thematicmapping.org and South Georgia GIS (2023). Figures were assembled in Inkscape . Antarctic fur seals  move between the sea and their resting areas via the sampling location and a group of moulting king penguins (Aptenodytes patagonicus) was present in the vicinity. Consequently, organic debris and feathers were abundant below and between rocks in the sampled area.In January 2023, we recorded the presence of ladybirds on the southern side of Stromness Bay, South Georgia Figure\u00a0. DespiteC.\u2009undecimpunctata Linnaeus (1758). Specimens had small and elongate bodies  and of the head (1.1\u2009\u00b1\u20090.05\u2009mm) \u2013 and these were not significantly related to sex (two\u2010sided Welch 4C.\u2009undecimpunctata Linnaeus (1758) on the sub\u2010Antarctic island of South Georgia. There is little doubt that the presence of this Eurasian species is due to human activity. C.\u2009undecimpunctata may be reproducing on South Georgia given the presence of both sexes and the number of individuals found relative to search effort. However, the species was detected only in a small area and not at any other sampling site on the northern peninsulas nor in King Haakon Bay and may therefore be at an early stage of biological invasion ; data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); project administration (supporting); software (lead); supervision (supporting); validation (lead); visualization (lead); writing \u2013 original draft (lead); writing \u2013 review and editing (lead). Helen E. Roy: Formal analysis (supporting); validation (supporting); writing \u2013 review and editing (supporting). Peter Convey: Conceptualization (supporting); funding acquisition (supporting); investigation (supporting); methodology (supporting); project administration (supporting); writing \u2013 review and editing (supporting). Paul Brickle: Conceptualization (supporting); funding acquisition (supporting); methodology (supporting); project administration (supporting); resources (supporting); writing \u2013 review and editing (supporting). Rosemary J. Newton: Conceptualization (supporting); funding acquisition (supporting); methodology (supporting); project administration (supporting); writing \u2013 review and editing (supporting). Wayne Dawson: Conceptualization (supporting); data curation (supporting); formal analysis (supporting); funding acquisition (lead); methodology (supporting); project administration (lead); resources (lead); supervision (lead); validation (supporting); writing \u2013 original draft (supporting); writing \u2013 review and editing (supporting).The authors declare no competing interests."}
+{"text": "Diabetes mellitus is defined as a group of metabolic diseases characterized by hyperglycemia, which when untreated can lead to long-term complications, including micro- and macrovascular complications. Tight glycemic control with intensive insulin therapy has been suggested to reduce the risk of such complications in several diabetes populations; however, such an approach can also be associated with risks and challenges. There are currently several modalities available to deliver insulin and monitor glucose levels to achieve glycemic goals in diabetic patients. In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of insulin delivery systems and glucose-monitoring modalities in diabetic patients receiving intensive insulin therapy. Studies from 44 publications included in the review compared the effects of continuous subcutaneous insulin infusion (CSII) with multiple daily injections (MDI) and/or real time-continuous glucose monitoring (rt-CGM) with self-monitoring of blood glucose (SMBG) among children, adolescents, or adults with either type 1 (T1DM) or type 2 diabetes (T2DM), or pregnant women with pre-existing diabetes (either T1DM or T2DM). This comparative effectiveness review evaluated which modality results in improved glycemic control, less hypoglycemia, better quality of life, and/or improved clinical outcomes. The numerous technologies and the challenges that clinicians face when determining which patient population may benefit from different insulin delivery systems and glucose-monitoring approaches motivated AHRQ to synthesize the available information to assist health professionals in making evidence-based practice decisions for their patients. The review also delineates advances in insulin delivery and glucose-monitoring systems, practical methods to achieve tight glycemic control and strategies to minimize associated risks, as well as highlights gaps in research and areas that need to be addressed in the future.To (a) educate health care professionals on the findings from AHRQ\u2019s 2012 comparative effectiveness review on insulin delivery and glucose-monitoring modalities in patients with diabetes; (b) apply review findings to make treatment decisions in clinical practice; and (c) identify shortcomings in the current research and future directions relating to the comparative effectiveness of insulin delivery and glucose-monitoring modalities for patients with diabetes.The AHRQ systematic review of randomized clinical trials reveals that both insulin delivery modalities (CSII and MDI) demonstrate similar effectiveness on glycemic control and severe hypoglycemia in children and adolescents with T1DM and in adults with T2DM. In adults with T1DM, hemoglobin A1c decreased more with CSII than with MDI with low strength of evidence, but one study heavily influenced these results. In children and adults with T1DM, the use of CSII was associated with improved quality of life compared with MDI, with low strength of evidence, while there was insufficient strength of evidence to make conclusions regarding the quality of life for adults with T2DM. The study investigators suggest that the modality to deliver intensive insulin therapy can be individualized to patient preference in order to maximize quality of life. On all measured outcomes, there was insufficient or low strength of evidence regarding pregnant women with pre-existing diabetes.The AHRQ investigators found studies comparing the effectiveness of glucose-monitoring modalities in individuals with T1DM only. The systematic review demonstrates that rt-CGM is associated with greater lowering of A1c compared with SMBG (high strength of evidence) without affecting the risk of severe hypoglycemia (low strength of evidence) or quality of life (low strength of evidence) in nonpregnant individuals with T1DM, particularly when compliance with device use is high. Additional findings suggest that the use of sensor-augmented insulin pumps (rt-CGM + CSII) is superior to the use of MDI/SMBG use in lowering A1c in nonpregnant individuals with T1DM (moderate strength of evidence). Comparison of other outcome measures did not yield firm conclusions due to low or insufficient evidence."}
+{"text": "Retirement from sport is a life transition that has significant implications for athletes\u2019 physical and mental health, as well as their social and professional development. Although extensive work has been done to review the retirement experiences of athletes, relatively less work has been done to examine and reflect on this expansive body of literature with a pragmatic aim of deciding what needs to happen to better support retiring athletes. This study used scoping review methodology to review current academic reviews, gray literature articles, and support programs on athletic retirement. This review followed the Joanna Briggs Institute reviewer\u2019s manual guide on scoping reviews and adhered to the PRISMA-ScR checklist. Academic articles were identified from PubMed, Embase, Web of Science and Scopus. Gray literature articles and support programs were identified using advanced Google searches. This study identified 23 academic reviews, 44 gray literature articles, and 15 support programs. Generally, the results suggest that athletic retirement encompasses a drastic shift in identity, a loss of social networks, a lack of career ambitions, and potential risks to physical and mental health. While there was a gap in the academic literature regarding practical strategies to support retiring athletes, the gray literature suggests many creative ideas. Stepwise programming may be beneficial to help athletes: (a) make sense of their athletic experience and see retirement as an ongoing process; (b) develop a well-rounded sense of self identity and understand how to apply their unique skills and strengths in new ways; (3) gain control over their retirement transition by establishing a clear plan and adjusting to new routines and opportunities; and (4) normalize the transition experience by \u201cliving in the next\u201d and building confidence in new life directions. Future research may benefit from developing and evaluating more programming to support athletes through the retirement transition. Retirement from a high-performance sport is a life transition that has significant implications for physical and mental health, as well as social and professional development . AthletiReviews of the academic literature on athletic retirement have generated mixed findings regarding the impact of retirement from sport on mental and physical health , 11, 12.Several approaches can be used to examine individuals\u2019 retirement experiences, including approaches from the field of social gerontology where retirement is seen as a career transition that results in the termination of paid work \u201326, and Regardless of the approach taken, there appears to have been extensive work done to review the retirement experiences of athletes in both academic and non-academic settings. Despite these important advancements, relatively less time has been taken to examine and reflect on the expansive body of literature, with a pragmatic aim of deciding what needs to happen next to better support retiring athletes. Despite numerous evidence syntheses, athletes still face physical, mental, and emotional struggles after retirement with a lack of appropriate supports. Though nearly every move an athlete makes is scrutinized, relatively little attention is paid to an athlete\u2019s transition to life after sport. In light of the current state of the literature, this review presents a scoping review of the athlete retirement transition experience, focusing on existing reviews of the academic and gray literature, with a pragmatic aim to improve future practices.The objective of this scoping review is to review other academic reviews, gray literature articles, and support programs that address athletes\u2019 experience transiting into life after sport, with a pragmatic aim of identifying how athletes can be supported through the retirement process. To encompass a wide range of athlete experiences, this review includes both amateur and professional athletes. This review will address the following specific questions: (1) what are the main characteristics of academic and gray literature studies that review athletes\u2019 transition experiences? (2) what does the current body of synthesized literature say about the key barriers and enablers to a successful athletic retirement transition? (3) what does the current body of synthesized literature say about the negative and positive impacts of athletic retirement? and (4) what does the current body of synthesized literature say about the programming needed to better support athletes\u2019 transition into life after sport?other reviews as our primary evidence source [We followed the Joanna Briggs Institute reviewer\u2019s manual guide on scoping reviews, with a focus on e source . We wante source .rd, 2022, with search terms related to athletes, retirement, and reviews. Results were limited to English. We ensured our search was specific enough to yield highly relevant reviews we knew we wanted to include. To find relevant gray literature sources, several targeted advanced Google searches were conducted between August and September 2022. The advanced Google searches included search terms related to athletes, retirement, and organizations that our research team identified as highly relevant . For pragmatic reasons, only the first 50 sources  were used for each advanced Google search. Our full search strategy can be viewed in The search strategy was developed by the lead authors (PV and MS). To find relevant academic sources, a search of the databases PubMed, Embase, Web of Science and Scopus were conducted on July 23For our academic search, included papers were restricted to full-text, original, peer-reviewed evidence syntheses . The reviews had to focus on athletes as their primary population . We decided to include amateur and professional athletes to encompass the wide range of athletes who experience the retirement transition process. The reviews also had to have a clear focus on athletes\u2019 retirement or transition into life after competitive sport . Although we did not constrict our paper eligibility by the type of review, the review had to include a clear search strategy . For our gray literature search, advanced google searches either identified: (a) programs that support athlete transitions, or (b) non-academic articles about athlete transitions. No restrictions were put on the date or location of included sources, although certain search terms focused on American and Canadian programs specifically.Reviews from the academic database searches were handled using Covidence  reference management software. Reviews were deduplicated and imported for a 2-level screening process. During level 1 screening, titles and abstracts were double screened by two reviewers (AR and LA) using the eligibility criteria. Publications with titles and abstracts not meeting the eligibility criteria were excluded. During level 2 screening, full-text papers that passed level 1 were screened by the same two reviewers (AR and LA). Studies that met the eligibility criteria were included for full data extraction. Discrepancies during level 1 and 2 screening were discussed over several meetings with final decisions on screening made by PV. Programs and articles from the gray literature search were handled using google sheets. One reviewer (JC) scanned the advanced google searches for relevant programs and articles using the eligibility criteria. The reviewer copied and pasted relevant programs and articles into a google sheet, which was then reviewed by PV. After discussion between JC and PV on the included programs and articles, the final gray literature source inclusion was finalized by PV.Data from the included academic reviews were extracted using a data extraction form that included information on reviews\u2019 title, author, year, journal, review type, study objective, databases searched, date range searched, population limitations, setting limitations, number of papers included, paper types included , paper locations, paper populations , and the key thematic constructs identified in the review. The thematic information we extracted included information on (a) the barriers and enablers of athlete retirement transitions, and (b) the negative and positive outcomes of athletic retirement. Barriers to retirement transitions and negative outcomes after retirement were indicated using a negative text symbol  high athletic identity, or (-) worsening anxiety and depression). Enablers and positive outcomes were indicated using a positive sign  planned retirement, or (+) relief from pressure and expectation). The data was initially extracted by one reviewer (IH) and then reviewed and refined by the lead authors (MS and PV).articles were extracted using a data extraction form that included information on the title, author, host origination, organization mission, organization location, key themes about (a) athletes\u2019 unique experiences, (b) athletes transition challenges and enablers, and (c) strategies or programs for improving the transition experience. Data from included gray literature programs were extracted using a data extraction form that included information on the title, author, host origination, organization mission, organization location, and the program\u2019s offerings for athletes . The data was initially extracted by one reviewer (JC) and then reviewed and refined by the lead authors (MS and PV).Data from included gray literature sources  were extracted using two different data extraction forms. Data from the gray literature The lead author (PV) completed a descriptive analysis of the data collected from the included papers that aligned with the objectives of this review. For the academic sources, we start by presenting an overview of the review characteristics. We then present a summary of the major findings across the reviews depending on the review topic  reviews that explore the general psychosocial experiences of retiring athletes, (b) reviews that specifically explore the cognitive and mental health experiences of retiring athletes, and (c) reviews that specifically explore the musculoskeletal and cardiovascular experiences of retiring athletes. For the gray literature sources, we first present an overview of the gray literature source characteristics. We then present a summary of the major themes across the gray literature sources, including summaries about (a) the unique experiences of athletes themselves, (b) athletes\u2019 experiences with retirement, specifically, and (c) support programming for retiring athletes. All reviews were published in the last 10 years (between 2013\u20132022). In total, 10 reviews explored the general retirement experiences of athletes, 8 reviews explored athletic retirement with concussion, cognitive, and mental health concerns, and 5 reviews explored athletic retirement with musculoskeletal and cardiovascular health issues. The majority of the reviews were systematic reviews (n = 20), in addition there was a scoping review (n = 1), a critical review (n = 1), and a literature review (n = 1). Most reviews combined athletes from multiple different sports (n = 14); the remaining reviews focused on soccer players (n = 5), cricket players (n = 1), rugby players (n = 1), American football players (n = 1), and gymnasts (n = 1). Most reviews included athletes from multiple countries (n = 21), however, 2 reviews specifically focused on athletes in the United States. The number of articles examined in each review ranged from 4 articles to 219 articles, with the mode being 17 articles. Most reviews included male and female participants (n = 15), with the exception of reviews that focused on females only (n = 1), males only (n = 3), or did not report on gender (n = 4). Most reviews focused on quantitative studies (n = 16); however, several reviews included multiple study designs (n = 5). Only 1 review did not report the designs of the studies they included. The majority of reviews focused on professional and elite athletes (n = 11); several reviews featured sub-elite athletes (n = 6), such as club or high school athletes, and a substantial number of reviews did not report the level of the athletes in the studies included (n = 7).We identified 23 academic reviews of literature examining the retirement transitions of athletes. A detailed description of the academic reviews included in this overarching review is provided in the Among the 10 reviews that explored the general retirement experiences of athletes, we identified numerous barriers and facilitators that affected athletes\u2019 ability to smoothly transition into life after sport. Barriers included: (1) having a high athletic identity; (2) high perfectionism and comparison; (3) athletic career dissatisfaction; (4) involuntary retirement ; (5) amount of other life changes occurring at the same time as retirement; (6) despair about future career; (7) lack of coping strategies; (8) low social support; (9) lack of transition planning; (10) education and resource dissatisfaction; (11) previous concussions; (12) raising body mass index; and (13) onset of osteoarthritis. Facilitators included: (1) having a good sport-life balance ; (2) positive self-perception and self-control; (3) athletic career satisfaction; (4) voluntariness of retirement; (5) gradual reduction of training; (6) length of time since retirement; (7) retirement planning; (8) support program involvement; (9) planned occupation after retirement ; (10) educational attainment; (11) financial planning; (12) social support network; (13) continued relationships with coaching staff; (14) strong coping strategies  crisis preparedness.In addition to barriers and facilitators that affected athletes\u2019 retirement transition, we also identified numerous negative and positive impacts of athletic retirement itself. Negative impacts included: (1) worsening anxiety and depression; (2) feelings of burnout; (3) feelings of grief, loss, and void; (4) sleep disturbance and distress; (5) adverse alcohol use; (6) adverse smoking behaviours; (7) brain atrophy and dementia; (8) difficulty establishing new a lifestyle routine; (9) adverse nutrition behaviour; (10) disordered eating; (11) body dissatisfaction; (12) compensatory exercise; (13) high incidence of osteoarthritis incidence; (14) high incidence of join pain/back pain; and (15) high incidence of skin cancers. Positive impacts included: (1) relief from pressure and expectation; (2) high capacity for resilience and toughness; (3) greater or similar long-term quality of life; (4) greater capacity in certain mental proficiencies; and (5) difficulties with transition will fade over time.Among the 8 reviews that explored the relationship between athletic retirement and cognitive or mental health outcomes, several reviews examined and found that history of concussion during sport was a significant risk factor for cognitive impairment  and mental health issues among retired athletes. Only one review reported mixed findings about this association . Most reAmong the 5 reviews that explored the relationship between athletic retirement and musculoskeletal and cardiovascular health issues, 4 reviews specifically focused on osteoarthritis prevalence among retired athletes, while 1 review focused on cardiovascular disease risk . Among tS3 and We identified 15 unique programs from our gray literature search that provide information about support for athletes through their athletic retirement transition. In addition, we identified 44 unique non-academic articles that describe and provide practical advice on athletic retirement transitions. Athlete retirement transition programs were based in different regions including, Canada (n = 7), the United Kingdom (n = 2), the United States (n = 2), Australia (n = 1), and South Africa (n = 1); while some programs had a clear global presence (n = 2). A full description of the programs and articles we identified in the gray literature search can be viewed in the Based on our analyses of the gray literature, 10 features emerged as unique aspects of the athlete experience: (1) living in a highly structured environment ; (2) living in a high pressure and stimulating environment ; (3) athletics is experienced as a way of life ; (4) high identity association with being an athlete ; (5) young career termination ; (6) high focus on body function and image ; (7) experiencing injury and/or significant bodily changes ; (8) large personal sacrifices during their career ; (9) unique financial situations ; and (10) gaining distinctive skillsets that can be transferable to other life circumstances .In terms of the athletic retirement transition, 10 key challenges and 5 key opportunities emerged from the gray literature. Challenges include: (1) athletic termination as a crisis ; (2) athletic retirement as a long process, not a quick event ; (3) loss of identity ; (4) lack of purpose in day-to-day life ; (5) lack of stimulation and psychological demands ; (6) loss of significant relationships ; (7) physical adaptations ; (8) financial concerns ; (9) mental health issues, ; and (10) substance use concerns. Athletes\u2019 transition opportunities relate to: (1) exploring new social networks and lifestyle opportunities ; (2) exploring other career interests ; (3) having the chance to unwind ; (4) the stamina and strength gained in athletics ; and (5) being psychologically disciplined and accountable .Factors that influence whether an athlete has a positive or negative transition experience were found to be context dependent and related to issues such as: (1) voluntariness of retirement; (2) timing of retirement; (3) duration of the transition; (4) amount of other life changes during retirement; (5) positive or negative reflections on athletic career; (6) financial and career planning for retirement; (7) fitness and dietary planning for retirement; (8) personal brand built through athletics; (9) high athletic identity association; (10) ongoing injury issues; and (11) prioritization of retirement planning.The primary themes that emerged in relation to athlete retirement transition supports include the deliverer of support, the receiver of support, the delivery mode of support, and the content of support. Regarding the deliverer of the support, many different groups provided athletes with support, including: (1) athletic organizations; (2) third-party organizations ; (3) sports psychologists and counsellors; (4) family, friends, mentors, and peers; and (5) coaching staff and other team personnel . Regarding the receiver of supports, many different groups also accepted support, including (1) athletes themselves; (2) coaching staff; (3) athletic organizations; and (4) parents, family, friends, and partners. Regarding the delivery mode of support, avenues tend to be resource-based  or systems-based . Resource-based supports include: (1) resource repositories; (2) educational information; (3) employment lists; (4) extracurricular activities lists; (5) educational opportunities lists; (6) videos with education/advice; (7) podcasts sharing lived experiences; (8) speaker series sharing lived experiences; (9) social media stories; (10) assessment tools; (11) reflection workbooks; and (12) guided journaling. Systems-based provisions include: (1) person-to-person support (online or in-person); (2) email or text-based support; (3) stepwise multicomponent programming; (4) team-integrated programming; (5) small group workshops; (6) membership to a community network; and (7) conferences or retreats. Regarding the content of support, the following issues were addressed: (1) personal wellbeing; (2) identity shifting; (3) mental health; (4) social networks; (5) personal relationships; (6) career building; (7) educational development; (8) physical health; (9) diet and exercise; (10) financial planning; (11) stories about others lived experiences; (12) education about transitioning; (13) personalized sports psychology; and (14) stepwise programming.S5 Table.Stepwise programming tended to include multifaceted interventions that featured the following steps: (1) come to terms with their retirement and see the retirement transition as a process; (2) develop a well-rounded sense of self identity and understand how to apply their unique skills and strengths in a new setting; (3) gain control over their retirement transition by establishing a future plan and adjusting to new routines and opportunities; and (4) normalize the transition experience by \u201cliving in the next\u201d and building confidence in new life direction. The contents of these steps have been fully detailed in high athletic identity is consistently associated with difficulties in transitioning into life after sport. Among elite athletes, it is not uncommon for their social networks, career ambitions, physical goals, psychological stimulation, and sense of self-worth to be distinctly tied to their sport [This paper presents a scoping review of the synthesized academic and gray literature regarding athlete retirement transitions. Our analyses of review articles from the academic literature illustrate that possessing a ir sport , 36. It ir sport , 44. Their sport , 45.ended their career on a low . In line with prior research [strong athletic identity combined with a traumatic career termination puts athletes in a very difficult scenario early in their lives [In addition to the challenge of athletic identity, the academic literature highlighted an important threat for athletes who research , 46, 47,ir lives . In lineir lives \u201351, thishealthy sport-life balance over the course of their athletic career can better transition into life after sport. Developing interests outside of sport and making time to develop contingency plans for life after sport helped ameliorate the transition. A second notable enabler was that athletes who can gain a sense of perceived control over their athletic termination, and gradually reduced their athletic participation, are able to transition better into retirement. Although supporting athletes to maintain balance, plan for their retirement, and gradually detrain themselves may seem counterintuitive to sports organizations who want the most out of their current athletes, our paper indicates that athletes who plan for retirement may actually perform better while still competing.Although identity loss, career regret, and abrupt lifestyle modifications were common conditions among retiring athletes, several key factors emerged across the academic literature as enablers of positive retirement transitions. The first notable enabler was that athletes who create a While much attention has been placed on the need to enhance athlete mental health and wellbeing , 53, lescognitive impairment, mental health issues, and osteoarthritis complications [Across the synthesized literature is a consensus that retiring athletes are at a particularly high risk of experiencing ications , 7, 36. a wide range of supports from different sources in order to address different needs. Stepwise programming, where athletes work through a series of ongoing interventions to prepare for a retirement transition, emerged as a robust enabler of a positive transition experience. Gradual, longstanding, embedded investments into retirement planning may be highly advantageous for improving athlete retirement transition outcomes. Researchers and practitioners may deeply benefit from investigating the mechanisms that best support the development of a well-rounded sense of self throughout an individual\u2019s athletic career and through the retirement transition experience.Despite indicating that retirement planning facilitated a better transition to athletic retirement, a clear gap in the academic literature exists with regard to how to develop and implement specific strategies for retirement planning based on sport and level. Fortunately, much of the gray literature focuses on these specific details, suggesting a multitude of creative ideas for how to better support athletes transition into life after sport. What is clear across the gray literature is that athletes need This review is the first of its kind to examine existing review articles from academic literature as well as current evidence from gray literature on retirement from sport. Limitations of this review include that we only included studies published in English and therefore may have excluded potential studies published in a different language. In an effort to be inclusive of the existing literature on athletic retirement, our review incorporates reviews of studies that combine different types of sport, multiple geographic regions, individuals of varying gender, and combines data on professional as well amateur athletes. Retirement experiences are likely to differ based on factors like these. Future research may benefit from focusing on developing and evaluating retirement support interventions based on characteristics of the individual athlete, the sport, as well as regional variations and other contextual factors.This review scopes the current synthesized academic and gray literature on athlete retirement transitions, with a pragmatic focus on how retiring athletes can be better supported. We identified and examined 23 academic reviews of literature examining the retirement transitions of athletes, 15 unique programs from gray literature that aimed to provide information about support to athletes through their athletic retirement transition experience, and 44 distinct non-academic articles that described and provided practical advice on the athletic retirement transition. The literature illustrates that feelings of loss, identity crisis, career regret, and difficulties with abrupt lifestyle modifications are common experiences in an athlete\u2019s retirement transition. While the academic review literature presented a gap in evaluating programs that aim to ameliorate athletic retirement, the gray literature provided multiple creative ideas for how to improve programming to support athletes\u2019 transition into life beyond sport.S1 Checklist(PDF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file."}
+{"text": "We review the latest information related to the control of fruit softening in tomato and where relevant compare the events with texture changes in other fleshy fruits. Development of an acceptable texture is essential for consumer acceptance, but also determines the postharvest life of fruits. The complex modern supply chain demands effective control of shelf life in tomato without compromising colour and flavour.Solanum lycopersicum) are discussed with respect to hormonal cues, epigenetic regulation and transcriptional modulation of cell wall structure-related genes. In the last section we focus on the biochemical changes closely linked with softening in tomato including key aspects of cell wall disassembly. Some important elements of the softening process have been identified, but our understanding of the mechanistic basis of the process in tomato and other fruits remains incomplete, especially the precise relationship between changes in cell wall structure and alterations in fruit texture.The control of softening and ripening in tomato ( Solanum lycopersicum) and other fruits is essential to the successful function of the modern fresh market supply chain. Substantial losses during transportation, susceptibility to post harvest diseases and limited keeping quality, result from fruits that ripen and soften rapidly. This has led to the use of a range of natural ripening mutations in commercial tomato breeding that slow the ripening and softening processes. The best known of these is the ripening inhibitor (rin) mutation. The use of the rin mutation in commercial practice has been very important in extending tomato shelf life, but it has detrimental effects on colour and flavour  and downstream genes Fig.\u00a0.Fig. 1HPlant hormones, such as ethylene, act as endogenous and exogenous cues that govern the transition stage from fruit development to ripening. Extensive studies have shown that fruit ripening is modulated by a complicated network of feedback and crosstalk among different phytohormones including ethylene, abscisic acid (ABA) and auxin  and ABA 8\u2032-HYDROXYLASE (SlCYP707A2) genes, which are genes involved in ABA biosynthesis and catabolism, resulted in elevated pectin levels and improved texture and shelf life and several genes encoding major cell wall catabolic enzymes were down regulated , a gene which encodes an ABA receptor, has revealed a role for SlPYL9 in regulating ABA signalling and ripening in tomato by affecting expression of ripening-related genes involved in ethylene production and cell wall modification , \u03b2-GALACTOSIDASE (Fa\u03b2GAL4) are positively regulated by ABA and negatively regulated by auxin , CELLULASE 1 (CEL1), and CELLULASE 2 (CEL2) were significantly up-regulated by ABA treatments, thus accelerating ripening in strawberry  within the QTL was cloned. This FIS1 gene encodes a GA2-oxidase, an enzyme that inactivates endogenous GAs and their precursors  also participate in modulating tomato fruit ripening via an interplay with ethylene. In several recent studies GA has been demonstrated to play a negative role in regulating tomato ripening. It is associated with suppression of the expression of ripening associated transcription factors and inhibiting ethylene production , and RNA methylation. Many of these events have now been shown to be associated with the progression of normal ripening and softening in tomato and other fruits  subfamily played a positive role in regulating fruit softening through the activation of the same set of cell wall related genes regulated by SlHDA1/3  proteins within the polycomb repressive complex act as repressors of gene expression via histone modifications , non-ripening (nor) and Colourless non-ripening (Cnr) , ENDO--\u0392-MANNANASE 4 (LeMAN4) and \u03b1-EXPANSIN 1 (LeEXP1), CEL2, XYLAN 1,4-BETA-XYLOSIDASE1 (XYL1)   was highly ripening-related. Repression of SlFSR significantly reduced the expression of multiple cell wall modification-related genes including PL, PG, TBG4, CEL2, XYL1, PECTIN ESTERASE (PE), MANNOSIDASE (MAN1), XYLOGLUCAN ENDOTRANSGLUCOSYLASE/HYDROLASE (XTH5) and EXP1, and prolonged shelf life, but did not influence other aspects of fruit ripening. These observations reveal the potential role of SlFSR in targeted control of tomato fruit shelf life by regulating cell wall metabolism  TF, SlLOB1 has been shown by Shi to act as a transcriptional activator of a broad suite of cell wall\u2013related genes and to control softening  were direct targets of SlHY5. However, the interplay between SlHY5 and these regulators needs further investigation  in Arabidopsis  (Wang et al., In a similar way to the pectin domain, disassembly of the hemicellulose and cellulose domains in the wall also appear to be a common feature of ripening in tomato and other fruits, but the contribution of these events to texture changes is even less well understood (Pos\u00e9 et al., Cell wall enzymes and other factors - In both tomato and strawberry the expression of genes encoding enzymes with PL activity has been demonstrated to be important in softening of these fruits. In the absence of PL expression, tomato fruit softened more slowly and HG was retained at cell junctions in the pericarp (Uluisik et al., The action of PL on wall mechanical properties has been studied in onion cells. Here lateral mobility of cellulose microfibrils was greatly increased at the nm-scale after PL treatment. However, concomitant effects on wall loosening and tensile properties were absent (Zhang et al., EXP1 is silenced (Brummell et al., EXP1 expression alters the extent of pectin depolymersation (Brummell et al., EXP1 has been shown to be important in tomato softening and there is an inhibitory effect on the process when SlLOB1 (Shi et al., EXP1 are strongly suppressed in SILOB1 RNA interference lines and induced in SlLOB1-overexpressing fruits. Other cell wall-related genes that show related patterns of expression in the SlLOB1 lines included CEL2 which encodes an endo-\u03b21,4-glucanase and genes encoding an alpha-xylosidase and a \u03b2-1,4 endomannase. As already mentioned, EXPs may enhance the ability of cellulase to act on cellulose microfibrils (Zhang et al., New insights into the mechanisms involved in cell wall disassembly are now coming from studies of ripening-related TFs. Shi investigated the genes impacted by suppressing or upregulating the expression of the TF"}
+{"text": "Dear Editor,1][. The 2019 Lancet paper by Colvin et al.5][. The United States Food and Drug Administration (orFDA) has issued a black-box warning for this class of drug in a setting ofCABG6][. Cardinale etal.11][ study. Markham et al.12][, and the way to which can only be paved by sustainableconcepts like multimodal analgesia.The opioid-sparing links of multimodal analgesia ought to be nurtured in the present eraof ERAS with a primary patientcentric approach of an enhanced recovery in cardiacsurgery While a traditionalist might argue fddling with the position that opioids haveenjoyed in the cardiac surgery, any degree of opioid stewardship materializes fromevidence in ERAS (an evidence-based augmented patient recovery)"}
+{"text": "In the original publication , ref. ,  corresponding microscopic model diagrams before and after growing VACNTs, respectively. Reprinted with permission from Elsevier 2023 [36].The citation has now been inserted in the caption of Figure 3 and should read: SEM images of CF: (a) adsorption and desorption curves; (b) the pore width. Reprinted with permission from Elsevier 2023 [36].The citation has now been inserted in the caption of Figure 4 and should read: BET analysis results [36] of CF with growing VACNTs in situ: (The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."}
+{"text": "Myeloid sarcoma is a rare clinical entity that presents as an isolated proliferation of leukemic cells, concurrently with or at relapse of acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), chronic myeloid leukemia (CML), and myeloproliferative neoplasm (MPN). Myeloid sarcoma disrupts the normal architecture of its surrounding tissues. When it forms in long bones, it can cause their pathological fracture. We recently experienced a rare case of MDS presenting with myeloid sarcoma in the femur that eventually resulted in its pathological fracture. Detailed chromosomal analysis of the bone marrow cells suggested emergence of myeloid sarcoma during the fast-paced progression of MDS just after acquiring trisomy 22. A comprehensive review of previous cases of myeloid sarcoma-associated pathological fracture indicated possible involvement of structural rearrangements of chromosomes 9 and 22. Management of myeloid sarcoma should continue to improve, and clinicians should note that myeloid sarcoma with specific chromosomal alterations needs extra medical attention to prevent pathological fracture. Myeloid sarcoma is a tumor mass consisting of myeloblasts with or without maturation involving any anatomical site. Most often, myeloid sarcoma is formed in patients with acute myeloid leukemia (AML), either at the time of diagnosis, during or after chemotherapy. This medical condition is well established in AML patients with recurrent genetic abnormalities, especially in cases of core binding factor AML that are characterized by the presence of either t8;21)  or inv(16)    scan was immediately taken, but did not locate any origins of fever. The complete blood counts showed white blood cells (WBC) of 6,700 /\u03bcL (13% neutrophils) and platelets of 1.02\u2009\u00d7\u200910Myeloid sarcoma is a tumor composed of immature myeloid precursor cells. It sometimes develops as a de novo isolated sarcoma without bone marrow involvement . Besides, extensive review of the past literatures on myeloid sarcoma-associated pathological fractures, we have identified 18 cases that had been reported with description of the results of cytogenetic analyses. In a sharp contrast to the chromosomal alterations seen in myeloid sarcoma in general, our detailed review elucidated that the incidence of t in myeloid sarcoma with pathological fractures (8/19 cases) is considered to be much higher than expected. Thus, we suspect the potential yet vital role of chromosomes 9 and/or 22 alterations in the development of myeloid sarcoma-associated pathological fractures. Given that the present case developed myeloid sarcoma soon after the immature myeloid cells acquired additional chromosomal alteration of\u2009+\u200922 (Fig.\u00a0As shown in Table 1In summary, we have experienced a rare case of MDS presented with a myeloid sarcoma in the right femur that eventually resulted in its pathological fracture. Reviewing the past cases, the possible involvement of the rearrangements of chromosomes 9 and 22 is suspected in the occurrence of myeloid sarcoma-associated pathological fractures. To seek the optimal management of myeloid sarcomas and prevention of associated complications, clinicians are encouraged to pay extra medical attention to the myeloid sarcoma cases involving chromosomes 9 or 22 alterations."}
+{"text": "This cross-sectional study assesses the prevalence of conflicts of interest (COI) associated with guideline-recommended drugs among Infectious Diseases Society of America clinical practice guideline authors and compliance with the Council on Medical Specialty Societies and Institute of Medicine guidelines. The prevalence and nature of COI among authors of infectious diseases CPGs are poorly understood. We assessed the prevalence of COI associated with guideline-recommended drugs among Infectious Diseases Society of America (IDSA) CPG authors and compliance with Council on Medical Specialty Societies (CMSS) and Institute of Medicine (IOM) guidelines.5Conflicts of interest (COI) among clinical practice guideline (CPG) authors are commonSTROBE) reporting guideline and was determined to be exempt by the HealthPartners institutional review board because it was non\u2013human participants research.In this cross-sectional study, we searched all IDSA CPGs from June 1, 2017, to March 31, 2022 (N\u2009=\u200937). We excluded guidelines not published primarily by IDSA (n\u2009=\u200917) and guidelines without recommendations regarding specific antimicrobials (n\u2009=\u200910). We identified all CPG authors, their status as chair or co-chair, disclosed relationships, and relationship time frames. We included relationships only with pharmaceutical companies that developed or sold drugs. We extracted all drugs recommended in each CPG and excluded drugs recommended only in a clinical trial or sold only outside the US. We searched US Food and Drug Administration websites to identify drug manufacturers and approval dates. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  and a pharmaceutical company if the company manufactured a guideline-recommended drug at the time of publication. Companies associated with a manufacturer as a subsidiary or acquisition were included. Conflicts of interest described in the present tense were considered active relationships and categorized as high-level COI , for the analysis.We assessed the prevalence of COI and high-level COI and guideline compliance with the following IOM and CMSS recommendations: (1) most panel members are free of COI relevant to guideline subject matter and (2) panel chairs (or \u22651 chair if co-chairs) are free of COI relevant to guideline subject matter.Clostridioides difficile infection (CDI 2018) (21), and COVID-19 2021 (12)  disclosed a relationship with any pharmaceutical company, and one-third (48 of 149 [32.2%]) had 1 or more COI or high-level COI . The ant021 (12) . Most CP021 (12) . Four CP6 We also focused on the tense of disclosures in our analysis, which is vulnerable to misclassification. To ensure that IDSA CPGs remain a trusted source, improving the review and management process for CPG COI is needed.Relationships between IDSA CPG authors and the pharmaceutical industry are common. Approximately one-third of authors disclosed relationships with manufacturers of guideline-recommended drugs, and multiple IDSA CPGs were nonadherent to CMSS and IOM standards. Our findings warrant further attention considering that even the appearance of bias in CPGs can have negative consequences\u2014public distrust in science and health care, including concerns about ties between clinicians and pharmaceutical companies, has been increasing. Study limitations are that we did not assess the accuracy of COI disclosures using third-party data, which may have resulted in underreporting of COI."}
+{"text": "Antimicrobial stewardship programs (ASP) have demonstrated improvement in patient outcomes, reduction of antimicrobial adverse drug events (ADE) and a decrease in antimicrobial resistance in hospitals. Antimicrobials maintain the second highest rate of ADEs in long-term care facilities. Prescribed antimicrobials in nursing homes may be unnecessary or inappropriate in upwards of 75% of cases. There is limited evidence available quantifying the impact of pharmacist-led ASP interventions in long-term care facilities. The purpose of this project is to evaluate the effectiveness of antimicrobial stewardship interventions completed at the Salisbury Veterans Affairs Health Care System Community Living Center (SVAHCS CLC).\u00ae was proposed from May 2018 to January 2021. The primary objective is to determine the effectiveness of ASP interventions in the CLC based on acceptance rate. Secondary objectives include to assess safety of select implemented CLC ASP interventions through reported ADEs within 30 days of performed CLC ASP intervention and determine potential cost savings of the implemented ASP interventions.This is a retrospective quality improvement project. Eligible subjects included Veterans residing in the SVAHCS CLC to which an ASP intervention documented in TheraDocClostridioides difficile infection. There was a total potential cost savings of $101,704.A total of 379 interventions were included. Of these interventions, 370 were accepted (98%), 5 were accepted with modification (1%) and 4 were rejected (1%). The most common ASP interventions included lab monitoring, renal adjustment, pharmacokinetic consults and duration changes. The most common indications for many ASP interventions performed were osteomyelitis, influenza and bacteremia. Vancomycin, cefepime and ceftriaxone were the most common antimicrobials involved for which ASP interventions were performed. Of the 131 interventions assessed for safety, one Veteran experienced ADEs within 30 days of the intervention including nephrotoxicity and Most Common InfectionsASP Intervention Acceptance Rate and ADEs within 30 Days of ASP InterventionThis study demonstrates that pharmacist-led ASP interventions proposed in the SVAHCS CLC were effective with a high rate of acceptance. These interventions resulted in a low rate of ADEs and potential cost savings for the facility.All Authors: No reported disclosures"}
+{"text": "Nature reveals an interaction between SWI/SNF subunits and mitotic chromatin, which is essential for establishing gene bookmarks and preserving cell identity.1 The findings deepen our understanding of how SWI/SNF complexes regulate transcriptional memory heritability for cell fate commitment  and polybromo-associated BAF (PBAF) complexes that were found bound to mitotic chromatin.4 Like many transcription factors, SWI/SNF subunits are expected to be degraded during mitosis.3 It is thus reasonable that SWI/SNF subunits that interact with chromatin in dividing cells may have implications for their participation in fate commitment or propagation of transcriptional blueprint. This idea may have motivated the curiosity of Zhu and colleagues to interrogate how the inheritance of somatic phenotypes is underscored by the gene expression modulatory activity of SWI/SNF subunits that linger at mitosis.1The SWI/SNF or BAF complexes are chromatin remodelers assembled on a modular basis and in a context-specific manner to dictate gene expression patterns that influence cell state and function.1 employed a biochemical fractionation strategy to investigate the presence, subcellular localization, and interaction of SWI/SNF complexes with chromatin in synchronized mouse embryonic stem cells spanning the cell cycle. It was identified that SMARCB1 and SMARCE1 were bound to mitotic chromatin, whereas other SWI/SNF subunits, including SMARCA4 (Brg1), were disengaged or residually bound. They subsequently used live cell imaging to substantiate the observation by in situ visualization of mitotic chromatin localization of SMARCB1 and SMARCE1 alongside SOX2, a classic mitotic chromatin-bound factor. The outcome of chromatin immunoprecipitation and sequencing, which was tweaked by Cut & Run sequencing approach, revealed the promoter region as the preferential genomic location of SMARCB1 and SMARCE1 in mitotic cells  and BAF170 (SMARCC2) as the earliest assembled subunits of SWI/SNF complex5 may benefit expanding the range of SWI/SNF subunits involved in mitotic bookmarking and transmission of the transcriptional memory in cell cycle stages. Knowing the expression dynamics of SWI/SNF subunits driving gene bookmarking in the M-phase of lineage stem cells and cancer cells can lend therapeutic information.For future work, it would be interesting to probe the plausible contribution of SMARCC1 (BAF155) in mitotic bookmarking as it was observed bound to mitotic chromatin, although at a mild intensity."}
+{"text": "Misoprostol is a prostaglandin E1 (PGE1) analogue that has been on the World Health Organization (WHO) List of Essential Medicines since 2005.Brazil has one of the most restrictive regulations in the world related to the use of misoprostol establishing it is exclusively for hospital use with special control, and sale, purchase and advertising prohibited by law.Misoprostol is currently the reference drug for pharmacological treatment in cases of induced abortion, both in the first trimester of pregnancy and at more advanced gestational ages.Misoprostol is an effective medication for cervical ripening and labor induction.Misoprostol is an essential drug for the management of postpartum hemorrhage.The use of misoprostol is recommended for the following situations: legal abortion, uterine evacuation due to embryonic or fetal death, cervical ripening before labor induction (uterine cervix maturation), labor induction and management of postpartum hemorrhage.Misoprostol 800 mcg vaginally (four 200 mcg pills) is recommended for uterine evacuation in pregnancy loss up to 13 weeks.In cervical preparation for surgical abortion at less than 13 weeks of pregnancy, the use of misoprostol 400 mcg vaginally 3-4 hours before the procedure is recommended.The use of misoprostol alone according to the gestational age for uterine evacuation is recommended for termination of pregnancy in legal abortion.The use of vaginal misoprostol according to the gestational age is recommended for uterine evacuation in case of fetal death: at 13-26 weeks, 200 mcg every 4-6 hours; at 27-28 weeks, 100 mcg every 4-6 hours; and over 28 weeks, 25 mcg every six hours.The use of misoprostol at an initial dose of 25 mcg vaginally every 4-6 hours is recommended for cervical ripening and induction of labor with a live fetus in pregnancies over 26 weeks.The use of misoprostol for cervical ripening and induction of labor with a live fetus is not recommended in women with a previous cesarean section due to the greater risk of uterine rupture.Misoprostol is a safe and effective option for women with premature rupture of membranes and unfavorable uterine cervix, as long as they do not have contraindications for taking the medication, for example, previous cesarean section.Rectal misoprostol 800 mcg is recommended as part of the drug treatment of postpartum hemorrhage.In Brazil, misoprostol should be made available to all health services at all levels of care, and it is desirable that outpatient use be allowed, when indicated.Misoprostol is a synthetic analogue of prostaglandin E1 (PGE1) with gastric secretion inhibitory and mucosal protection properties through the production of bicarbonate and mucus. It was first approved to be used to protect the stomach mucosa in patients using non-steroidal anti-inflammatory drugs.Misoprostol is a synthetic analogue of PGE1. It is metabolized in the liver, deesterified and becomes the active metabolite, misoprostol acid. It has the ability to bind to uterine smooth muscle cells, increasing the strength and frequency of uterine contractions.Although other prostaglandins can cause myocardial infarction and bronchospasm, misoprostol is not associated with these effects. Toxic doses have not been well established and cumulative doses of up to 2,200 mcg in 12 hours are well tolerated without significant adverse effects.The Food and Drug Administration (FDA) classifies misoprostol as a category X drug  in the first and second trimesters of pregnancy. Animal studies have shown a significant reduction in fertility with the use of high doses (6.25 to 625 times the maximum human therapeutic dose). In pregnant rabbits, doses of 300 to 1,500 mcg/kg of misoprostol on days 7-19 of embryogenesis have been associated with teratogenic effects.Misoprostol is used for uterine evacuation in first trimester pregnancy loss. On ultrasound examination, pregnancy loss can be characterized by the following aspects: presence of gestational sac without yolk sac or embryo and with mean diameter \u2265 25 mm; embryo with crown-rump length greater than or equal to 7 mm without cardiac activity; no embryo with a heartbeat two weeks after an examination demonstrating an empty gestational sac or no embryo with a heartbeat at 11 or more days after an examination demonstrating a gestational sac with yolk sac. In these situations, three approaches are possible: expectant management, mechanical uterine evacuation, or pharmacological evacuation.Brazil has one of the most restrictive regulations related to induced abortion - induced abortion is only legally permitted in cases of pregnancy resulting from rape, risk to the woman's life and fetal anencephaly \u2013 and to the use of misoprostol in the world. In a study of countries in Africa, Asia and Latin America, Brazil was close only to Vietnam among those with greater restrictions on access to medical abortion in the world.In cervical preparation prior to surgical abortion in pregnancies over 12-14 weeks, the use of misoprostol 400 mcg  2-3 hours before surgical treatment is routinely recommended.The use of misoprostol on an outpatient basis is considered effective and safe for the treatment of induced abortion, especially in the first 12 weeks of pregnancy. The use of misoprostol during this period has minimal adverse effects, such as diarrhea, vomiting, nausea and fever, which can be easily treated by professionals outside the hospital setting.When the diagnosis of fetal death is established, the health professional assisting this pregnant woman and her family must always be able to answer the posed questions with empathy and embracement, even if there are no answers to all. A systematic review including 14 controlled and randomized studies that evaluated the use of misoprostol in fetal death in the second and third trimesters found 100% effectiveness in uterine evacuation within 48 hours.In cases of fetal death after more than 24 weeks, labor induction depends on the conditions of cervical maturation. In patients with a favorable cervix (Bishop index \u2265 6), labor induction can be started with oxytocin without the use of misoprostol for previous cervical ripening. In patients with an unfavorable cervix and without previous uterine scar, misoprostol is the agent of choice for preparing the cervix and inducing labor.25-26 weeks: misoprostol 400 mcg vaginally or sublingually every 4-6 hours;27-28 weeks: misoprostol 100 mcg vaginally or sublingually every 4-6 hours;Over 28 weeks: misoprostol 25 mcg vaginally every six hours.In patients with previous segmental scarring and unfavorable cervix at 24-28 weeks, cervical preparation can be performed with a mechanical method  followed by the use of oxytocin. The use of misoprostol seems to be an acceptable alternative at this gestational age, since the risk of uterine rupture is low. In a review study in which misoprostol was used at this gestational age, the risk of uterine rupture was 0.28% (95% CI: 0.08-1.00) in patients with a previous cesarean section versus 0.04% (95% CI: 0.01-0.20) in patients without a previous cesarean section.In the labor induction process, when the situation of the uterine cervix is unfavorable, a maturation process is recommended to shorten the duration of induction and increase the chance of vaginal delivery. When the Bishop score is less than 6, the cervix is generally considered unfavorable, and mechanical and/or pharmacological methods can be used in this process.Women planning a vaginal birth after a previous caesarean section  may need labor induction. There are two concerns: reduced chances of vaginal birth after caesarean section (VBAC) and increased risk of uterine rupture. Having a previous vaginal delivery and a favorable cervix are the main predictors of induction resulting in VBAC.No previous vaginal delivery \u2013 for example, in a study, the risks of rupture during TOLAC-induced in women without a previous vaginal delivery versus a previous vaginal delivery were 1.5% and 0.6%, respectively;Use of prostaglandins \u2013 induction with prostaglandins appears to be associated with a greater risk of uterine rupture than induction with oxytocin or cervical ripening with mechanical methods followed by administration of oxytocin.Risk of rupture with prostaglandin use\u2013 Data from large randomized trials and from good quality observational studies on the effects of prostaglandins alone or in combination with other agents for cervical ripening in TOLAC are not available. Much data on prostaglandin use in women with a previous caesarean section has been derived from observational studies in which misoprostol (PGE1) was used. Reports on the use of other prostaglandins, such as prostaglandin E2, are limited by their small size, the co-administration of other agents and the lack of stratification by previous vaginal delivery.Unspecified prostaglandin\u2013 Concern over the use of prostaglandins arose following the publication of a large population-based retrospective cohort study that analyzed data from 20,095 primiparous women who delivered after a single previous cesarean section.Repeat cesarean sections without labor: 1.6 ruptures per 1,000 planned repeat cesareans;Spontaneous labor: 5.2 ruptures per 1,000 spontaneous deliveries;Induced labor (without prostaglandins): 7.7 ruptures per 1,000 labors induced without the use of prostaglandins;Induced labor (with prostaglandins): 24.5 ruptures per 1,000 labors induced using prostaglandins. Compared to repeat cesarean delivery, the relative risk of rupture with the use of prostaglandins was 15.6 (95% CI: 8.1-30.0).However, despite the very large number of cases, the information in this study is from a database and individual reviews of medical records were not performed to check other medications administered. The risk of uterine rupture reported in this retrospective study was lower in another large prospective study.American College of Obstetricians and Gynecologists (ACOG \u2013United States)Society of Obstetricians and Gynecologists of Canada (SOGC \u2013 Canada)National Institute for Health and Care Excellence (United Kingdom)In conclusion, the use of misoprostol in women with previous cesarean is not recommended given the higher risk of uterine rupture. Note that mechanical methods are available, effective and safe.Premature rupture of membranes (PROM) is one of the most common complications of term and preterm pregnancies, but there is a gap in knowledge about how management affects the cesarean rate. As gestational age at delivery is the critical factor influencing perinatal outcome, expectant management is generally adopted when far from term. In PROM at term, the risk of maternal and fetal infectious morbidity increases with longer duration of membrane rupture. Therefore, expectant management should be brief, with instructions for induction of labor.Postpartum hemorrhage affects around 2% of all patients, and in only 25% of cases the risk factors are pronounced. The obstetrician must perform prophylaxis in 100% of cases and be aware of the occurrence of PPH, even if drug prophylaxis is performed. There is strong evidence that the association of uterotonics prescribed in the immediate postoperative period of childbirth reduces blood loss greater than 500 mL: ergometrine plus oxytocin  and misoprostol plus oxytocin  and reduces the need for blood products .Oxytocin:In post-vaginal delivery: single dose of 10 IU intramuscularly right after birth;In cesarean section: 5 IU in slow intravenous infusion in three minutes and maintenance solution ;Misoprostol: single dose of 600 mcg rectally;Ergometrine: single dose of 0.2 mg intramuscularly.For the drug treatment of PPH, the use of misoprostol 800 mcg rectally is recommended. It is important to remember that since the onset of action of rectal misoprostol is slower than that of other uterotonics, it should be used as an adjuvant to treatment with oxytocin. Misoprostol should not be used in isolation, maintaining uterine massage until the onset of its effect, which may take 15-20 minutes. Always consider the use of tranexamic acid 1 g intravenously over 10 minutes, with the possibility of repeating the 1 g dose in 30 minutes if bleeding persists.Circular letter number 182/2021 of the Office of the President of the Brazilian Federal Council of Medicine,In obstetric practice, misoprostol has been widely used in legal abortion, uterine emptying due to embryonic or fetal death, cervical ripening and labor induction, and management of PPH. Contrary to the accumulated scientific evidence, Brazil has one of the most restrictive regulations in the world related to the use of misoprostol. The great difficulty in acquiring, storing and dispensing the medication imposed by Ordinance No. 344/1998 of Anvisa, still in force, contributes to denying the right to safer outpatient treatments for women who need it. These restrictions also hinder the availability of this medication, essential and mandatory, in obstetric care services.National Commission Specialized in Childbirth, Puerperium and Abortion Care of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Alberto Trapani J\u00faniorVice-President:Alessandra Cristina MarcolinSecretarySheila Koettker SilveiraMembros:Elias Ferreira de Melo JuniorLiduina de Albuquerque Rocha e SousaMarcia Maria Auxiliadora de AquinoMirela Foresti Jim\u00e9nezRicardo Porto TedescoTenilson Amaral OliveiraNational Commission Specialized in Antenatal Care of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Fernanda Garanhani de Castro SuritaVice-President:L\u00edlian de Paiva Rodrigues HsuSecretaryAdriana Gomes LuzMembros:Jorge Oliveira VazEliana Martorano AmaralEugenia Glaucy Moura FerreiraFrancisco Herlanio Costa CarvalhoJoeline Maria Cleto CerqueiraJose Meirelles FilhoLuciana Silva dos Anjos Fran\u00e7aMarianna Facchinetti BrockMary Uchiyama NakamuraPatricia Goncalves TeixeiraRenato AjejeSergio Hecker LuzNational Commission Specialized in Gestational Trophoblastic Disease of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Antonio Rodrigues Braga NetoVice-President:Jos\u00e9 Mauro MadiSecret\u00e1rioMauricio Guilherme Campos ViggianoMembros:Bruno Maurizio GrilloChristiani Bisinoto de SousaClaudio Sergio Medeiros PaivaElaine Azevedo Soares LealElza Maria Hartmann UbertiFabiana Rebelo Pereira CostaIzildinha MaestaJose Arimatea dos Santos JuniorMaria do Carmo Lopes de MeloRita de Cassia Alves Ferreira SilvaSue Yazaki SunTiago Pedromonico ArrymNational Commission Specialized in High Risk Pregnancy of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Rosiane MattarVice-President:Alberto Carlos Moreno ZaconetaSecretaryMylene Martins LavadoMembros:Arlley Cleverson Belo da SilvaCarlos Alberto MaganhaElton Carlos FerreiraFelipe Favorette CampanharoInessa Beraldo de Andrade BonomiJanete VettorazziMaria Rita de Figueiredo Lemos BortolottoFernanda Santos GrossiRenato Teixeira SouzaSara Toassa Gomes SolhaVera Therezinha Medeiros BorgesNational Commission Specialized in Fetal Medicine of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Mario Henrique Burlacchini de CarvalhoVice-President:Jos\u00e9 Antonio de Azevedo Magalh\u00e3esSecretaryRoseli Mieko Yamamoto NomuraMembros:Alberto Borges PeixotoCarlos Henrique Mascarenhas SilvaCarolina Leite DrummondEdward Araujo J\u00faniorFernando Artur Carvalho BastosGuilherme Loureiro FernandesJair Roberto da Silva BragaJorge Fonte de Rezende FilhoMarcello Braga ViggianoMaria de Lourdes BrizotNadia Stella Viegas dos ReisReginaldo Ant\u00f4nio de Oliveira Freitas J\u00faniorRodrigo RuanoNational Commission Specialized in Maternal Mortality of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Marcos Nakamura PereiraVice-President:Rodolfo de Carvalho PacagnellaSecretaryMelania Maria Ramos de AmorimMembros:Acacia Maria Louren\u00e7o Francisco NasrDouglas Bernal TiagoElvira Maria Mafaldo SoaresFatima Cristina Cunha PensoIda Perea MonteiroJo\u00e3o Paulo Dias de SouzaLucila NagataMaria do Carmo LealMonica Almeida NeriMonica Iassan\u00e3 dos ReisJacinta Pereira MatiasPenha Maria Mendes da RochaNational Commission Specialized in Obstetric Emergencies of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Alvaro Luiz Lage AlvesVice-President:Gabriel Costa OsananSecretarySamira El Maerrawi Tebecherane HaddadMembros:Adriana Amorim FranciscoAlexandre Massao NozakiBrena Carvalho Pinto de MeloBreno Jos\u00e9 Acauan FilhoCarla Betina Andreucci PolidoEduardo CordioliFrederico Jose Amedee PeretGilberto NagahamaLaises Braga VieiraLucas Barbosa da SilvaMarcelo Guimar\u00e3es RodriguesRodrigo Dias NunesRoxana KnobelNational Commission Specialized in Sexual Violence and Pregnancy Interruption Provided for by Law of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Robinson Dias de MedeirosVice-President:Cristi\u00e3o Fernando RosasSecretaryHelena Borges Martins da Silva ParoMembros:Aline Veras Morais BrilhanteAnibal Eus\u00e9bio Fa\u00fandes LathamD\u00e9bora Fernandes BrittoEdison Luiz Almeida TizzotIsabelle Cantidio Fernandes DiogenesKenia Zimmerer VieiraMichele Lopes PedrosaOsmar Ribeiro ColasRivaldo Mendes de AlbuquerqueRosires Pereira de AndradeSuely de Souza ResendeZelia Maria CamposNational Commission Specialized in Professional Defense and Appreciation of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Maria Celeste Osorio WenderMembros:Carlos Henrique Mascarenhas SilvaEtelvino de Souza TrindadeHenrique Zacharias Borges FilhoJuvenal Barreto Borriello de AndradeLia Cruz Vaz da Costa Dam\u00e1sioMaria Rita de Souza MesquitaMirela Foresti Jim\u00e9nezSergio Hofmeister de Almeida Martins CostaCelia Regina da SilvaAljerry Dias do RegoRosires Pereira de AndradeMaria Auxiliadora BudibCarlos Alberto Sa MarquesHilka Flavia Barra do Espirito Santo Alves Pereira"}
+{"text": "The current systematic review sought to identify quantitative empirical studies that focused on the transdiagnostic factors of intolerance of uncertainty, emotional dysregulation and rumination, and their relation with depression and post-traumatic stress disorder (PTSD). The overall research aim was to examine the relationship between these transdiagnostic factors and their relation with depression and PTSD symptoms. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Out of the 768 articles initially identified, 55 met the inclusion criteria for the current review. The results determined that intolerance of uncertainty is indirectly related to depression and PTSD symptoms, mainly through other factors including emotion dysregulation and rumination. Additionally, emotional dysregulation is a significant predictor of both depression and PTSD symptoms. Rumination is a robust factor related to depression and PTSD symptoms, this relationship was significant in cross-sectional and longitudinal studies. This review provides evidence on the transdiagnostic factors of intolerance of uncertainty, emotional dysregulation and rumination in the relationship with depression and PTSD symptoms. Depressive, anxiety, and substance use disorders are among the leading contributors to the global disease burden  lack of awareness, understanding, and acceptance of emotions; (b) the inability to control behaviors when experiencing emotional distress; (c) lack of access to situationally appropriate strategies to modulate the duration and/or intensity of emotional responses to meet individual goals and situational demands; and (d) unwillingness or reluctance to experience emotional distress as part of seeking meaningful activities in life  guidelines  Empirical quantitative research reports published in a peer reviewed journal (2) Written in English or Spanish language, (3) Outcome measures related to depression or PTSD symptoms or diagnosis. Studies were excluded if the following criteria was met: (1) No depression or PTSD outcome measure, (2) No rumination, intolerance of uncertainty or emotional dysregulation measure, (3) Not depression PTSD comorbidity, (4) Children or adolescent sample, (5) Insufficient or inappropriate data reported , specifically USA (21 studies), and Canada (3 studies). Followed by 25.5% from European countries, 16.4% from Asia including China (4 studies), Japan (1 study), India and Iran (2 studies each), 7.2% from Oceania particularly, Australia (4 studies), and 7.2% from South America including Argentina (2 studies), Colombia and Chile (1 study each). Community-based studies were the most frequent type (39%), followed by undergraduate student sample (27.1%), clinical sample (18.6%), and trauma exposed sample (15.3%). Most of the studies were cross-sectional (66.1%), followed by longitudinal (28.6%) and a minority were experimental (5.4%).Eleven studies examined the relation between intolerance of uncertainty and depression symptomatology. Empirical evidence indicates that intolerance of uncertainty is a significant predictor of depression symptoms, even when anxiety symptoms where accounted for (Barry et al., Six studies that examined the relation between intolerance of uncertainty and PTSD symptoms. This evidence indicates that intolerance of uncertainty is a significant predictor of PTSD symptoms. These result remained significant even after covarying for other PTSD risk factors including: rumination, neuroticism, and worry (Boelen et al., When the relation between intolerance of uncertainty and PTSD symptoms DSM-V clusters was examined, there was a significant association to the avoidance, hyperarousal and emotional numbing symptom clusters (Oglesby et al., We identified 8 studies that assessed the relation between emotion dysregulation and depression symptoms. Results indicated that emotion dysregulation was positively associated with depressive symptoms, even when controlling for baseline mindfulness (Diehl et al., Seven studies assessed the relation between emotional dysregulation and PTSD symptoms. Longitudinal assessments found that emotional dysregulation was significantly associated with the probability of developing PTSD symptoms 4\u00a0months later (Fujisato et al., Thirteen studies examined the relation between rumination and depression symptoms. Results from longitudinal associations indicated that rumination predicts depressive symptoms and that depressive symptoms predict rumination at 4-year follow-up (Whisman et al., Ten studies examined the relation between rumination and PTSD. Repetitive and anticipatory rumination moderated the relationship between PTSD and MDD symptoms (Roley et al., The current systematic review sought to identify quantitative empirical studies that focused on the transdiagnostic factors of intolerance of uncertainty, emotional dysregulation and rumination, and their relation with depression and/or PTSD. This review identified 55 studies that reported the association between the transdiagnostic factors of interest in depression and PTSD symptoms.Intolerance of uncertainty was a consistent significant predictor for both depression and PTSD symptoms, as suggested by other authors (McEvoy et al., Emotional dysregulation has been found to relate to depression as well as many other psychiatric symptoms including PTSD (Aldao et al., Rumination is an important factor related to the maintenance and exacerbation of depression and PTSD symptoms (Olatunji et al., This systematic review had a number of limitations that should be taken into account when interpreting the results and addressed in future research. First, even though studies in Spanish were included in an attempt broaden the scope, the majority of the studies were conducted in North American and European countries. Furthermore, taking into consideration the evidence that culture may play a significant role in the manifestation of psychopathology Rathod, , the resThis review provides evidence that the transdiagnostic factors of intolerance of uncertainty, emotional dysregulation and rumination are consistent significant predictors for both depression and PTSD symptoms. Particularly, intolerance of uncertainty is indirectly related to depression and PTSD symptoms through other factors including emotion dysregulation and rumination. Meanwhile, emotional dysregulation is a significant predictor of both depression and PTSD symptoms. Rumination is a robust factor related to depression and PTSD symptoms, this relationship was significant in cross-sectional and longitudinal studies. Both emotional dysregulation and rumination can mediate the relationship between several risk factors including intolerance of uncertainty and depression and PTSD symptoms. This study provides insight into understanding these factors in the onset and maintenance of depression and PTSD symptomatology. Consequently, contributing to the evidence that allows the development of theoretical and empirically supported transdiagnostic models. Which may ultimately promote the development of cost-effective treatments that targets underlaying mechanism or factors, thus promoting preventative alternatives for multiple disorders."}
+{"text": "Motivation is an important factor in therapy and potentially even more so in an online setting. Earlier research shows that more autonomously motivated patients have better outcomes and completion rates than more controlled motivated patients\u00b4. However, little is known about how motivation type influences treatment effect in an online setting and in patients with binge eating disorder specifically.This study set out to investigate how motivation type as per the Self-Determination Theory would affect treatment adherence and effect in a sample of 148 patients, undergoing an Internet-based Cognitive Behavioral Therapy (iCBT) for BED.The study was mixed-methods. A sample of 148 patients gave two written qualitative statements regarding their motivation for seeking treatment and reasons for choosing online therapyThe statements were transformed into quantitative units via the condensation method. The themes were categorized according to the model by Ryan and Deci based on level of autonomy and perceived locus of causality.This was compared with completion rate and outcomes on eating disorder symptomatology. Completion was designated into three groups. Low adherers - less than six sessions (n=54), high adherers \u2013 between 7 and 10 sessions (n =56) and full adherers - 10 session plus follow up (n=37).The effect of the treatment was measured via the Eating Disorder Examination Questionnaire (EDEQ) and Binge Eating Disorder Questionnaire (BEDQ).Perceived locus of causality and level of autonomy, did not affect level of adherence or outcome of treatment in either setting. This unexpected result may suggest that internet-based therapy is less dependent on motivation types, when comparing with face-to-face treatment.None Declared"}
+{"text": "Correction to: Japanese Journal of Radiology (2021) 39:84\u201392 10.1007/s11604-020-01040-1In the original publication, the last sentence under heading Patients in section Materials and methods should read as:All patients gave written informed consent for the procedure.The revised Ethical approval statement should read as:Ethical approval All procedures performed in these studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments. All patients gave written informed consent for the procedure. The institutional review board of our hospital approved retrospective data analysis."}
+{"text": "After this article was published, similarities were noted between this article  and submIn response to queries about these concerns, the corresponding author provided the underlying data in During editorial follow-up, the following errors in article  were notThere are two instances in The Nakano study  involvedThe Lehmann study  T stage The Matrana study  T stage In Table 1:The univariate analyses  instead of the multivariate analyses  from Kubackova\u2019s research [An expert statistical reviewer assessed the updated PLOS ONE Editors issue this Expression of Concern.The concerns about specific results were resolved in discussions with the authors and reviewer, and the dataset received from the authors provides a level of assurance as to the provenance of this work. Nevertheless, PLOS remains concerned about similarities between  and otheS1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(CSV)Click here for additional data file."}
+{"text": "There is a large gap between the need for anticoagulation and the use of drug therapy for this purpose in ambulatory care. Major lower-extremity orthopedic surgery such as total hip replacement and total knee replacement are associated with an increased risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to symptomatic outcomes such as pulmonary embolism (PE). Prophylaxis and treatment of patients with symptomatic VTE occurs in 2 phases. Initial therapy focuses on rapid achievement of effective anticoagulation and usually involves subcutaneous low-molecular-weight heparin. Long-term prophylaxis with the vitamin K antagonist, warfarin, reduces the risk of recurrent VTE from about 27% (without prophylaxis or inadequate prophylaxis) to 4% during the first 3 months of observation."}
+{"text": "Malnutrition is a common condition in cancer patients which is usually associated with functional limitations, as well as increased morbidity and mortality. Based on the support of the young sections of Italian Association of Medical Oncology (AIOM), Italian Association of Radiotherapy and Clinical Oncology (AIRO) and Italian Society of Surgical Oncology (SICO) merged into the NutriOnc Research Group, we performed a multidisciplinary national survey with the aim to define the awareness of nutritional issues among healthcare professionals delivering anticancer care. The questionnaire was organized in four sections, as follows: Knowledge and practices regarding Nutritional Management of cancer patients; Timing of screening and assessment of Nutritional Status; Nutritional Treatment and prescription criteria; Immunonutrition and educational topics. The modules focused on esophagogastric, hepato-bilio-pancreatic and colorectal malignancies. Overall, 215 physicians completed the survey. As regards the management of Nutritional Status of cancer patients, many responders adopted the ERAS program (49.3%), while a consistent number of professionals did not follow a specific validated nutritional care protocol (41.8%), mainly due to lack of educational courses (14.5%) and financial support (15.3%). Nearly all the included institutions had a multidisciplinary team (92%) to finalize the treatment decision-making. Cancer patients routinely underwent nutritional screening according to 57.2% of interviewed physicians. The timing of nutritional assessment was at diagnosis (37.8%), before surgery (25.9%), after surgery (16.7%), before radiochemotherapy (13.5%) and after radiochemotherapy (7%). Most of the responders reported that nutritional status was assessed throughout the duration of cancer treatments (55.6%). An important gap between current delivery and need of nutritional assessment persists. The development of specific and defined care protocols and the adherence to these tools may be the key to improving nutritional support management in clinical practice."}
+{"text": "Sussex cattle breed is characterized by their distinctive solid red coat colour and white tail switch. Sussex cattle are known for being easy to handle and manage, making them an ideal choice for cattle farmers. The phenotypic characterization of this cattle breed in South Africa is unknown. Hence, the objective of this study was to characterize the morphological structure, phenotypic and body indices traits of Sussex cattle in South Africa at Huntersvlei farm, Frere State province of South Africa. One hundred and one weaners (n = 101) between 6 and 8 months old  and fifty yearlings between 12 and 15 months old  were used in this study. Body weight at weaning, yearling and linear body measurements such as head length (HL), head width (HW), ear length (EL), ear width (EW), sternum height (SH), withers height (WH), heart girth (HG), hip height (HH), body length (BL), rump length (RL), and rump width (RW) were measured. Moreover, the animals were assessed for coat colour and horn presence. Descriptive statistics, Pearson\u2019s correlation and Principal Component Analysis (PCA) were used to describe the Sussex cattle breed. The results indicated that male Sussex cattle had highly significant (p < 0.01) mean numeric values for the BW and morphometric traits. The results further showed that Sussex cattle had highly significant (p < 0.01) increase for the BW and morphometric traits as age advances in all sexes. Interaction effect of sex and age showed a highly significant (p < 0.01) effect with BW and measured morphometric traits, while moderately significant (p < 0.05) with EW. Male Sussex cattle showed highly significant (p < 0.01) higher mean numeric values for the body index (BI), length index (LI) and compact index (CI) indices. While female Sussex animals showed highly significant (p < 0.01) mean numeric values for area index (AI) and proportionality (PR). Body weight showed a positive highly significant (p < 0.01) correlation with the measured morphometric traits except for the moderate significant (p < 0.05) correlation with EL. Coat colour traits ranged from 15 (9.93%), 103 (68.21%) to 33 (21.85%) for light, moderate and dark colours, respectively. While horn presence traits ranged from 48 (31.79%), 42 (27.81%) to 61 (40.40%) for polled, scur and horned respectively. The PCA results extracted only two components in both sexes of the animals. The morphological variations obtained in this study could be complemented by performance data and molecular markers of single nucleotide polymorphism (SNP) to guide the overall breed characterization, conservation and development of appropriate breeding and selection strategies. Livestock plays an important role in the social, economic and cultural stability of rural households in many parts of the world . MASA 22 reporteThe experimental procedures were conducted following the University of South Africa (UNISA) Ethics code for the use of live animals in research, ethics reference number: 2022/CAES_AREC/171.This study was conducted at Huntersvlei farm also known as Rhys Evans Group (RE) in the Free State Province, South Africa. The farm is situated in Viljoenskroon, Fezile Dabi municipality; the site, temperatures, latitudes, longitude, and rainfall of the study area similar as described by Bila . HuntersAll the animals used in the study were exposed to a traditional management grazing system which allows animals to freely graze in the camps during the day and afternoon. Fresh clean water was always available in the camps. Animals received a routine inspection and dipping for herd health management purposes. The linear body measurements were taken while the animal was in a standing position with head raised up and weighed on all four feet. A functional handling facility with a crowding pen, working crush and head clamp was used for handling the animals to minimize movement during the measuring process.Morphometric traits and live body weight at two different stages were taken. The first stage was at weaning age in one hundred and one (n = 101)  South African Sussex weaner animals between 6 and 8 months old. Second stage yearling age is 50  South African Sussex yearling animals are between 12 and 15 months old. The animals used in the study at weaning age were between six to fifteen months old. The live body weight at the two stages was measured using a balance weighing scale whereas linear body measurements were measured using a measuring tape calibrated in centimetres (cm). The body weight at weaning, yearling and morphometric traits, namely head length (HL), head width (HW), ear length (EL), ear width (EW), sternum height (SH), withers height (WH), heart girth (HG), hip height (HH), body length (BL), rump length (RL), and rump width (RW) were measured following the guideline defined by Lomillos and Alonso , Tyasi eTo prevent individual variations in measurements, only one individual was taking the body weight and morphometric traits. The horn presence was assessed using three point scale  following the guidelines reported by Grobler et al. . Moreove2) test was used to find the significant difference on qualitative traits. Procedure of correlation (PROC CORR) was used to determine Pearson\u2019s correlation matrix. These analyses were then followed by a principal component analysis (PCA) to reduce the dimensionality of the morphometric data using the procedure of principal component (PROC PRINCOMP and PROC FACTOR). Furthermore, to examine the morphometric traits and body indices that have the most discriminating power the stepwise discriminant analysis was applied using the STEPDISC procedure (PROC STEPDISC). The significant difference was observed at P<0.05 and highly significant at P<0.01.The Statistical Analysis System  version The overall summary of the collected data  discoverMeans and standard deviation for the sex effect on body weight and morphometric traits is given in The overall summary of the collected data  discoverMeans and standard deviation for the overall sex effect on body indices is given in In females, the BI showed a positive highly significant (p < 0.01) correlation with LI, while moderately significant (p < 0.05) correlated with PI and insignificant (p > 0.05) correlated with CI . PI showThe overall summary of the collected data  discoverThe frequency and percentage of coat colour and horn presence observed in males and females of Sussex cattle at Huntersvlei farm population are presented in The frequency and percentage of coat colour and horn presence observed in males and females of Sussex cattle at Huntersvlei farm populations are presented in The predicted factor loading extracted by factor analysis, eigen-values and variation explained by each factor are presented in The CDA for morphometric traits of South African Sussex cattle are presented in The CDA for body indices traits of South African Sussex cattle are presented in This study was exclusively based on specific phenotypic and morphometric traits of Sussex cattle at Huntersvlei farm in the Free State, Province, South Africa. Phenotypic variation of local animal resources shows a genetic diversity that may be worth conserving for future uses while better understanding of the external features assists to facilitate the implementation of conservation policies intended to ensure local resources survival . FirstlyFurthermore, the results of the study showed that the coat colour both in male and female populations had a highly significant effect with males showing a maximum incident of dark coat colour while females showing a maximum incident moderate coat colour. On the other hand, the horn presence showed a significant effect amongst the sexes with males showing a maximum occurrence of horn presence and females showing a maximum occurrence of polledness. Bila and Tyasi  showed tThe importance of morphological characterization of cattle breed\u2019s genetic resources cannot be emphasized. The present study is based on morphometric and certain phenotypic traits of Sussex cattle at Huntersvlei farm in South Africa. The study findings displayed the morphological and phenotypic variations between ages and genders of the Sussex cattle breed at Huntersvlei farm. It was found that the Sussex cattle breed in the study area have developed some diverse phenotypic traits such polled, scur and horns. Moreover, the Sussex cattle at Huntersvlei farm showed that the male animals had a much darker red brown colour in comparison to female animals. The correlation results shown that in male BW had highest positive association with HH, BL and WH and hence can be used as markers to predict BW using regression equations. The extracted principal components from different morphometric traits symbolize the general body size and shape of the Sussex cattle population at Huntersvlei farm. Stepwise canonical discriminant analysis showed that head width, head length, hip height, sternum height, heart girth and rump width are the suitable discriminating morphometric traits in the Sussex cattle breed. Furthermore, an investigation on the molecular characterization using molecular markers SNP will complement the results obtained from morphometric variation. Lastly these findings might be helpful in breed characterization, conservation and developing breeding and selection strategies.S1 FileIt is an Excel file with variables fully explained in column P and Q of the sheet.(XLSX)Click here for additional data file.S2 FileIt is an Excel file with variables fully explained in column E, F and G of the sheet.(XLSX)Click here for additional data file."}
+{"text": "Based on studies showing the use of autologous skin cell suspensions (ASCS) leads to burn wound closure with significantly smaller amounts of harvested donor skin, the Food and Drug Administration approved the first ASCS for the reconstruction of thermal injuries in September, 2018. The benefit of needing less donor skin to heal a given soft tissue wound has led to off-label usage of ASCS in a variety of clinical situations, such as necrotizing soft tissue infections (NSTI), toxic epidermal necrolysis (TEN), and traumatic injuries with soft tissue loss among others. Here, we report on a single-institution case series of ASCS usage for closure of soft tissue wounds caused by nonthermal mechanisms.We performed a retrospective chart review of all patients treated with ASCS for an indication of non-thermal soft tissue wounds at our American Burn Association-verified academic burn center between April 1, 2018 to June 1, 2022. Descriptive demographic data were collected.+ 17 yrs, mean length of stay 46 + 30 days) were found to have undergone closure of their wounds using ASCS during the time period of the chart review. Indications were NSTI (n=2), frostbite (n=2), antiphospholipid syndrome (n=2), and TEN (n=2). ASCS was used as a sole therapy for the TEN patients while ASCS was used in combination with meshed autografting for all other patients. The mean size of wounds treated with ASCS was 2835 + 2670 cm2, and the mean ASCS take rate was 86 + 7%. No ASCS-related complications were found.Eight patients (6 male/2 female, mean age 57 These results bolster the off-label use of ASCS solutions for closure of nonthermal wounds while the surgical world awaits the results of an ongoing Phase III trial on this questionThis study seeks to contribute to the literature supporting off-label uses of ASCS in non-thermal injuries & diseases."}
+{"text": "The chest bone, or sternum, protects the heart and lungs and aids in breathing motion. It is included on chest radiographs of dogs and cats, but little information is available for veterinarians on what abnormalities or diseases affect the chest bone in companion animals. We reassessed chest radiographs of dogs and cats taken in our hospital over a 2 year period to describe these changes. We found that abnormalities of the chest bone were visible in 24% of dogs and 29% of cats, with the most common abnormality being age-related degeneration. Most of the abnormalities noted were of minor clinical importance, but in some animals, conditions that could be painful or otherwise affect well-being were seen.Evaluation of the sternum is part of the routine examination of small animal thoracic radiographs. However, descriptions on frequency and type of abnormalities are lacking. This retrospective observational study aimed to describe abnormal radiographic findings of the sternum in a cross-section of client-owned dogs and cats undergoing thoracic radiography between 1 January 2019 and 1 January 2021 for reasons unrelated to diseases of the sternum. The study population consisted of 777 dogs  and 183 cats . Sternal abnormalities were observed in 189/777 (24%) dogs and 53/183 (29%) cats, mostly around the intersternebral cartilages, accounting for 32/80 (40%) dogs and 20/35 (57%) cats. This was followed by an abnormal number of sternal segments . Pectus excavatum was observed in 6/777 (0.8%) dogs and 6/183 (3%) cats, and pectus carinatum in 18/777 (2%) dogs and 2/183 (1%) cats. Post-traumatic changes, such as subluxation, were observed in nine dogs (1.1%) and three cats (1.6%). Presumed prostatic carcinoma metastasis and malignant lymphoma were observed in two dogs (0.2%). Incidental radiographic sternal abnormalities are common in cats and dogs but mostly of unknown clinical relevance. An evaluation of the sternum is part of the routine examination of small animal thoracic radiographs, as it forms the ventral contour of the thoracic cavity. The sternum contributes to the bony protection of the intra-thoracic cardiopulmonary structures, as well as to the stability and breathing motion of the thorax.manubrium sterni), is wider and longer than the other sternal segments. The manubrium of the sternum is the point of insertion of the sternocephalicus muscle and has lateral shelves of bone accommodating the attachment of the costal cartilages of the first pair of ribs. The body of the sternum (corpus sterni) consists of six rectangular to cylindrical-shaped sternebrae. The most caudal last sternebra, or xiphoid process (processus xiphoideus), is flat and long, occasionally with a foramen in its caudal half. The xiphoid process is prolonged caudally by the xiphoid cartilage (cartilago xiphoidea), which supports the cranial part of the ventral abdominal wall and from which the linea alba extends caudally to the symphysis pelvis. The individual sternebrae are connected by intersternebral cartilages, forming cartilaginous joints , and the sternum is covered on the ventral and dorsal surface by thickened periosteum, forming the sternal membrane (membrana sterni). Whilst the costal cartilages of the first pair of ribs articulate directly with the manubrium of the sternum, the costal cartilages of the second to seventh ribs articulate with the consecutive intersternebral cartilages between the individual sternal segments, and both the costal cartilages of the eighth and ninth rib pairs articulate with the intersternebral cartilage between the seventh sternebra and the xiphoid process. The first eight paired sternocostal joints are synovial joints, but no synovial joint was found at the ninth sternocostal articulation The costal cartilages of the last four pairs of ribs do not directly articulate with the sternum but connect via the costal arch or are floating ribs, and these ribs are therefore considered asternal ribs ) if normally distributed or as median (range) if the distribution was skewed. Data were analyzed using IBM SPSS Statistics (Version 28). Independent samples n = 145), Labrador Retriever (n = 62), Chihuahua (n = 28), Bernese Mountain Dog (n = 26), Golden Retriever (n = 23), French Bulldog (n = 23), Labradoodle (n = 22), and German Shepherd (n = 21). One hundred and fourteen dogs were of brachycephalic breed. The three most common indications for thoracic radiography in dogs were metastasis screening (n = 252), cough (n = 94), and dysphagia (n = 57). An example of a thoracic radiographs of a dog on which the sternum was considered unremarkable is provided in The study population consisted of 777 dogs. The group of dogs had a mean age of 7.3  years and consisted of 400 males (188 neutered) and 377 females (252 neutered) of various breeds, the most common being mixed breed (n = 8), post-traumatic changes (n = 5) or shape deformity of the sternum (n = 1), and an abnormal number of sternebrae in combination with shape deformity (n = 4) or post-traumatic changes (n = 1).Sternal abnormalities were observed in 189/777 (24%) dogs . Nineteen = 108; 14%), most of which were considered degenerative type changes such as mineralisation of the sternal cartilages or formation of bony spurs . Marked degenerative changes, such as narrowing of the intersternebral cartilage space (n = 13), vacuum phenomenon (n = 13), and subluxation (n = 5), were mainly observed in the mid-section of the sternum, between the 3rd and 4th and 4th and 5th sternebrae (n = 16). The mean age of dogs with degenerative changes  was significantly higher than the mean age of dogs without these changes .Abnormalities were most frequently observed in the area of the intersternebral cartilages in dogs . Less than eight sternal segments were observed 46 dogs (6%): seven sternebrae were visible in 40 dogs, six sternebrae in four dogs, and three and four sternebrae in one dog each. The latter resulted in morphologically abnormal short sternum (n = 5) or four (n = 2) sternebrae. Three dogs with lower number of sternebrae showed border effacement of the ventral thoracic diaphragmatic surface and the caudal ventral cardiac silhouette due to cranial excursion of the diaphragm, but none of these animals had evidence of peritoneopericardial herniation. Supernumerary sternal segments  were observed in 16 dogs (2%), affecting predominantly medium and large breed dogs. The most common breed affected was Labrador Retriever (n = 7).An abnormal number of sternal segments was the second most seen abnormality in dogs ( sternum . The lown = 8) and Chihuahua (n = 5) were overrepresented.Pectus excavatum was observed in six dogs (0.8%), and the severity was considered mild in five dogs and moderate in one dog based on vertebral indices . Pectus excavatum involved the caudal sternum in five cases and the mid-sternum in one mixed breed dog. One case was considered likely to have a traumatic instead of congenital origin based on clinical history. Four of the five dogs with suspect congenital pectus excavatum were brachycephalic breeds, including two out of seven Pugs . Mild pen = 9, of which five were in combination with other degenerative changes) (Presumed post-traumatic changes were observed in 12 dogs (1.5%), although none of these dogs were presented for thoracic radiography because of a history of trauma or suspect traumatic lesions of the sternum; the indication in eight of these dogs was metastasis screening. The presumed post-traumatic changes mainly consisted of dislocation (changes) . These cOne Chihuahua with malignant lymphoma had multiple pathological fractures associated with osteopenia . An aggrn = 112), Maine Coon (n = 16), mixed breed (n = 11), and British Shorthair (n = 10). The most common indications for thoracic radiography in cats were dyspnea (n = 40), metastasis screening (n = 37), and post-accident trauma (n = 18). An example of a thoracic radiographs of a cat on which the sternum was considered unremarkable is provided in The study population consisted of 183 cats. The group of cats had a mean age of 7.3  years and consisted of 105 males (89 neutered) and 78 females (66 neutered) of various breeds, most commonly Domestic Shorthair (n = 3) or degenerative changes (n = 3).Sternal abnormalities were observed in 53/183 (29%) cats . Six catp = 0.002). Concurrent gas opacity in the intersternebral cartilage space or associated subluxation of sternebrae was not observed in any of the cats with signs of degenerative changes of the intersternebral cartilages.Degenerative changes, consistent of mineralization of the sternal cartilages or formation of bony spurs, were observed in 15 cats (8%). Cats with degenerative changes were significantly older than those without  or sixth and seventh sternebrae (n = 5). The other nine cats with seven sternebrae had an absence of one sternal segment. One Domestic Shorthair had six individual sternebrae, caused by complete fusion of the fourth and fifth sternebrae and the absence of one sternal segment , of which seven cats had nine sternebrae. Nineteen cats had seven individual sternal segments, which, in ten cats was caused by complete fusion of the first and second sternebrae ( segment .Pectus excavatum was observed in six cats (3%), and the severity was considered mild in four cats and moderate and severe in one cat each  . The typn = 2), partial fusion of sternebrae (n = 3), and narrowing of the intersternebral cartilage space without signs of degeneration (n = 1).Signs of traumatic luxation were observed in three cats (1%). One cat had undergone recent cardiopulmonary resuscitation, and the other two cases showed more chronic changes with malformed fusion of the dislocated sternebrae. One of these cats had a history of sternal fracture 10 years prior and the other cat had no known history of trauma . Other aThe sternum develops from the fusion of bilateral mesodermal bars which unite from day 25 of gestation in dogs and day 28 of gestation in cats, starting cranially at the manubrium of the sternum and ending caudally at the xiphoid process ,24. OssiAs in previous reports, pectus excavatum mostly affected the caudal sternum in dogs in our study population, which is the typical form of pectus excavatum . Komsta In agreement with a previous publication by Hassan and colleagues (2018), we observed pectus carinatum predominantly in small breed dogs, except for in one English Springer Spaniel . In thatAlthough neoplastic disease was the most common indication for thoracic radiography in dogs, only two cases presented with radiographic aggressive bone lesions affecting the sternum. One dog diagnosed with malignant lymphoma presented with pathological fractures of multiple sternebrae, the other dog was diagnosed with prostatic carcinoma and had an aggressive bone lesion affecting the second and third sternebrae. However, the sternal lesions were not biopsied in these dogs and therefore it remains unknown if these aggressive bone lesions indeed were caused by neoplastic disease. Skeletal involvement affecting the spine has been described in canine multicentric lymphoma ,30, but synchondroses sternales, mostly consistent of mineralization of the sternal cartilages or formation of bony spurs, was the most common finding in our study, with a prevalence of 14% in dogs and 8% in cats. In 13 of the dogs affected, gas opacity was observed in between the sternebrae on the left lateral view radiograph. Gas accumulation within synovial joints and intervertebral disc spaces is termed vacuum phenomenon. This gas consists of 90\u201392% nitrogen and its presence has been associated with intervertebral disc degeneration in dogs [synchondrosis sternalis in dogs, similar to the above-mentioned association between vacuum phenomenon in the intervertebral disc space and intervertebral disc degeneration in dogs [Age-related degeneration of the  in dogs ,36,37. T in dogs  and, in  in dogs . In our Sternal dislocation is infrequently reported in veterinary literature and is most often considered to be of traumatic origin ,16,17. BOur study had several limitations. First, the retrospective design prohibits adequate correlation between radiographic findings and clinical signs. For example, it cannot be reliably determined if sternal dislocation in dogs with severe intersternebral cartilage degeneration was associated with pain or other clinical signs, because no specific history and physical examination addressing these findings were performed in these cases. Secondly, the large variety in breeds in combination with the relatively low number of cases for each disorder impedes drawing firm conclusions on any breed predispositions. Thirdly, the use of radiography instead of a cross-sectional technique such as computed tomography results in a lower sensitivity for detection of abnormalities because of the inferior contrast resolution and problems of superimposition inherent to radiography. Moreover, computed tomography would allow a better representation of the anatomy. For instance, computed tomography was reported to be useful for evaluation of thoracic asymmetry and sternal torsion in cats with pectus excavatum, which cannot be done with radiography . In addiSternal abnormalities are common incidental findings on thoracic radiographs of companion animals and were observed on thoracic radiographs of 24% of dogs and of 29% of cats in our study population. Clinically relevant abnormalities, such as severe degeneration of the intersternebral cartilage space, dislocation, or aggressive bone lesions, were only recognized in few cases, whilst most animals showed abnormalities that were unlikely to cause clinical complaints."}
+{"text": "To determine the extent to which primary care physicians have been willing to incorporate computerized protocols and clinical information systems into their practices.A survey was fielded to both primary care and non hospital-based specialty group practices of five physicians or more.The types of these technologies in use and the degree to which the physicians themselves were active users.Findings (n=197 or a 38% response rate) are presented grouped by three stages of software application adoption: (1) transaction; (2) decision support; and (3) expert systems or simulation of human thought. Transaction systems, particularly applications that support practice administration such as registration, billing, and scheduling, have the highest percentage of adoption (82% to 97%). Expert systems are uncommon (3% to 6%), with slightly higher penetration of telephone triage (such as \"ask-a-nurse\") and prevention reminders applications . Within group practices, physician \"hands-on\" use of systems is low for viewing (28%), and even lower for entering patient information (6% to 8%).Emerging knowledge technologies such as medical decision support or expert systems are not widely accepted and may even threaten traditional physician domains of expertise. Explicit consideration of potential physician opposition should be included in planning pharmaceutical management strategies that depend on \"hands-on\" physician computer use to be successful."}
+{"text": "Rheumatoid pulmonary nodule can be detected in up to 32% of rheumatoid arthritis (RA) patients and approximately one-third of nodules may cavitate. We aimed to evaluate characteristics of patients with RA developing cavitary pulmonary nodular (CPN) lesions under disease-modifying antirheumatic drugs (DMARDs), follow-up of both cavitary and solid nodules, and their outcome with the treatment.RA patients who presented with CPN lesions during follow-up were recruited retrospectively in this case series analysis. Total numbers and mean diameters of cavitary and solid nodules in each thorax computed tomography (CT) have been determined and followed up by two experienced pulmonary physicians. Moreover, changes in treatment after the development of the CPN lesions and characteristics of cavitary nodules were collected.Eleven patients with CPN lesions were reported. At the time of CPN diagnosis, more patients were taking leflunomide than methotrexate (81% vs 19%). Half of the patients were receiving biologic therapy and only 18% were taking anti-TNF drugs. After a median of 24 (3\u201365) months of follow-up, the regression of CPN lesions was determined in 45% (5/11) of patients. Four of these 5 (80%) patients were switched to a treatment regimen without leflunomide and three of them to nonanti-TNF biologic treatment or targeted synthetic DMARDs .CPN lesions seen in RA patients are often pulmonary manifestations of the underlying disease; however, one must rule out malignancies or infections. If lesions progress under DMARDs, it is advised to discontinue synthetic DMARDs (LEF/MTX) and switch to another biological DMARD with different modes of action Rheumatoid arthritis (RA) is a chronic inflammatory disease typically involving small joints. Pulmonary involvement is the most common extraarticular manifestation of the disease. Pulmonary disease, which is a major source of morbidity and mortality in RA, manifests most commonly as interstitial lung disease (ILD), airways disease, rheumatoid nodules (RN), and pleural effusions .The prevalence of rheumatoid pulmonary nodules, also called necrobiotic nodules, ranges from less than 0.4% in radiological studies to 32% in lung biopsies of patients with RA [Nodules usually present a diagnostic challenge rather than therapeutic. Nodules in RA patients should be evaluated similarly to those in any other patient presenting with solitary or multiple pulmonary nodules, as nodules may reflect the presence of infection, malignancy, or other inflammatory diseases. Biologic drugs are now widely used for treating RA. Various side effects, mainly infection, have been described with these drugs. The efficacy of these agents for the treatment of pulmonary involvement of disease has not been specifically evaluated in large placebo-controlled randomized trials.We report characteristics of 11 patients with RA developing cavitary pulmonary nodular (CPN) lesions under disease-modifying antirheumatic drugs (DMARDs) and follow-up of cavitary nodules and their outcome with the treatment were reported.RA patients who presented with CPN lesions during follow-up between September 2009 and April 2019 in rheumatology outpatient clinic were recruited retrospectively in this case series analysis. Diagnosis of the CPN lesions was made with computed tomography (CT) scan and indication for imaging of these patients were constitutional/respiratory symptoms or any abnormality at routine annual conventional radiography during biological treatment. Characteristics of the patients, positron emission tomography (PET), and biopsy (if available) findings were collected from patient reports. Patients without biopsy were the ones who did not accept biopsy or who had contraindication for biopsy (with cardiac failure and arrhythmia treated by the cardiac pacemaker). In addition to these, changes in treatment after development of the CPN lesion and characteristic of cavitary nodules were collected. Outcome assessment focused mainly on the number and characteristics of all nodules  with the modification of treatments, but we also evaluated cavitary nodules separately. Total numbers and mean diameters of cavitary and solid nodules in each CT have been determined with the agreed decision of two experienced pulmonary physicians, who were aware of the clinical data of the patients. An increase in total nodule count or new cavitation of a solid nodule at CT was accepted as a progression of the lesion. It is also accepted as a progression of the lesion if there is a 20% or more increase of mean nodule size even though total and cavitary nodule count is stable. A decrease in total or cavitary nodule count and a 30% or more decrease in mean nodule size is accepted as regression of the lesion.The study was approved by the local clinical research ethics committee (reference number: 09.2019.592)Before initiation of biologic drugs (except rituximab), each patient was screened for tuberculosis and underwent conventional radiography, clinical pulmonary examination, and ppd/QuantiFERON test, and tuberculosis prophylaxis (9 months of isoniazid) was given to 5 of them as the results of these tests.Two patients received antituberculosis treatment after the detection of CPN; the negative QuantiFERON test turned positive during abatacept treatment in 1 patient (case 4) and biopsy of the nodule was necrotizing granuloma for the other one although tuberculosis bacilli were not detected (case 8). After antituberculosis treatment, there was no regression at the cavitary nodules.Respiratory symptoms were reported by 2 patients and constitutional symptoms by 2 patients while the others were asymptomatic during the diagnosis of CPN. All patients were seropositive, 2 patients had p ANCA (antinuclear cytoplasmic antibody)-positive, but the ELISA test for anti-MPO (myeloperoxidase) and PR3 (proteinase) were negative. Extensive examinations for microbial organisms (mycobacteria and opportunistic infections) were all negative .A total of 48 CTs were evaluated by two experienced pulmonary physicians. We are presenting CT findings showing cavitary and solid nodules of our patients in Fluorodeoxyglucose (FDG) PET/CT scan examination of nodules was performed to exclude malign conditions in 7 patients. We determined that both mediastinal lymphadenopathy (LAP) and cavitary-solitary nodules had increased uptake with a standardized uptake value (SUV) of 1.6\u20137.9 FDG. Salivary gland adenocarcinoma was detected in one of the patients with 12 FDG uptake value at the submandibular area, but biopsy from mediastinal lymph node (11 FDG) showed tuberculosis-negative necrotizing granuloma.We evaluated CTs of patients for the total (solid/cavitary) nodules at the end of 28 (3\u201365) months follow-up and 4 (36.3%) patients were diagnosed with regressed lesions while 7 (63.7%%) patients had progressive lesions compared to previous CTs  and switch to biological DMARDs with different modes of action. In addition, improvement of the CPN lesions might be seen with non-TNF biologic treatment or targeted synthetic DMARDs ."}
+{"text": "Scientific Reports 10.1038/s41598-021-03609-w, published online 10 January 2022Correction to: The Acknowledgements section in the original version of this Article was incomplete, where the grant number of one of the funding agencies was omitted.\u201cSP would like to acknowledge support of the National Science Centre of Poland within the OPUS programme.\u201dnow reads:\u201cSP would like to acknowledge support of the National Science Centre of Poland within the OPUS programme (2020/39/B/ST2/01524).\u201dThe original Article has been corrected."}
+{"text": "In India, unsafe sex has been documented among truck drivers. This study explores the factors influencing their attitude of trucker towards condom use.A cross-sectional study design was adapted for this study in which 25 factors were chosen to assess attitude toward condom use on 7 point validated Likert scale UCLA Multidimensional Condom Attitude Scale on 5 subcomponents -Reliability, Pleasure, Stigma associated with condom use, embarrassment about negotiation and use of condom and about purchasing condom. Hundred truck drivers were recruited using convenient sampling and Mann-Whitney U and Kruskall Wallis Test were used to validate the subcomponents among those practicing unsafe sex.Positive attitudes regarding reliability and effectiveness of condom were significantly higher among adult entrants and those resting more than 10 hours during journey whereas positive attitude regarding pleasure associated with condoms and stigma towards it is significantly higher among truck drivers travelled long distances and resting more than 10 hours.Adolescent entrants, those who have not travelled long distances and not rested more than 10 hrs requires improvement in the attitude towards condom use. WHO reports globally 36.9 million people are living with HIV. 1In South-east Asia, 1.7 million people are living with HIV and number of people living with HIV in India is 2100000.2Sexual promiscuous lifestyle is common among truck drivers and therefore susceptible of acquiring HIV infection. 12There seems to be few studies highlighting the attitude toward condom use among truck drivers. This study was undertaken with an objective to assess the attitude towards condom use and its predictors among truck drivers at transhipment location in Meerut district, IndiaThis cross-sectional study was conducted at Trans-shipment area in Meerut district, India which is home to over two hundred transporters and over 500 trucks are available at any given point of time. Furthermore, a typical halt can range from thirty minutes to two days and work hours of most transporters are eleven hours.Hundred truck drivers were recruited who were having a valid driver's license from the trans-shipment area using convenient sampling procedure.A pre-tested validated questionnaire comprising closed ended questions was used to document socio-demographic-occupational profile and for assessment of attitude towards condom use University of California Los Angeles Multidimensional Condom Attitude Scale (UCLA MCAS) was used.13The truck drivers were briefed about the purpose of the study, importance of their participation, its consequential benefit to truck drivers and assurance of their confidentiality. After briefing them, the informed consent was taken from truck driver agreeing to participate and regardless of the participation, the truck drivers were given condoms and advices related to health issues. Truck drivers having wrong perception about condom were educated about the benefit of condom The pilot study, modification of questionnaire, recruitment of participants for main study and data analysis was done from a period of August 2014 to September 2015.Occupation profile: Type of truck drivers (based on distance traversed), average number of days away from home, average resting time during trip and type of entrant (adolescent or adult)Unsafe sex: Our criterion for unsafe sex was operationally defined as inconsistent use of condom with high risky sexual partners like CSW and MSM irrespective type of intercourse-vaginal, anal or oral (Fellatio) and practicing either Cunnilingus or Analingus or both.Attitude towards Condom Use: The 25 item UCLA MCAS 7-point Likert scale was used to assess the attitude towards condom use. The UCLA MCAS has 5 subscales (or domains) - Reliability and Effectiveness of Condoms, Pleasure associated with Condom, Stigma associated with condom use, Embarrassment about negotiation and use of condom and Embarrassment about purchasing condoms. 13Reliability and effectiveness subscale included 1) Condoms are an effective method of preventing the spread of Aids and other sexually transmitted diseases 2) Condoms are unreliable (reverse scored) 3) I think condoms are an excellent means of contraception 4) Condoms do not offer reliable protection (reversed score) 5) Condoms are an effective method of birth control. Pleasure associated with condoms included 1) Use of condom is an interruption of foreplay (reversed score) 2) Condoms ruin the sexual act (reversed the score) 3) Condoms are a lot of fun 4) The use of condom can make sex more stimulating 5) Condoms are uncomfortable for both parties (reversed score)Stigma associated with Condom use included 1)Women think men who use condoms are jerk (reversed score) 2)If a couple is about to have sex and the man suggests using a condom, it is less likely that they will have sex (reversed score) 3) People who suggest condom use are a little bit geeky (reversed score) 4) Men who suggest using a condom are really boring (reversed score) 5) A woman who suggests using a condom does not trust her partner (reversed score). Embarrassment about negotiation and use of condom include 1) It is really hard to bring up the issue of using condoms to my partners (reversed score) 2) When I suggest using a condom I am almost always embarrassed (reversed score) 3) It is easy to suggest my partner that we use a condom 4) I never know what to say when my partner and I need to talk about condoms or other protection (reversed score) 5) I am comfortable talking about condoms with my partner. Embarrassment about purchasing condoms include 1) I always feel really uncomfortable when I buy condoms (reversed score) 2) I don't think that buying condoms is awkward 3) It is very embarrassing to buy condoms (reversed score) 4) It would be embarrassing to be seen buying condoms in a store (reversed score) 5) It would be embarrassing to be seen buying condoms in a store (reversed score)The analysis was done in SPSS 21.The total score for each item = +  +  +  +  +  +  / Total Response (100)Mean score% for each subscale = (mean score \u2013 1)/Minimum value = 1 and maximum value = 7The mean score for individual participant in different subscales was computed and non-parametric test [Kruskall Wallis and Mann-Whitney U Test] were applied to find the predictors of attitude regarding condom use.The study was a component of a dissertation and Subharti Medical College  Institutional Committee approved the dissertation (SMC/PG-13/2013).Of the 100 participants, most were married (72%), literate (90%), adult entrant (69%), travelled long distance (77%) average time away from home less than 10 days (71%) and resting during journey less than 10 hours (65%).The attitude among truck driver regarding reliability and effectiveness of condom is 88.3% , pleasure associated with condom is 70.3% , stigma associated with condom is 73.7% , embarrassment about negotiation and condom use is 76% and purchasing condoms is 75.8%.The mean score for attitude regarding reliability and effectiveness of condoms is significantly higher among adult entrants than adolescent entrants and those resting more than 10 hours during journey whereas mean score for regarding pleasure associated with condoms is significantly higher among truck drivers travelled long distances and resting more than 10 hours. Furthermore, the mean score for attitude regarding stigma associated with condom use is significantly higher among truck drivers travelled long distance and attitude regarding embarrassment about negotiation and use of condom was significantly higher among truck drivers resting more than 10 hours. However, mean score for attitude regarding embarrassment about purchasing condom use was significantly higher among adult entrants and those who have travelled long distance. This seems to be the first study for elaborative assessment of attitude toward condom use among truck driver population in India using UCLA Multidimensional Condom Attitude Scale. The findings of the study indicate in almost all domains the attitude of truck driver was far from satisfactory.This scale was used among 20 recruited community members assessing difference in attitude towards condom use between those consuming alcohol and does not consuming it.18The study is subjected to limitation because of small sample size recruited using convenience sample and social desirability bias may have influence on the response of the participants. Hence it is recommended the study be conducted on a large sample size using probability sampling.The age of the entrant, travelling long distances and resting time more than 10 hours were predictors significantly affecting attitude of truck drivers regarding condom use."}
+{"text": "C) to the neurotoxic pathogenic form (PrPTSE) via a yet undefined but profoundly complex mechanism. Despite several decades of research on PrD, the basic understanding of where and how PrPC is transformed to the misfolded, aggregation-prone and pathogenic PrPTSE remains elusive. The primary clinical hallmarks of PrD include vacuolation-associated spongiform changes and PrPTSE accumulation in neural tissue together with astrogliosis. The difficulty in unravelling the disease mechanisms has been related to the rare occurrence and long incubation period (over decades) followed by a very short clinical phase (few months). Additional challenge in unravelling the disease is implicated to the unique nature of the agent, its complexity and strain diversity, resulting in the heterogeneity of the clinical manifestations and potentially diverse disease mechanisms. Recent advances in tissue isolation and processing techniques have identified novel means of intercellular communication through extracellular vesicles (EVs) that contribute to PrPTSE transmission in PrD. This review will comprehensively discuss PrPTSE transmission and neurotoxicity, focusing on the role of EVs in disease progression, biomarker discovery and potential therapeutic agents for the treatment of PrD.Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are invariably fatal and pathogenic neurodegenerative disorders caused by the self-propagated misfolding of cellular prion protein (PrP TSE) of normal cellular prion protein (PrPC) (Prusiner Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are progressively rapid and fatal neurodegenerative diseases (NDs) with a defining hallmark of vacuolation in the brain tissue , Gerstmann\u2013St\u00e4ussler\u2013Scheinker (GSS) and fatal familial insomnia (FFI) while sporadic CJD (sCJD) presents with disease aetiology from unknown origins. PrD with acquired aetiologies from exposure to pathogenic prions includes iatrogenic CJD (iCJD), vCJD, and kuru. To date, various human-to-human iCJD transmissions occurred due to incomplete decontamination of surgical equipment, corneal grafting, dura mater grafting, cadaveric pituitary-derived growth hormone or gonadotrophin, and blood transfusions  denaturation, proteinase K (PK) treatment and high-performance liquid chromatography (HPLC) purification yielded the significant component of a single protein ranging 27\u201330\u00a0kDa in size (PrP 27\u201330) TSE isofoC has high endogenous expression in neurons and is encoded by only one exon out of three exons in the PrPC gene at chromosome 20  anchor at the C terminus (residue 230) and two N-linked glycans at residues 181 and 197. Nuclear magnetic resonance (NMR) examination of PrPC structure revealed an intrinsically disordered N-terminal tail (residues 23\u2013128), three \u03b1-helical regions (two of them linked by a disulphide bridge) and a short anti-parallel \u03b2-sheet , where it is packaged in extracellular vesicles  and released into the extracellular environment  was developed  model \u2013based structure  isolation of infectious prions from different prions strains for dynamic and multi-angle light scattering (DLS/MALS) analysis showed quaternary structure difference resulting in PrPTSE strain heterogeneity  polymorphism   fragment on SDS-PAGE gels, three different PrPres subtypes have been identified, which include type 1 (21\u00a0kDa), type 2 (19\u00a0kDa) and type intermediate   is a technique that converts normal brain homogenate PrPTSE deposition are the characteristic features of prion-infected brains, the mechanism of neurotoxicity has remained elusive. However, several studies have investigated the synergistic effect generated by the interaction of PrPC and PrPTSE, providing some explanation on the neurotoxic effects of PrPTSE. Grafting neural tissue overexpressing PrPC into PrPC null mice brains and intracerebrally injecting scrapie prions produced severe histopathological changes exclusively in the grafted tissue  starvation followed by ATP depletion    and exosomes classified based on biogenetic pathway and size. Apoptotic bodies (500\u20135000\u00a0nm) arise from the cell fragmentation during apoptosis, microvesicles (200\u20131000\u00a0nm) from outward budding and shedding from the plasma membrane, and exosomes 40\u2013200\u00a0nm) which are released intercellularly following production via the endosomal pathway and fusion of the MVB to the plasma membrane , and many have predicted targets in crucial neuronal signalling pathways. This suggests that EVs could carry brain-associated miRNAs and into the blood  play key roles in gene regulation either by inducing mRNA degradation or repression of mRNA translation. A plethora of miRNAs are present in the brain, indicating that complex physiological and neuronal development functions of miRNAs are more enriched in the brain regions, which shows the complex physiological functions of the brain , a regulator of ceramide biosynthesis, reduced exosomes as well as miRNA secretion, an effect that was reversed following overexpression \u2013infected N2a cells overexpressing murine prion protein demonstrated upregulation in the redox chaperone, protein disulphide isomerase (PDI)  and ATPase (complex V). A more recent study validated mitochondrial respiratory chain deficiency in human sCJD brain temporal cortex with immunohistochemistry, demonstrating a loss of all mitochondrial complexes (I\u2013V)  and Alzheimer\u2019s disease (AD). An early study of scrapie-infected hamster brain cerebral cortex transmission electron microscopy images depicted alterations in mitochondrial morphology and depletion of mitochondrial matrix and cristae \u2013derived EVs from human placenta intravenously delivered to multiple sclerosis mice demonstrated increased motor abilities, reduced DNA damage and increased myelination  \u2013derived EVs injected into the bloodstream ameliorated neuroinflammation and increased cognitive function in immunocompetent mice (Leavitt et al. EV research is a burgeoning field elucidating the dynamic nature of intercellular communication in the local and distal areas of the body, and has opened a new horizon to decipher the fundamental biological processes in health and disease. Studies exploiting EVs as the biomarker source and their subsequent role in pathogenic and neurotoxic processes aid a better understanding of the complexity of PrD. The gaps in the study of proteomics and lipidomic cargo from the infectious EVs of several prion strains would help to reveal common neurotoxicity-related pathways. Moreover, the functional study of infectious prion EVs in communication with the glial cells can reveal these EVs\u2019 immunomodulatory and inflammatory effects. While secondary lymphoid organs, including the spleen, are indicated as an early accumulation site for prion replication following peripheral prion infection, isolating EVs from these organs for infectivity and cargo assessment would result in better understanding of EVs\u2019 associated roles. Future studies utilising emerging technologies to examine the nanoscale world of EVs will shed more light on this growing field, promoting strain-specific biomarker discovery for disease diagnosis and enabling the engineering of EVs for disease treatment."}
+{"text": "This study aimed to use data analytics to retrospectively identify the prevalence of inpatients across a system of hospitals with a BAAL who received and tolerated the culprit or related beta-lactam (BL) without proper documentation in the allergy profile of the electronic medical record (EMR). Findings from this study could prioritize direct non-invasive delabeling opportunities as a feasible process measure for resource limited antimicrobial and diagnostic stewardship programs (ADSP).> 18 years of age, 2) inpatients at a NM System Hospital (NMSH) with > 1 overnight stay between 8/1/2020 and 8/1/2022, 3) a BAAL in the allergy profile of the EMR, and 4) received > 1 dose of a BL during the study period. Patients who only received aztreonam were excluded. The primary objective of this study was to determine the prevalence of inpatients with a BAAL who received and tolerated the culprit BL antibiotic during the study period without proper documentation in the allergy profile of the EMR. The secondary objectives were 1) to determine the prevalence of inpatients with a BAAL who received and tolerated a related BL antibiotic during the study period without proper documentation in the allergy profile of the EMR and 2) to determine the prevalence of reported BL allergy reactions and severity risk.Eligible patients were generated by a data analyst using the Northwestern Medicine (NM) Enterprise Data Warehouse. Patients eligible for inclusion: 1) adults Results of our study identified up to 751 inpatient BAALs (9.7%), including 87 BAALs of high priority, as valuable targets for early direct non-invasive delabeling, requiring minimal effort and resources from ADSP.Using data analytics to empirically assess digital allergy information could streamline the antimicrobial stewardship process, proactively identifying and prioritizing BAALs to cast a wider net and efficiently achieve process measure outcomes related to allergies compared to conventional methods of delabeling.Anju T. Peters, MD MSCI, Astra Zeneca: Advisor/Consultant|Astra Zeneca: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Optinose: Advisor/Consultant|Sanofi Regeneron: Advisor/Consultant|Sanofi Regeneron: Grant/Research Support"}
+{"text": "In the published article, there was an error in the legend for (A) Immunization and challenge schedule with prime and boost (day 0 and 21), intranasal challenge (day 42), and bleeds . On day 45 mice were euthanized for the harvesting of lungs and nasal turbinates. (B) Viral levels in the nasal turbinates of mice as measured by tissue culture infectious dose 50 (TCID50). (C) Viral levels in the left lung of mice as measured by TCID50. P-values are indicated for the significance of differences and NS denotes no statistical difference. Vaccines were Fluad (T) (blue) and Fluzone (T) (red) with saline (black) and non-infected controls (white). Yamagata-lineage challenge virus was mouse-adapted B/Florida/04/2006.\u201d\u201cMeasuring viral titers in the nasal turbinates and lungs of mice following vaccinations and subsequent challenge with Yamagata-lineage influenza B virus. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Existing data on adverse effects (AEs) of COVID-19 vaccines among people living with human immunodeficiency virus (PLHIV) are currently limited.A cohort study was conducted among PLHIV receiving care at two clinics during COVID-19 epidemics in Thailand (2021-2022). The PLHIV received various types and regimens of COVID-19 vaccines based on vaccine availability and the national policies. Data on vaccine types and AEs were collected and assessed using the online survey system.Of the 398 vaccinated PLHIV, 365 (92%) had CD4 count at enrollment \u2265 200 cells/\u00b5L, 382 (96%) were virologic suppressed, 153 received two doses and 245 received three doses of COVID-19 vaccines. Inactivated and viral vector were the most common vaccine types received by the PLHIV as the first and second doses , while mRNA vaccine was the most commonly used as a booster dose (57%). For the first and second vaccine doses, the most common AEs were fever (15% and 11%) and injection site pain (11% and 11%). The mRNA vaccine significantly caused more overall AEs, injection pain, fatigue, and rashes than the other two types, while the mRNA and viral vector vaccines significantly caused more fever than the inactivated vaccine. For a booster dose, viral vector vaccine significantly caused more injection site pain and headache than the other two types. Most of the PLHIV reported that the AE intensity was similar between the first and second doses (49%) and was more for a booster dose compared to the first dose (50%). The majority of all AEs of the first, second and booster doses spontaneously recovered without treatment  or required symptomatic treatment without hospitalization . By multivariable analysis, receipt of viral vector or mRNA vaccine and age less than 40 years were independently associated with any AEs of the primary series vaccines, while having AEs from the previous dose and female sex were factors associated with any AEs of a booster vaccine.The three types of COVID-19 vaccines were generally safe among PLHIV. Most of the AEs were non-severe and did not require hospitalization. PLHIV who were elderly, female or had AEs from the previous vaccine dose should be closely monitored for AEs of the vaccines.All Authors: No reported disclosures"}
+{"text": "Mental disorders, musculoskeletal diseases (MSDs) and their comorbidities are major threats to work and functional ability. The relationship between mental health and the common MSDs has not received enough attentionTo study the socio-professional characteristics of workers suffering from work related MSDTo evaluate the association of work related MSDs with anxiety and depression disordersA descriptive cross-sectional study conducted among workers with work-related MSDs who consulted the occupational medicine department of the Charles Nicolle Hospital between January 2022 and September 2022. A remote survey was conducted among these workers to screen for anxiety and depressive disorders using the Hospital anxiety and Depressive ScaleThe study population consisted of 54 workers with MSDs with a sex ratio (M/F) of 0.74. The average age was 44.4 [27-61 years]. The average professional seniority was 14.9 years\u00b17 years and the sectors with the highest prevalence of MSDs were the health sector (22%), the food industry (13%) and the textile industry (11%). The workers reported MSDs of the lumbar spine in 61%, gonarthrosis in 31%, followed by MSDs of the upper limb in 25%. The prevalence of anxiety and depressive disorders were respectively 46% and 38%. There was no significant association between socio-demographic factors and anxiety depressive disorders. The anxiety disorder was associated with MSDs of the lumbar spine .Anxiety and depressive disorders were common among workers with MSDs related to work. Interventions targeting psychological distress and work-related psychosocial characteristics may reduce their musculoskeletal pain.None Declared"}
+{"text": "Toxoplasma encephalitis (TE) is the most frequent cause of expansive brain lesions among acquired immunodeficiency syndrome (AIDS) patients; however, the optimal timing of antiretroviral therapy (ART) initiation in these patients remains controversial.This was a multicenter prospective observational study, and eligible patients were recruited from eleven treatment centers in China.In total, 87 patients were included, and 38 of them were assigned to the Early ART group (initiating ART within 2 weeks after anti-Toxoplasma treatment initiation), while the remaining 49 patients were allocated to receive deferred ART (initiating ART at least 2 weeks after anti-Toxoplasma treatment initiation). Our results indicated that the incidence of immune reconstitution inflammatory syndrome (IRIS)  and the number of death events  were not significantly different between the two groups at Week 48. The timing of ART initiation was also found to not significantly contribute to human immunodeficiency virus (HIV) viral load control. The difference in the number of patients who maintained an undetectable HIV viral load of <50 copies/mL in each of the two groups of patients was calculated to not be statistically significant at Week 24  and Week 48 . Meanwhile, median CD4+ T-cell counts were also observed not to reach statistical significance between the two groups, both at Week 24  and Week 48 .In our study, early ART initiation was observed to not confer statistically significant differences in the incidence of IRIS, mortality, and HIV virological and immunological outcomes, when compared to deferred ART initiation.All Authors: No reported disclosures"}
+{"text": "In recent decades, vagus nerve stimulation (VNS) therapy has become widely used for clinical applications including epilepsy, depression, and enhancing the effects of rehabilitation. However, several questions remain regarding optimization of this therapy to maximize clinical outcomes. Although stimulation parameters such as pulse width, amplitude, and frequency are well studied, the timing of stimulation delivery both acutely (with respect to disease events) and chronically (over the timeline of a disease\u2019s progression) has generally received less attention. Leveraging such information would provide a framework for the implementation of next generation closed-loop VNS therapies. In this mini-review, we summarize a number of VNS therapies and discuss (1) general timing considerations for these applications and (2) open questions that could lead to further therapy optimization. What VNS implementation strategies have worked best ?Moving forward, what open questions and strategies can be assessed for further optimizing VNS therapy and timing?Implanted vagus nerve stimulation (VNS) is utilized for a number of applications, including improving cardiovascular function  the reactive neurostimulator (RNS) by NeuroPace and 2) VNS with AutoStim Mode by LivaNova. The former uses neural recordings for early seizure detection, while the latter uses relative increases in heart rate (characteristic of seizure activity) for a similar purpose  uses brief bursts of closed-loop VNS paired with events to promote neural plasticity and recovery following disease or dysfunction . Overall, the ultimate role of closed-loop VNS for treating cardiovascular disease will be affected by a number of exciting innovations, including neurogram decoding of cardiovascular information Zanos  and machWhile therapeutic intervention for disease states that are symptomatic  but not perceivable is important, such disease progression is usually preceded by a series of interconnected subclinical states  detect disease events and better time VNS and (2) intervene earlier in disease progression to maximize the clinical benefits of VNS (Fig.\u00a0 detect d"}
+{"text": "Sorghum bicolor (L.) Moench] utilizes the cytoplasmic-nuclear male sterility (CMS) system for seed production and subsequently harnesses heterosis. Since the cost of developing and evaluating inbred and hybrid lines in the CMS system is costly and time-consuming, genomic prediction of parental lines and hybrids is based on genetic data genotype. We generated 602 hybrids by crossing two female (A) lines with 301 diverse and elite male (R) lines from the sorghum association panel and collected phenotypic data for agronomic traits over two years. We genotyped the inbred parents using whole genome resequencing and used 2,687,342 high quality  single nucleotide polymorphisms for genomic prediction. For grain yield, the experimental hybrids exhibited an average mid-parent heterosis of 40%. Genomic best linear unbiased prediction (GBLUP) for hybrid performance yielded an average prediction accuracy of 0.76\u20130.93 under the prediction scenario where both parental lines in validation sets were included in the training sets (T2). However, when only female tester was shared between training and validation sets (T1F), prediction accuracies declined by 12\u201390%, with plant height showing the greatest decline. Mean accuracies for predicting the general combining ability of male parents ranged from 0.33 to 0.62 for all traits. Our results showed hybrid performance for agronomic traits can be predicted with high accuracy, and optimizing genomic relationship is essential for optimal training population design for genomic selection in sorghum breeding.Hybrid breeding in sorghum [ Heterosis is the phenomenon by which the interest . Mid-parc values . The genulations . IMPH ar1 hybrid . Therefo1 hybrid .Sorghum bicolor (L.) Moench] is one of the self-pollinated crops that is bred as a hybrid crop, particularly in the United States (US) and Australia. Beginning in the 1950s, sorghum breeding in the US started utilizing the cytoplasmic-nuclear male sterility (CMS) system to produce hybrid cultivars  of R lines crossed to two female testers. The male lines used for generating single crosses are accessions included within the US sorghum association panel (SAP) that represent the genetic and phenotypic diversity of sorghum across the globe and could be used in allele mining and prebreeding (A sorghum hybrid diversity panel (SHDP) of 602 hybrids was generated by crossing 301 diverse male restorer (R) lines to two CMS female (A) testers: ATx642 (PI656029) and ATx2928 (PI629059) . The malHelicoverpa zea) and fall armyworm (Spodoptera frugiperda) infestation. Fields were watered using overhead irrigation only as needed to prevent drought stress.The hybrids and parental lines from the SHDP were planted along with the commercial check in a modified randomized complete block design with two replications in May 2019 and May 2020 at the Clemson University Pee Dee Research and Education Center  in Florence, SC. The modification was done by blocking each complete replication into smaller blocks based on previously observed maturity and height phenotypes for the male parent of the hybrids to avoid shading effect of taller lines on neighboring plants. There were a total of 40 blocks per replication and each block consisted of 30 individual plots. Each plot had two rows with a row length of 6.096 m and a row spacing of 0.762 m. The experimental hybrids, their parental lines and check hybrid variety (83P17) were randomized completely for each small block nested within each replication. Preplant fertilizer was blended based on soil sample results and per field recommendations for cereal grain production. In 2019, the fertilizer blend consisted of granular muriate of potash  at 300 kg haPhenotypic data were collected for days to anthesis (DTA) when about 50% of the primary panicles in the plot were at mid-anthesis. Plant height (PH) was measured from the base of the plant to the top of the representative panicle within the plot after physiological maturity. Plants were harvested when the majority of the plants in the plot reached post-physiological maturity (grain moisture below 18%) using a Wintersteiger Delta two row combine plot harvester. Harvest dates ranged from 16 to 18 September in 2019 and 17 to 25 September in 2020. Total harvest weight of the grain from each plot and the average moisture content of the harvested grain was used to calculate grain yield (GY) in bushels/acre and subsequently converted to ton per hectare  lines of the female parents were used to evaluate female parent performance. The following model was used to adjust for spatial variability within each experimental year:whereThe adjusted means (BLUPs) of wherewherevcftools   8) by redist function in R ..8). Suppd by GNP .For genomic GCA and genomic GCAe shared . For thee shared . Mean prGCAs of male lines were estimated from the genomic GCA model  using alThe ability to predict testcross performance in hybrids was evaluated for male general combining abilities (mGCA) using the GCA and GCAo models , Fig. 5.Hybrid sorghum breeding is based on a CMS system where male sterile females (A lines or seed parents) are crossed to restorer males (R lines or pollinator parents) to produce seed of commercial Following the wide range of diversity in the parental genotypes, the  to 20%) . The comSince the possible hybrid combinations even in a medium sized breeding program far exceeds the capacity to test them in actual hybrid crosses, one of the main motivation for the use of GP in hybrid breeding is to be able to estimate hybrid genetic value of those untested hybrid crosses  or only female parent (T1F) were shared between training and validation sets to understand the effect of parent testing on the accuracy of single cross predictions. While single-cross performance was predicted with high accuracy in T2 scenario, a strong decline (12\u201390%) in prediction accuracy was observed in T1F compared to T2. This is expected because the predictions from the model in T2 rely not only on kinship between male parents , as in the case of T1F, but also on information from other crosses in the training set that involves the male parent of predicted hybrid with the other female tester. Plant height showed the greatest decline in prediction accuracy in T1F, which could be due to very limited phenotypic variability among female lines for PH, and as a result, accuracy for PH could have been driven primarily by male parent. GP of sorghum hybrids using GBLUP model and cross-validation involving leave one parent out strategy (similar to our T1F) showed mean prediction accuracies (0.31\u20130.54) for grain yield that was similar to accuracy from our T1F prediction scenario (Prediction of testcross performance of inbred lines in hybrid combinations has been studied across multiple crop species ( studied . PredictThe phenotypic distribution of agronomic traits and consistent heterotic advantage of experimental Studies exploring the role of genetic diversity and genomic relationship on GP for trait phenotypic values as well as trait heterotic values are essential for optimization of training population for predicting hybrid performance. In silico simulation studies have highlighted strategies for application of rapid recurrent genomic selection combined with progeny testing to facilitate separation of heterotic groups, reduction in breeding cycle, and ultimately increase in long term genetic gain (jkac311_Supplementary_DataClick here for additional data file."}
+{"text": "To examine the federal government's current health care initiatives in the Centers for Medicare and Medicaid Services (CMS) to improve quality of care and cost-effectiveness around the prescription drug benefit.The government has a unique perspective on quality and outcome. Pharmacists need a working knowledge of 3 areas: (1) Medicare Part D, (2) medication therapy management efforts, and (3) demonstration projects. All of these will make demands on health care providers but should result in better outcomes data and patient care. All of these areas also have value components, and all have strategic implications as 2006 moves into 2007.CMS does not consider managing cost and providing value to be mutually exclusive and is attempting to move America's health care toward a value based program."}
+{"text": "Suicide rates in Azerbaijan rank among the top 3 highest of all Muslim majority countries. Further, approximately 40% of women in Azerbaijan report being physically or sexually abused. Women experiencing interpersonal violence report higher rates of suicide ideation and attempts (34%) than women in the general population. No prior studies have specifically explored protective factors against suicide and interpersonal violence in Azerbaijan.This study aims to address this gap and to identify culturally relevant protective factors against suicide and violence against women in Azerbaijan.A total of 51 women with lived experience and mental health providers participated in either in-depth qualitative interviews or focus groups. The interview guide for the focus groups and one-on-one interviews were developed by the study PI. A list of questions served as the basis for the discussions and was revised and expanded as the groups progressed. For the qualitative analyses, conventional content analysis following a systematic process of coding and classification was utilized.Three main protective factors against suicide were identified: 1) psychological support (33%); 2) psychoeducation to raise awareness of suicide and reduce stigma (28%); and 3) providing financial opportunities/supports (10%) and for violence against women 1) advocacy (28%); 2) psychological support (28%); and 3) changing cultural values (17%).This study fills a much-needed gap in our understanding of suicide and violence against women in Muslim populations. Our findings suggest that for intervention to be relevant and effective, prevention programming needs to span micro, mezzo, and macro levels.None Declared"}
+{"text": "There is a modest but consistent association between violent behavior and schizophrenia. Persons with schizophrenia are at a modestly increased risk of committing violence ,with approximately half of victims being relativesOur study examined the factors attributed to violent behaviour within the relationship patient-caregiver in schizophrenia according to caregivers.This is a cross-sectional study among caregivers of patients with schizophrenia during the period from June to August 2022.Patients who attended our department of psychiatry at the Razi.The questionnaire was divided into three sections. The first section contained items regarding patient- and caregiver-related information.In the second section, caregivers were asked questions about their experience of violence perpetration and victimization involving their relative with schizophrenia in the past 12 months.Beyond frequency, caregivers were also asked to specify, the causes of the violence perpetrated and sufferedThe third section contained two measures, i.e. the Depression Anxiety and Stress Scales (DASS-21) and the abridged version of the Zarit Burden Interview (ZBI), assessing psychological distress and caregiving burden, respectively. The protocol of the study was approved by the ethics committee of the Razi Psychiatric Hospital.The majority of caregivers were females (63.6%), and consisted of patients\u2019 parents (50.9%).The most endorsed causes of violence victimization were symptoms of illness (57.3%), followed by refusal to adhere to treatment (49.1%), drug reaction (23.6%), and negative events; while the most reported causes of violence perpetration were refusal to adhere to treatment (42.7%), Symptoms of illness (37.3%), and limitation of patients\u2019 activities and/or liberty (32.7%).Bivariate analysis showed that lower patients\u2019 economic status (p=.042), tobacco (p=.015) and alcohol use (p=.014) as well as taking Trihexyphenidyl (p=.001) were significantly and positively associated with violence perpetration by caregivers against their relatives with schizophrenia.Multivariable analysis (Logistic regression) revealed that caregivers\u2019 levels of burden remained significantly associated with violence victimization occurrence , while only having other person in charge of caring represented a significant factor associated with perpetration of any form of violence against patients .It is important for medical staffs to provide caregivers with professional knowledge about patients\u2019 real motivation for violence in order to improve their skills of problem-solving.None Declared"}
+{"text": "Clostridioides difficile infection (CDI) is a priority. Infection control measures to prevent CDI target symptomatic (infected) patients. These patients are placed on contact precautions (CP), requiring hand hygiene and use of gloves and gowns. However, asymptomatic (colonized) patients may be a reservoir for cross contamination, and evidence is scarce regarding prevention measures with this population. To address this gap, our study evaluates the effect of universal gloving (UG) for all patient contact to prevent transmission from these patients. However, the gloving intervention involves complex behavioral practices with wide variations in compliance; thus, data on intervention implementation provides critical context. Here we provide a preliminary analysis of intervention fidelity.Prevention of A cluster randomized trial (CRT) is being conducted in ten VA hospital patient units; 5 units randomized to standard of care (CP) and 5 units to the intervention (UG plus CP). A secondary outcome of the study is intervention fidelity (gloving compliance). This analysis includes monthly observation data on hand hygiene (HH) and gloving compliance for UG and HH, gloving, gowning for CP in both groups using a standardized observation tool. Compliance was calculated using the total number of compliant observations divided by the total number of observations.Table 1). Gloving compliance with UG was lower than expected and significantly lower than gloving compliance for CP in the intervention group (Table 2). Table 3 compares HH and gloving between UG (intervention group) and CP (both groups). Gloving compliance was significantly higher with CP than with UG.1012 Observations were conducted between May 2022 and April 2023. HH, gloves and gown compliance for CP did not differ between groups (Results TablesTable 1 - 3Intervention fidelity is critical to support rigor of the CRT, but our results showed lower than expected compliance for both gloving and HH despite the UG intervention. A pilot interview identified the healthcare worker requirement for practicing both HH and gloving as a barrier. Additional investigation into barriers to gloving and HH compliance within the context of a UG intervention is ongoing.All Authors: No reported disclosures"}
+{"text": "Scientific Reports 10.1038/s41598-022-24353-9, published online 28 November 2022Correction to: The original version of this Article contained an error in the Funding section.\u201cThis work was supported by the funds from the National Natural Science Foundation of China (No. 81971842 to Lianbo Zhang) (grant numbers 81973120 to Liu) and National Key R&D Program of China (grant numbers #2018YFC1311600 to Liu).\u201dnow reads:\u201cThis work was supported by the funds from the National Natural Science Foundation of China (No. 81971842 to Lianbo Zhang).\u201dThe original Article has been corrected."}
+{"text": "During 2013, the 11 countries of the World Health Organization (WHO) South-East Asia RegionRubella is the leading cause of vaccine-preventable birth defects ; 3 develRCV1 was introduced in five SEAR countries  before 2013 and in the remaining six SEAR countries  for measles and rubella elimination was established during 2016 and developed an updated framework for verification of measles and rubella elimination during 2020  obtain the highest level of national commitment from SEAR countries and support from partners; 2) strengthen routine immunization and achieve \u226595% coverage with RCV1; 3) conduct high-quality SIAs; 4) enhance surveillance sensitivity and increase collection of specimens for rubella virus detection and genotyping; and 5) leverage elimination activities to enhance measures to restore routine immunization services and reduce immunity gaps for all vaccine-preventable diseases. With the regional birth cohort representing 24% of the world\u2019s infants surviving beyond age 1 year, progress toward rubella elimination in SEAR represents an important opportunity to decrease rubella-related death, disability, and illness worldwide.During 2013, coverage with the first dose of rubella-containing vaccine (RCV1) in the World Health Organization South-East Asia Region was 12%, and only five countries in the region had introduced RCV into their routine immunization programs.By 2021, all 11 SEAR countries had introduced RCV1, and estimated regional RCV1 coverage increased from 12% to 86%; rubella incidence declined by 80%. Maldives and Sri Lanka achieved rubella elimination; Bhutan, North Korea, and Timor-Leste have halted endemic transmission of rubella virus for >36 months.SEAR has made substantial progress toward rubella elimination. To achieve regional rubella elimination by 2023, optimal and accelerated measures to implement all elimination strategies are needed."}
+{"text": "Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co) at three environmentally different sites. Based on molecular and morphological analyses, we characterized their associated AMF communities. Cj was more densely colonized than Co and that root colonization intensity was significantly correlated with soil AMF diversity. The communities comprised 15 AMF genera dominated by Glomus and Paraglomus and 1443 operational taxonomic units (OTUs) of which 1067 and 1170 were in roots and soil, respectively. AMF communities were significantly different among sites, and the root AMF communities were significantly different from those of soil at each site. The root and soil AMF communities responded differently to soil pH. At the genus level, Glomus and Acaulospora were abundant in roots while Paraglomus and Redeckera were abundant in soil. Our findings suggest that AMF colonizing roots are protected from environmental stresses in soil. However, the root-soil-abundant taxa have adapted to both environments and represent a model AMF symbiont. This evidence of strategic exploitation of the rhizosphere by AMF supports prior hypotheses and provides insights into community ecology.Arbuscular mycorrhizal fungi (AMF) in the roots and soil surrounding their hosts are typically independently investigated and little is known of the relationships between the communities of the two compartments. We simultaneously collected root and surrounding soil samples from The online version contains supplementary material available at 10.1007/s00248-023-02223-9. Arbuscular mycorrhizal fungi (AMF) are ubiquitous symbiotic microorganisms that live in both the soil and in roots of their hosts upon which they bestow diverse benefits , 2. AMF AMF communities and species richness may be similar or dissimilar between the roots and surrounding soil . DiffereCamellia japonica ), and vesicles (vesicular colonization [VC]) following McGonigle et al. [Five ethanol-conserved root systems were selected randomly for the assessment of mycorrhization frequency (MF) and intensity in Cj and Co. The roots were stained with Trypan blue in lactoglycerol . Under ae et al. , except We performed statistical analysis using R v. 4.2.2  softwareWe used a permutation-based multivariate analysis of variance (PERMANOVA) in the vegan R package to examine the effects of site, host species, and compartment on the AMF community. Similar and dissimilar communities were detected by analysis of similarity (ANOSIM) based on Bray-Curtis model in the vegan R package. The AMF community was ordinated and visualized using the ggplot2 R package v. 3.4.0. Next, we applied the multinomial species classification method (CLAM) in the vegan R package to identify the AMF OTUs and genera in each compartment of the rhizosphere (root or soil) and those significantly associated with a host (Cj or Co) . We alsoParaglomus occultum AJ276082 served as the outgroup in the phylogenetic tree for which we relied on the clade only when its SH-aLRT \u2265 80% and UFBoot \u2265 95%. The tree was annotated and displayed using Interactive Tree of Life  [The sequences of the top 10 most abundant OTUs (dominant) of each group of samples were aligned using MEGA11 and their maximum-likelihood phylogenetic positions were determined using an automatic model finder, tested with PhyML (SH-aLRT) and ultrafast (UFBoot) bootstraps over 1000 randomizations, all implemented in IQ-TREE 2 . ParagloL, v. 5) .The soil pH was significantly different between sites and host species but the interaction between the two factors was not significant Table . It wentrbcL for Cj and Co (ON156682\u2013ON156726) in BankIt (2569115).After excluding unconfirmed samples, for\u00a0the remaining 94 samples, Illumina MiSeq amplicon sequencing produced 1,114,607 amplicon sequences clustered into 108,048 OTUs. After quality filtering and sequence annotation, we obtained 555,657 Glomeromycota amplicon sequences of excellent quality that clustered into 1445 AMF OTUs. After being rarefied, the normalized AMF community data comprised 226,634  Glomeromycota amplicon sequences in 94 (100.00%) samples and clustered into 1443 AMF OTUs. We deposited the sequence read archives in the National Center for Biotechnology Information (PRJNA714473), the representative nucleotide sequences of the AMF OTUs generated (MZ479751\u2013MZ481498) in GenBank (SUB9891895), and the partial nucleotide sequences of Site, host species, and compartment significantly affected the composition and structure of the AMF community at the OTU level Table S. In UTCBOTU richness of the root AMF community was less than that of the surrounding soil , two unknown clades, and some unknown Glomeraceae . Arbuscles, hypha, and vesicles were observed in Cj and Co , the soil explorers (more abundant in soil than in roots), and the explorers of both, thereby validating the hypothesis of strategic taxon-based colonization in the AMF community  and Chamaecyparis obtusa (Co), collected from three sites in Japan. Normalized community data was used to build these curves, 2411 Glomeromycotan amplicon sequences per sample. Despite the differences in the number of samples per group, it is noticeable that OTU richness of the arbuscular mycorrhizal fungi (AMF) community was higher in soil than rootsESM 2Online Resource 2 Venn diagrams of shared operational taxonomic units (OTUs) in roots and soil communities of arbuscular mycorrhizal fungi (AMF) associated with Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co), collected from three sites in Japan. Notice that the number of OTUs exclusively in roots of Cj (Cj Root) or Co (Co Root) has reduced considerably when data from all sites were consideredESM 3Online Resource 3 Phylogenetic tree for the placement of the dominant (top 10 most abundant) operational taxonomic units (OTUs) in the intra- and extraradical communities of arbuscular mycorrhizal fungi (AMF) associated with Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co) collected from three sites in Japan. Maximum likelihood tree was built using the representative sequences of the dominant OTUs (29 nucleotide sequences) and 53 reference nucleotide sequences downloaded from NCBI GenBank and MaarjAM databases. Best model and parameters were selected with automatic model finder in IQ-TREE 2. SH-aLRT test and ultrafast bootstrap (UFBoot) over 1000 randomizations were performed and UFboot \u2265 95% are shown at the nodes where SH-aLRT \u2265 80%. Accessions of the dominant OTUs (in bold) and scientific names of reference sequences followed by their accessions were used for labeling. All sequences contained an average of 550 bp of the small subunit ribosomal DNA between the primer pairs NS31 and AM1 (EPS 1595 kb)ESM 4Online Resource 4 Classification of AMF OTUs in two habitats using multinomial species classification method (CLAM) for the host (Cryptomeria japonica and Chamaecyparis obtusa) and the compartment (root and soil). Only root samples were used for the host-related classification while root and soil samples were used for the compartment-related classification. Generalist, similarly abundant in both habitats; x specialist, more abundant in the habitat x than the other; Too rare, the OTUs is too rare to be classified with confidenceESM 5Online Resource 5 Anatomical structures of arbuscular mycorrhizal fungi (AMF) in stained roots of Cryptomeria japonica  and Chamaecyparis obtusa . a and d show vesicles and hyphae, respectively while others show different morphologies of arbusculesESM 6Cryptomeria japonica; Co, Chamaecyparis obtusa. b) The UTCBF and UTCF are mixed plantations of Cj and Co. The UTTF site is an adjacent Cj plantation and Co plantation. Table S2 Understory plant community composition of the study sites. a) + refers to the presence at the corresponding site. Table S3 Analyses of variance on soil pH, soil electrical conductivity, and host diameter at breast height a) Variables are soil pH, soil electrical conductivity (EC), and diameter at breast height (DBH) of the host tree. Factors are Site and Host. Sites are Chiba (UTCBF), Chichibu (UTCF), and Tanashi (UTTF). Hosts are Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Table S4 Permanova on the arbuscular mycorrhizal fungi (AMF) community at the OTU level. a) Sites are Chiba (UTCBF), Chichibu (UTCF), and Tanashi (UTTF). Hosts are Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Compartments are root and surrounding soil. Table S5 Mantel test showing the biotic and abiotic effects on the root and soil AMF communities associated with Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Significant effects  are in bold. a) Sites are Chiba (UTCBF), Chichibu (UTCF), and Tanashi (UTTF). Factors are Host and Compartment. Hosts are Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Compartments are root and surrounding soil. Table S6 Analysis of root and soil AMF communities similarities between Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). ANOSIM p-value < 0.05 (in bold) refers to significantly different communities. Table S7 Analyses of variance on the alpha diversity indices of arbuscular mycorrhizal fungi (AMF) community. a) Variables are number of operational taxonomic units (NOTUs) and Shannon index. Factors are Site, Host, and Compartment. Sites are Chiba (UTCBF), Chichibu (UTCF), and Tanashi (UTTF). Hosts are Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Compartments are root and surrounding soil. Table S8 Association of arbuscular mycorrhizal fungi (AMF) with host species  or compartments of the rhizosphere (Root and Soil) based on the multinomial species classification method (CLAM). Table S9 Mantel test showing the biotic and abiotic effects on the root and soil AMF communities associated with Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Significant effects  are in bold. Table S10 Permanova on the arbuscular mycorrhizal fungi (AMF) community at the genus level. Table S11 Analyses of variance on root colonization by type of arbuscular mycorrhizal fungi (AMF) morphotypes. Table S12 Pearson correlations showing the association of root and soil conditions with the root colonization of Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Correlation values are followed by the significance probability in parentheses. Significant correlations  are in boldTable S1 Summary of the study sites a) UTCBF, Chiba; UTCF, Chichibu; UTTF, Tanashi; MAP, mean annual precipitation; MAT, mean annual temperature; Cj,"}
+{"text": "This reParticipants of child\u2010bearing potential in HPTN 084, the trial that enrolled individuals assigned female at birth, were required to use long\u2010acting reversible contraceptives (LARCs) with a failure rate of <1%. This stringent requirement was in response to a safety signal associated with peri\u2010conception dolutegravir (DTG) use in women living with HIV . CAB injGood participatory practice (GPP) recommends that community stakeholders contribute to protocol development to ensure locally appropriate and acceptable trial procedures . FollowiN = 101) stakeholders from HPTN 084 countries (n = 82) and the United States (n = 19) attended the consultation, with most representing community (86%), global (7%) and other (7%) stakeholder groups as defined by GPP guidelines [n = 50) (range 43\u201352) stakeholders from sub\u2010Saharan Africa responded to polling questions , National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH), under award numbers UM1AI068619 (HPTN Leadership and Operations Center), UM1AI068617 , and UM1AI068613 (HPTN Laboratory Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional funding was provided by the Bill & Melinda Gates Foundation (OPP1154174) and ViiV Healthcare. Pharmaceutical support was provided by ViiV Healthcare and Gilead Sciences.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health."}
+{"text": "Objectives: Based on Sardjito Hospital surveillance data in 2020, the incidence of SSI in orthopedic implant surgery was 46 cases (4.7%), mostly in the outpatient clinic. We evaluated some of the potential risks and proposed redesign of infection prevention and control measures in April 2021 to improve the overall clean care at the orthopedic outpatient clinic. Methods: We conducted an operational study to redesign various components of clean care using a before-and-after evaluation of infection risk. The study was led by an IPC nurse and was supported by all levels of stakeholders at Sardjito Hospital, a referral and academic hospital in Yogyakarta, Indonesia, during May\u2013September 2021. Results: The redesigned components covered continuing professional development (CPD) through a workshop on clean care and wound care for doctors and nurses. The workshop also encouraged high-level management to make several important changes: (1) to redistribute medical staff schedules, (2) to start online patient registration to better distribute and decrease patient loads, (3) to set up the waiting room as well as the dressing room with strictly separate between dirty and clean areas, (4) to schedule daily general disinfection at noon during service hours, and (5) to perform routine air disinfection after daily clinic services as well as placing an additional portable HEPA filter for continuous air disinfection. After the these changes, during 2021, 7 SSIs occurred among postoperative orthopedic implant patients, a decrease of 85%. We observed more clean and neat rooms without patient overcrowding as well as easy and comfortable flow of patients and staff. Environmental pathogen germ counts decreased significantly. Conclusions: A redesign project at the orthopedic outpatient clinic reduced the incidence of postoperative SSIs and reduced the number of environmental pathogens. Overall clean care is a basic strategy in IPC for improving patient safety."}
+{"text": "In April, May, and June 2003, we conducted market research with decision makers from 3 payer segments to determine their perspectives on the potential introduction of statins to the U.S. over-the-counter (OTC) market.We selected a convenience sample of survey participants based upon prominence in the market, membership size, and by willingness to participate in our study. The 12 participating managed care organizations (MCOs) cover approximately 100 million lives. The 4 pharmacy benefit managers (PBMs) cover approximately 200 million lives. The 3 large employers (one employer withheld quantitative results) provide medical coverage to nearly 1.4 million employees, both actives and retirees. Each survey participant received a verbal description of an OTC statin and a proposed patient self-management system. We asked each participant a series of questions to obtain opinions on a number of issues related to the potential introduction of an OTC statin.Our research findings can be summarized in the following key(1) MCO representatives generally view OTC statins as a low-risk and beneficial addition to drug therapy options; (2) payer policies will continue to support access to prescription statins with no change in policy following introduction of an OTC option; (3) several of the MCOs and 75% of the PBMs anticipate a sharp, short-term increase in plan costs as a consequence of OTC statin availability; (4) survey participants believe that consumer or member reaction will be mixed and that consumer advertising and physician education will be important; (5) MCOs and PBMs are eager for involvement but cautious about partnerships with pharmaceutical companies; and (6) the details of any OTC statin offering will lay the foundation for its success.Based upon interviews conducted from April through June 2003, key decision makers from 4 PBMs, 12 MCOs, and 3 large employers generally considered the introduction of an OTC statin as a low risk and a beneficial addition to drug therapy. Most believed that increased awareness would result in an initial increase in plan costs, but long-term savings would accrue through improved care and availability of lower-cost OTC options for low-to-moderate-risk patients. The key concern is how to help patients gain enough knowledge and comfort to manage their own cholesterol therapy safely and successfully."}
+{"text": "Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria.We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America\u2019s National Institutes of Health/National Cancer Institute funded project titled \u2018Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria\u2019. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test.A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC+), and 47 (19.7%) were HIV-positive (HIV+/ICC+). The HIV+/ICC) patients were younger with median age 46 (IQR: 40\u201351) years compared to 57 (IQR: 45\u201366) among HIV-/ICC+) , with 12-month OS 84.1% (95%CI: 75% - 90%) and 67.6% (95%CI: 42%\u221284%) respectively.ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival. The World Health Organization (WHO) global estimates showed that 604,127 new cases of invasive cervical cancer (ICC) and 341,831 deaths occurred in 2020.Late presentation and diagnosis, lack of access to care, low resources, and ineffective treatment of ICC have contributed to the high mortality and poor survival for cases of ICC in Nigeria and most low- and middle-income countries (LMICs). \u20138 The dePrevious epidemiologic studies have focused on the survival outcomes of patients with cervical cancer based on stage at diagnosis, access to treatment by surgery or chemoradiation, but few have compared survival outcomes by HIV status., 11, 12 We conducted a cohort study at two academic hospital-based research sites in Jos  and Lagos , Nigeria. We enrolled women with histologically confirmed invasive cervical cancer, with and without HIV, as part of the United States of America\u2019s National Institutes of Health/National Cancer Institute funded project titled \u2018Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria\u2019 (U54CA221205) (see inclusion below).Eligible study participants were approached for enrollment at the two research sites between March 2018 and September 2022. Trained research staff screened and enrolled women aged 18 or older who were not pregnant, no history of hysterectomy, and were not undergoing cancer treatment at the time of recruitment. Participants were classified into two cohorts based on histopathological confirmation of ICC and HIV diagnosis: 1) HIV-positive women with ICC (study group: HIV+/ICC+), 2) HIV-negative women with ICC (control group): HIV-/ICC+). Participants\u2019 clinical and demographic information were obtained by interviewer-administered questionnaires at the time of enrollment into the study. The intent and procedures of the study were disclosed to the study participants and informed consent was obtained. The study protocol was reviewed and approved by the Institutional Review Boards (IRB) at UniJos (JUTH/DCS/ADM/127/XXVII/630) and UniLag (CMUL/HREC/02/22/327/V4) in Nigeria, and Northwestern University (NU) in the USA (STU00207051).The HIV status of study participants receiving care and treatment at the Presidential Emergency Plan for AIDS Relief (PEPFAR) program of the two participating institutions was extracted from the adult HIV treatment and care database. Women with unknown HIV status had rapid HIV diagnostic testing according to the national HIV testing serial algorithm, which involved the use of the Rapid Determine Test, Unigold, and STAT Pack rapid HIV diagnostic test kits. All HIV-infected women receiving care in the PEPFAR program at both study sites were on antiretroviral therapy (ART) at the time of study enrollment. Those whose HIV infection was diagnosed at enrollment were provided appropriate HIV counseling and linked to care and commencement of ART in the PEPFAR program of the participating institutions in accordance with the Nigerian National ART Guidelines.Suspected ICC cases were evaluated by the gynecologic oncology team at the Jos University Teaching Hospital (UniJos) and Lagos University Teaching Hospital (UniLag). Diagnostic evaluation of ICC included examination under anesthesia (EUA), and clinical staging according to the international federation of gynecology and obstetrics (FIGO 2009).  During tAs previously reported, the pauThe primary clinical outcome analyzed in this study was all-cause mortality with assessment of overall survival and time to death after invasive cervical cancer diagnosis. Overall survival (OS) is defined as time from ICC diagnosis to death with censoring at the date of last available follow up as obtained from clinic visits or telephone contact up to September 30th, 2022. The use of telephone for cancer follow up has been documented in a prior study in Jos Nigeria and in other studies in Africa., 20Study data were collected and managed using REDCap electronic data capture tools, 22 withDescriptive statistics were used to summarize baseline subject characteristics for ICC+/HIV+ and ICC+/HIV- groups, and overall. Continuous variables were summarized using median and interquartile range (IQR) and compared between groups using the Wilcoxon rank sum test. For categorical variables, frequencies and percentages were reported, and proportions were compared using Fisher\u2019s exact test. Frequencies of missing observations were tabulated, and missing observations were not included in these descriptive analyses.Primary objective was to determine the association between HIV status and overall survival (OS) among ICC+ patients. OS distribution was estimated using the method of Kaplan-Meier, and survival estimates are reported with the corresponding 95% confidence bands, 25th, median, and 75th percentiles survival times are presented. Overall survival was compared between groups using the log-rank test. Overall survival was estimated for HIV+ and HIV- groups, and by study site.Statistical analyses were performed using R v. 4.2.2 statistical software, and usiBetween March 18th, 2018, and September 30th, 2022, a total of 239 women with confirmed invasive cervical cancer were enrolled and are included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC+), and 47 (19.7%) were HIV-positive (HIV+/ICC+).The median age at study enrollment was 53 years (IQR: 44\u201365) among the ICC+ participants overall. HIV-positive patients were younger with median age 46 (IQR: 40\u201351) years compared to 57 (IQR: 45\u201366) among HIV-negative ; had a higher level of education with only 10.6% having no formal education as compared to 32.6% in the HIV- groups (p<.001); and a higher number of lifetime sexual partners with median of 3 (IQR: 1\u20134) partners among HIV+ patients vs. 1 (IQR: 1\u20132) in the HIV- group (p<0.001). Women without HIV had a higher number of childbirths  but comparable age at first childbirth (median 20 years old in both groups) and BMI (median 25 in both groups) to women with HIV. The most common histopathologic variant of ICC was squamous cell carcinoma in 80.4% of all cases and was similar among HIV+ and HIV- women . The majority of patients (68.1%) had moderately differentiated tumor grade , and the histopathologic variants and tumor grading were comparable in both groups. HIV+ women tended to be diagnosed with advanced stage more frequently (64.9%) than HIV- women (47.9%) although the difference was not statistically significant (p=0.10). Other descriptive statistics of the participants with ICC by HIV status have been summarized in Following diagnosis and enrollment of participants with ICC, types of treatments received were not significantly different for women with HIV and without HIV as shown in We also compared the survival outcomes by HIV status  and founThis manuscript discusses the descriptive epidemiologic characteristics and survival outcomes of women with and without HIV diagnosed with invasive cervical cancer enrolled in two large tertiary academic medical centers in Nigeria. We found that women with HIV were 11 years younger at diagnosis of ICC compared to women without HIV. Although there were no significant differences in baseline BMI, FIGO staging at diagnosis, histopathologic variants, tumor grading and types of treatment received, we found that overall survival was significantly better in ICC participants without HIV compared to those living with HIV. Our findings were similar with a larger Zambian cohort of ICC patients that showed women with HIV were 10 years younger at diagnosis with a poorer prognosis compared to those without HIV.The relatively low survival rates in our primary analyses likely reflect the fact that treatment options for cervical cancer are greatly limited in most LMIC settings including Nigeria, with a paucity of trained gynecologic oncology specialists and limited cancer centers with chemoradiation facilities. A recent review has corroborated the poor treatment facilities, particularly the lack of radiotherapy centers to compensate the poor surgical services for gynecological cancers in sub-Saharan African settings.These chaThe paucity of trained gynecologic oncologists and limited compliance to treatment guidelines is widespread in LMICs. This has been reported in a related study in Botswana in southern Africa that showed comparable findings of women with HIV being diagnosed with ICC at a much younger age compared to women without HIV, and the hazards of early mortality were significantly higher in women with HIV. The effeThe above findings have implications given the evidence of high incidence of cervical cancer in women living with HIV. It is imOur data showed comparable histologic types of ICC and tumor grading irrespective of HIV status. As in most literature, the most common histologic variant found in both HIV positive, and HIV negative cervical cancer tumors is squamous cell carcinoma variants. A previous study report of a retrospective cervical cancer cohort found that women living with HIV were significantly more likely to be diagnosed at advanced stages of cancer compared to HIV negative women. Our dataA previous histopathologic study of ICC showed that the commonest variant in both HIV positive and negative patients is the squamous cell type, and as in our study cohort is diagnosed at younger age in HIV-infected patients compared to HIV-negative patients. The studOur study findings are unique and are based on the strength of the enrollment protocol jointly developed by investigators from both participating sites in two distinct geographic zones in Nigeria in collaboration with Northwestern University. The histologic diagnoses and tumor grading were further subjected to peer review and quality improvement through a telepathology scanning and video conferencing platform involving the two participating sites and Northwestern pathology core. To the bCervical cancer remains a significant public health concern, diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis of this cancer at advanced stages in women living with HIV could partly explain the differences in overall survival. Strategies that strengthen access to primary prevention, early detection through screening, and early provision of effective treatment should be prioritized for all women- particularly those infected with HIV.Supplement 1"}
+{"text": "Frontotemporal dementia (FTD) encompasses a group of clinically, genetically and pathologically heterogeneous neurodegenerative disorders that mainly affect people under the age of 64 years. However, around 25% of those affected have a later age of onset. FTD represents 10\u201320% of all dementia cases [The clinical hallmarks of FTD include gradual yet progressive deficits in behaviour and/or language with the relative preservation of memory. Subtypes of FTD are identified clinically according to the symptoms that appear prominently at presentation. Clinical diagnoses include behavioral variant FTD (bVFTD), which accounts for nearly 60% of cases; primary progressive aphasia (PPA), which affects language; and the movement disorders progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) . With diC9orf72, progranulin (GRN) and MAPT, with C9orf72 repeat expansions being the most common. Neuropathologically, TAR DNA binding protein-43 (TDP-43), fused in sarcoma (FUS) and tau are three major proteins that cause pathological deposits in FTD post-mortem brains [C9orf72 expansions also have an additional pathology where di-peptide repeat proteins are also found deposited in patients. It is thought that disease pathogenesis is caused either by a gain of toxic function or a loss of nuclear function associated with protein dislocation from the nucleus, which in turn may lead to neuronal degeneration. FUS regulates the transcription of multiple genes, including the MAPT gene [A third of FTD cases are genetically linked with mutations occurring in"}
+{"text": "No objective technique exists to distinguish necrotic from viable tissue, risking over-excision in burns and loss of wound healing potential. Using delayed fluorescence imaging of indocyanine green (ICG), a method called second window ICG (SWIG), we have shown that high dose ICG persists in burn wounds in both animals and patients 24 hours after infusion. The necrotic avidity of ICG is proposed as the underlying mechanism, although inflammation also likely has a role. The objective of this study is to examine the hypothesis at both the tissue and cellular levels.To examine the localization of ICG in burn tissue, 4-mm biopsies taken from burn patients who underwent SWIG were embedded and sequentially sectioned for H&E (tissue architecture) and LDH (tissue viability) and ICG fluorescence imaging. To examine whether ICG preferentially binds to necrotic cells, primary skin cells (fibroblasts or keratinocytes) were subjected to thermal injury at 65\u00baC for 0 (untreated), 2.5 or 5 minutes. The cells were subsequently incubated with ICG at concentrations ranging from 0.5 to 5 \u03bcg/mL at 37\u00baC for 30 minutes. A necrosis and apoptosis detection kit with Yo-Pro\u2122-1 and propidium iodide (PI) was used to differentiate live, apoptotic and necrotic cell populations in flow cytometry. The ICG florescence intensity of each cell population was measured with flow cytometry.The fluorescence microscopic imaging revealed that ICG intensity was most intense in the superficial severely thermally-injured tissue and gradually decreased with depth. This zone of high ICG intensity was co-localized with high cellularity (shown in H&E) consisting of a mixture of nonviable skin cells (shown in LDH) and inflammatory infiltrates. Using flow cytometry, the optimal concentration of ICG with the highest ICG florescence median intensity (FMI) and the best separation of live, apoptotic and necrotic cell populations was 2.5 \u03bcg/mL, which was used for subsequent flow cytometry experiments. For both fibroblasts and keratinocytes, the ICG FMI was significantly higher in the necrotic cell population than that of either the live or apoptotic cell population, suggesting higher affinity of ICG to necrotic cells. The ICG FMI of necrotic cells with longer heat exposure (5 minutes) was significantly higher than that of necrotic cells with shorter heat exposure (2.5 minutes), suggesting that the binding sites for ICG increase with the degree of thermal injury.This study demonstrates the necrotic avidity of ICG in burned skin tissue and two primary skin cell types. Further studies are needed to study the ICG binding characteristics with inflammatory cell populations and single cell suspensions dissociated from human burn tissue.This, along with our pilot study of SWIG in patients, supports the feasibility of SWIG in guiding surgical decision-making in burn excision by defining thresholds of fluorescence intensity values."}
+{"text": "PLOS Biology demonstrates that combined therapy targeting enhancer of zeste homolog 2 (EZH2) and histone deacetylases (HDACs) may sensitize CRPC to both epigenetic and standard therapies.Development of resistance in castration-resistant prostate cancer (CRPC) involves epigenetic pathways. A new study in  Development of resistance in castration-resistant prostate cancer (CRPC) involves epigenetic pathways involving EZH2 and HDACs. This Primer explores a PLOS Biology study showing that combined epigenetic therapy targeting these enzymes can activate cellular stress pathways, which may sensitize CRPC to both epigenetic and standard therapies. Despite advances in diagnosis and treatment, prostate cancer remains the second-leading cause of cancer-related death in men and a significant health concern. This is attributable to its high incidence (an estimated 1 in 8 men are diagnosed with prostate cancer), late stage of diagnosis and development of treatment resistance. Prostate cancer develops in the prostate gland mainly due to dysregulated androgen signaling through the androgen receptor. Androgen receptor has a critical role in regulating the growth and differentiation of prostate cells and is frequently overexpressed or mutated in prostate cancer cells. Suppression of androgen receptor signaling by androgen deprivation therapy (ADT), which involves blocking the production or activity of androgens, has been a major treatment approach for prostate cancer. However, the effectiveness of ADT is limited, and prostate cancer cells can eventually develop resistance to this therapy by finding alternative ways to activate the androgen receptor signaling pathway, leading to development of castration-resistant prostate cancer (CRPC). CRPC consequently is an advanced stage of prostate cancer with limited treatment options. Understanding the biological mechanisms involved in maintenance of CRPC and ways to directly target the resistance mechanisms are therefore critical.Development of the CRPC state involves epigenetic reprogramming in response to persistent androgen receptor targeting, wherein the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) has a critical role. EZH2 is a histone methyltransferase that complexes with polycomb repressive complex 2 (PRC2) components to catalyze the trimethylation of histone H3 lysine 27 (H3K27me3), which is associated with gene repression . EZH2 ovIn addition to EZH2, another key epigenetic enzyme important in CRPC is the class of histone deacetylases (HDACs). HDACs are enzymes that remove acetyl groups from histone proteins in chromatin, which can lead to a tighter packing of DNA and a reduction in gene expression . HDACs aPLOS Biology, Schade and colleagues found that targeting the epigenetic functions of both EZH2 and HDACs together had a synergistic effect in killing CRPC cells, independent of androgen receptor activity [ATF3, which resulted in an acute cytotoxic effect both in vivo and in in vitro models of aggressive CRPCs. Schade and colleagues hypothesized that genes suppressed by EZH2 are incompletely derepressed upon inhibiting EZH2 alone because of sustained presence of deacetylated histones at the target gene regulatory elements  by performing expression analysis to identify up-regulated genes and pathways, ChIP-seq, and siRNA knock-down screens. reatment . ATF3 ha results  show thaFinally, combination epigenetic therapies have been a focus of research for various cancer types . While E"}
+{"text": "Streptococcus infections (iGAS) among children in the United States. Colorado and Minnesota observed an increase in the number of cases in the Fall 2022. Similarly, the Pennsylvania Department of Health issued a health alert that was then lifted in February 2023. Preliminary CDC data showed that iGAS infections were higher in some areas of the country compared to pre-pandemic levels. Lehigh Valley Reilly Children\u2019s Hospital is a community teaching hospital in Allentown, Pennsylvania. A rise in the number of children admitted with GAS infections was noted in the same period compared to previous years. The aim of our study was to determine the clinical characteristics of patients admitted with iGAS and non-iGAS infections during fall and winter 2022-2023.In December 2022 the CDC issued an alert about possible increase of invasive group A st 2022 through March 31st 2023 and diagnosed with GAS infection plus those admitted with the same diagnosis between 2018 and 2022.Retrospective chart review of patients 18 years and younger admitted to Reilly Children\u2019s Hospital between September 1There were 19 children admitted to the hospital with GAS infection: 6 (32%) with iGAS and 13 (68 %) with non-iGAS infections. The iGAS infections included bacteremia without source (2), myositis (1), pneumonia (2), and vascular infection (1). Non-iGAS infections included retropharyngeal abscess (3), peritonsillar abscess (2), parotid abscess (1), submandibular abscess (1), lymphadenitis (2), mastoiditis (1), cellulitis (1), pharyngitis (1), and erythema nodosum (1). Six children required intensive care and two were transferred to higher level care. Median age was 2.2 year for iGAS infections and 4.8 years for non-iGAS. All but one patient had no underlying medical conditions. There were no patient deaths. In 2018 there were zero cases of iGAS infection; in 2019: two cases; 2020: two cases; 2021: zero cases. There were no admissions between May 2020 and April 2022 for either iGAS or non-iGAS.The number of children admitted for iGAS and non-iGAS infections in the fall and winter of 2022-2023 surpassed the preceding 4 years combined. This is reflective of what was happening in some other areas of the country as a result of reduced exposure and lack of immunity due to pandemic restrictions.All Authors: No reported disclosures"}
+{"text": "Staphylococcus aureus (MSSA) bacteremia and/or abscess following sacroiliac (SI) joint injections for pain at an outpatient surgery center. Two recovered after treatment and one expired 9 days after the injection. CDPH-HAI and the LHD conducted an investigation.In February 2023, a local health department (LHD) notified the California Department of Public Health (CDPH) Healthcare-Associated Infections (HAI) Program of 3 patients hospitalized for methicillin-susceptible LHD and CDPH infection preventionist staff went on site to evaluate infection control (IC) practices. Whole genome sequencing (WGS) was performed on all available MSSA isolates at the CDPH Microbial Diseases Laboratory.Initial investigation revealed single-dose vials of one product had been used for multiple patients; this practice was discontinued. WGS found the 3 patient isolates were identical (0 single nucleotide polymorphism (SNP) difference). The same healthcare personnel (HCP) team had performed the procedures for all 3 infected patients. A site visit identified gaps in IC and injection safety practices. One HCP who provided care to all 3 patients had visible skin lesions on their hands, wore bracelets, and was unaware of a facility policy to report if they were unable to perform adequate hand hygiene. MSSA screening cultures were collected from 3 involved HCP and were positive in only the HCP with skin lesions. WGS showed that the HCP MSSA isolates were highly related to the patient isolates (0-2 SNP difference). We advised the facility to develop an IC program tailored to the procedures performed, including adverse event surveillance, adherence monitoring of hand hygiene and environmental services practices, and attention to injection safety. The MSSA colonized HCP was referred for treatment of their skin condition and decolonization and was restricted from patient care until their skin condition improved.Phylogenetic tree for MSSAA combination of injection safety and hand hygiene lapses led to MSSA transmission from an HCP to 3 patients. This cluster underscored the importance of IC programs in outpatient clinics and the risk of transmission of infectious agents from HCP to patients with gaps in IC practices. It also highlighted the contribution of WGS in investigating HAI outbreaks.All Authors: No reported disclosures"}
+{"text": "Frontiers in Physiology focused on emerging research on nuclear receptors and cardiovascular function in health and disease. Unlike cell membrane G-protein-coupled receptors that elicit biological responses through second messenger signaling, nuclear receptors are a large family of transcription factors that primarily bind to genomic DNA and regulate the expression of target genes, although non-genomic actions of nuclear receptors have also been identified . These studies demonstrate that 2ME2 downregulates AT1 receptor expression in the kidney cortex and liver without impacting angiotensin II binding affinity . The blood pressure-lowering effect of 2ME2 is independent of sex in Wistar rats infused with angiotensin II. In addition, prolonged 2ME2 treatment decreases heart rate and body weight in male SHRs. Collectively, this study demonstrated that 2ME2 plays a critical role in regulating the renin\u2013angiotensin system and resting heart rate through the downregulation of angiotensinogen and AT1 receptor . Sundin et al. determined that turbulent kinetic energy of blood flow in the healthy human thoracic aorta increases with dobutamine stress and is strongly related to cardiac output. Quantification by magnetic resonance imaging (MRI) was performed to determine 4D flow-based hemodynamic parameters and turbulent kinetic energy and evaluate dobutamine stress on thoracic aortas. Findings of this study demonstrate that turbulent kinetic energy with cardiac stress could serve as a risk assessment for aortic disease development . Future studies that focus on the therapeutic potential of 2ME2 to treat hypertension and MRI-based 4D turbulent kinetic measurement to assess cardiovascular disease progression are required.Two original research articles provide novel findings on the regulation of angiotensin type 1 (AT1) receptors by the estrogen metabolite, 2-methoxyestradiol (2ME2), and quantification of turbulent flow and aortic disease development. Imig focused on PPAR and FXR dual modulating drugs for the treatment of metabolic diseases, organ fibrosis, and hypertension. Evidence from clinical studies and animal hypertension models demonstrated that PPAR and FXR agonism can lower blood pressure and decrease end-organ damage in metabolic diseases and hypertension. This review article details the emerging dual modulating drugs that combine PPAR and FXR agonism with soluble epoxide hydrolase (sEH) inhibition or Takeda G-protein receptor 5 (TGR5) agonism (Imig). In preclinical studies, these novel drugs demonstrate reduced side effects in addition to anti-hypertensive, anti-fibrotic, and anti-inflammatory actions. Ertuglu et al. focused on PPAR\u03b3 regulation in salt-sensitive hypertension and insulin resistance. This review highlights the ability of PPAR\u03b3 agonists to increase insulin sensitivity and ameliorate salt sensitivity. These findings on the role for PPAR\u03b3 in pathogenesis of insulin sensitivity and salt sensitivity were coupled with newly found effects on the immune system and vascular function . These review articles provide a framework for future studies to explore nuclear receptor-based drugs in treating metabolic and cardiovascular diseases.Two review articles in this Research Topic focused on PPAR and farnesoid X receptor (FXR) therapeutics for hypertension and PPAR\u03b3 regulation in salt-sensitive hypertension and insulin resistance. Nuclear Receptors in Hemodynamics and Blood Pressure Control presents two original articles and two review articles that highlight emerging findings in the field that could lead to enhanced cardiovascular risk detection, therapeutics for hypertension including salt-sensitive hypertension, and development of dual modulating drugs for metabolic and cardiovascular diseases. Continued understanding of the contribution of nuclear receptors to controlling organ blood flow and blood pressure is needed for the development of effective therapies to combat hypertension and other cardiovascular diseases.The Research Topic"}
+{"text": "The advent of enhanced conjugate pneumococcal vaccines for adults has created a need to assess the burden of pneumococcal disease in different populations to support recommendations for vaccination. We assessed the epidemiology of invasive pneumococcal disease (IPD) in adults with underlying lung disease in Ontario, Canada.Streptococcus pneumoniae; annual audits ensure completeness. Isolates are serotyped at the National Microbiology Laboratory. Population data are from Statistics Canada, with estimates of prevalence of underlying conditions from ICES.Ontario introduced PCV7 and PCV13 for children in 2007 and 2010, and PCV13 for immunocompromised adults over 50 years in 2014. TIBDN performs population (pop\u2019n)-based surveillance for IPD in a pop\u2019n of \u223c4.5 million. Microbiology laboratories serving area residents report sterile site isolates of From 2014-2022, 2769 episodes of IPD occurred in adults; detailed clinical data are available for 2366 (85%), and serotyped isolates for 88%. Of these, 573 (24%) had no chronic underlying illness (undill); 1155 (49%) had an undill not affecting the lungs, 165 (7%) had asthma only, 409 (17%) had COPD (with/without asthma or other lung disease (OLD), 64 (2.7%) had OLD alone (most commonly ILD or bronchiectasis). Among those with asthma, 87 (53%) had another undill predisposing to IPD; compared to 290 (71%) of those with COPD and 45 (70%) of those with OLD. Persons with asthma were younger (median age 56y) than those with no or other undill (64y and 61y), and those with COPD or OLD (70 and 71y). Persons with lung disease were more likely to present with bacteremic pneumonia and less likely to have primary bacteremia or meningitis that those without or with other chrill. ICU admission and case fatality rates are in Table 1. The distribution of serotypes causing disease by conjugate vaccine types did not differ among those with lung disease and others . The incidence of disease in persons with asthma and COPD by age group is shown in Figure 2.The epidemiology of IPD differs somewhat in persons with lung disease compared to others, but conditions other than lung disease have a greater impact on incidence and outcome of IPD in adults. Enhanced PCVs likely provide cost-effective protection for 50-64 year olds with asthma/COPD.All Authors: No reported disclosures"}
+{"text": "Correction: Research Involvement and Engagement (2022) 8:8 10.1186/s40900-022-00337-xSearch strategy and study selection. The revised Appendix 3: Prisma flow chart and the Search strategy and study selection section is indicated hereafter and the changes in the given section have been highlighted in bold typeface.Following publication of the original article [1], the authors reported errors in Appendix 3: Prisma flow chart and would like to correct the number of studies under the heading The incorrect Search strategy and study selection section reads:248 papers were excluded leaving a total of 23 studies from the published literature search.After full-text screening, a further The correct Search strategy and study selection section should read:249 papers were excluded leaving a total of 23 studies from the published literature search.After full-text screening, a further Appendix 3: Prisma flow chart should read:Appendix 3: Prisma flow chartAll the changes requested are implemented in this correction and the original article [ article  has been"}
+{"text": "Schizophrenia is a chronic psychiatric illness with symptoms in positive, negative and cognitive domain.The interplay of dietary folic acid intake with common genetic variants that influence folate metabolism, has potential implications for Schizophrenia pathogenesis and treatment.Therefore, it\u2019s deficiency has been identified as a risk factor for Schizophrenia through epidemiologic, biochemical and gene association studies.1-To assess the efficacy of folic acid supplementation on severity of symptoms and overall functional status of patients2-To assess the correlation of serum folate levels with symptom severity and overall functional status of patientsexperimental Group A which received 5mg folic/day along with anti psychotic drugs and control Group B which received only anti psychotic drugs) and followed up for 3 months. Blood sample for measuring serum folate level was obtained from the experimental group at the beginning and at the end of the study period. Scales applied were Positive and Negative Syndrome Scale(PANSS) for symptom severity and Global Assessment of Functioning scale(GAF) for overall functional status.A randomized control trial study was carried out in the inpatient department of a psychiatric tertiary care centre on 40 participants who were between the ages of 18 \u2013 55 years,met diagnostic criteria for Schizophrenia (ICD 10) and had at least 2 years of illness duration while those with a co-morbid psychiatric illness, medical illness and substance abuse were excluded. The participants were then randomly allocated into two groups (table 1) and also in GAF scores between both the groups after 3 months(table 2). At the end of the study period,a strong negative correlation(r= -0.9) was found between serum folate level and total PANSS score in the experimental group (figure 1) while the correlation between GAF score and serum folate level was strongly positive (r= 0.8) (figure 2).A significant difference  was observed in PANSS scores at the end of the study between experimental group and control group( Image:Image 2:Our study is among the few to use a randomized controlled study design for assessing the effect of folic acid supplementation on severity of symptoms and global functioning in Schizophrenia,strongly suggesting the use of folic acid as an adjuvant treatment for Schizophrenia.None Declared"}
+{"text": "Serial point of care ultrasound (POCUS) exams are essential to assess acute pericardial effusions which can rapidly evolve into cardiac tamponade. A typical presentation includes dyspnea, tachycardia, and chest pain. Importantly, serial cardiac exams in such high-risk patients can detect other concurrent pathologies. We present an unusual case of a patient who initially presented with an acute circumferential pericardial effusion and upon serial POCUS exams developed an unexpected Takotsubo cardiomyopathy in the setting of cardiac tamponade.  A 63-year-old woman with a past medical history of Human Immunodeficiency Virus, asthma, and previously treated Hodgkin\u2019s lymphoma presented to the emergency department with 3 weeks of worsening shortness of breath. On initial assessment in the emergency department, the patient was hemodynamically unstable with a heart rate of 140 beats per minute (bpm) and a blood pressure of 88/68 mm Hg. Bedside point of care ultrasound (POCUS) was performed and demonstrated a moderate circumferential pericardial effusion with normal left ventricular function and a collapsible inferior vena-cava (IVC). Intravenous fluids were initiated with resolution of the patient\u2019s hemodynamic instability (Video S1). A computer tomography (CT) of the chest was also obtained in the emergency department which showed extensive mediastinal lymphadenopathy with right middle lobe consolidation. The patient was admitted for evaluation of the pericardial effusion and CT findings. Forty-eight hours after admission, the patient reported persistent midsternal chest pain and shortness of breath with a blood pressure of 110/60 mm Hg, heart rate of 127 bpm, and an oxygen saturation of 100% on 2-liters nasal cannula. Repeat troponin I was elevated at 1.02ng/ml (ref - <0.03 ng/ml). POCUS was performed which revealed mid-to apical left ventricular (LV) akinesis and an interval reduction of LV function along with right atrial systolic collapse, right ventricular diastolic collapse and a plethoric IVC (Video S2). Limited transthoracic echocardiogram done by the echocardiography lab shortly after confirmed the findings. These findings were concerning for Takotsubo/stress induced cardiomyopathy in the setting of tamponade physiology. The patient underwent a pericardiocentesis with removal of 240 mL of fluid with improvement of tachycardia and dyspnea. Formal echocardiography 48 hours after the procedure showed minimal residual effusion with improvement of LV function, which returned to normal within a week (Video S3). Cytology of the pericardial fluid showed inflammatory and mesothelial cells with no evidence of malignant cells. However, subsequent lymph node biopsy revealed recurrence of Hodgkin lymphoma to which her pericardial effusion was attributed. Cardiac tamponade is a pericardial syndrome characterized by impairment of diastolic filling of the ventricles causing reduction of cardiac output. The classically advanced signs of tamponade described as hypotension, distension of jugular veins, and diminished heart sounds (Becks Triad) are present in a minority of patients. The most common initial presenting symptoms are dyspnea and tachycardia, which may be present in the absence of hypotension Echocardiographic evaluation of tamponade includes: i) Quantity and quality of pericardial fluid ii) Systolic right atrial collapse iii) Diastolic right ventricular size and variability with the respiratory cycle iv) Interventricular septal shift of the left ventricle during inspiration v) Collapsibility of IVC Diastolic right ventricular collapse is specific for tamponade while IVC plethora is highly sensitive. Systolic right atrial collapse is often the earliest sign of tamponade. Comprehensive or advanced critical care echocardiography can be used to detect exaggerated respiratory cycle changes in mitral and tricuspid valve in-flow velocities as a surrogate for pulsus paradoxus In this patient the initial POCUS exam revealed a moderate sized pericardial effusion with a fully collapsible IVC making tamponade physiology less likely. When the patient developed new onset chest pain and shortness of breath this raised the concern for worsening tamponade. A repeat ultrasound revealed an unexpected finding of stress induced cardiomyopathy which can potentially be attributable to progressive tamponade development. Potentially the tamponade was further exacerbated by left ventricular dysfunction.In dog models right atrial and ventricular collapse occurred with significantly smaller volumes of pericardial fluid in the setting of induced left ventricular dysfunction Takotsubo-associated myocardial dysfunction is irrespective of vascular territories, and commonly presents as transient mid to apical akinesia, hypokinesia, or dyskinesia in the absence of obstructive coronary disease. Other findings include circumferential apical dilatation , basal hyperkinesia and a severely reduced left ventricular function This case highlights the importance of serial cardiac POCUS examinations in the evaluation of pericardial effusion. Additionally, it highlights the importance of recognizing an acute concurrent cardiac pathology that can quickly lead to a vicious cycle of cardiac dysfunction leading to decompensation. The authors confirm that consent to publish this case was obtained from the patient.All authors of this manuscript have no conflicts of interest. The authors listed have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript. Video S1 Video S2 Video S3"}
+{"text": "Since the development of optical coherence tomography (OCT), technological improvements have made this diagnostic imaging tool adaptable to clinical settings . OCT proA 2018 Cochrane review, \u201cOptical Coherence Tomography for Diagnosing Skin Cancer in Adults,\u201d provides an in-depth review of the accuracy of OCT for detecting skin abnormalities. Data from five test accuracy studies were obtained, permitting comparison of the index test to a reference standard. The diagnostic accuracy of OCT was assessed for melanoma (n=2) and keratinocyte carcinomas (n=3). There were insufficient data to determine the diagnostic accuracy of OCT for melanoma or cutaneous squamous cell carcinoma. In a sample of 346 lesions (n=2 studies), the sensitivity and specificity of OCT for detecting basal cell carcinoma (BCC) was potentially superior versus visual assessment and dermoscopic exam\u2014however, given a limited sample size and the high prior probability of BCC, results must be interpreted cautiously. Applied to a hypothetical population (n=1000 people), OCT had better outcomes than visual and dermoscopic exams, correctly identifying 53 more BCC lesions while reducing the incidence of false positives and unnecessary excisions by 87 [The high sensitivity and specificity of OCT for BCC diagnosis are noted in subsequent reviews and expert consensus ,4. An inThe insufficient number of studies available for inclusion, study heterogeneity, and restricted study populations limit the conclusions that may be drawn regarding the diagnostic utility of OCT . Include"}
+{"text": "In recent years, there has been an increase in the number of candidates for bariatric surgery and a decrease in psychiatric contraindications.We aim to make an descriptive evaluation of unfavorable feedback concerning mental health of the candidates for bariatric surgery of the Local Health Unit of Matosinhos .Descriptive analysis of unfavorable feedback of mental health of candidates for surgical treatment of obesity.From March 2017 to August 2022, the Mental Health Service of the Local Health Unit of Matosinhos issued 347 pre-surgical feedback. In 63 cases the initial opinion issued was unfavorable: 11 cases due to a psychiatric contraindication (not meeting conditions for intervention) and 52 cases had a conditional opinion . Regarding contraindications, these were due to alcohol use disorder (n=3), binge eating (n=3), intellectual development disorder (n=2), purgative behavior (n=1), psychotic disorder (n=1) and mood disturbance (n=1). In terms of conditional opinions, the issues mencioned were lack of motivation for surgery (n=22), psychopathology (n=20), doubts about informed consent (n=8) and need for multidisciplinary discussion/coordination (n= 7).There was an increase in eligibility of candidates for surgical treatment as most of the initial unfavorable opinions were conditional. This could be explained by the decline of complications associated with bariatric surgery, but also because psychiatric disorders are now being viewed as treatable. Notably people with eating disorders are now fit for surgery after a medical or psychotherapeutic intervention.None Declared"}
+{"text": "The pathogenesis of Psoriatic Arthritis (PsA) remains poorly understood. The underlying chronic inflammatory immune response is thought to be triggered by unknown environmental factors potentially arising from a defective immune function.To determine whether an impaired acute inflammatory response by Dendritic Cells (DCs) might compromise the clearance of bacteria and predispose to chronic inflammation in PsA.Mycobacterium tuberculosis, Mycobacterium avium paratuberculosis and a range of other bacteria and TLR ligands was determined. Phenotypical differences involved in cellular responses against (myco)bacteria were determined by qPCR and flow cytometry.The cytokine production by DCs from 13 healthy controls, 11 Rheumatoid Arthritis, 13 PsA and 8 psoriasis patients from The Netherlands and from 6 Scottish healthy controls and 6 PsA patients towards The secretion of the proinflammatory cytokines TNF\u03b1 and IL-6 by PsA DCs was impaired upon in vitro challenge with mycobacteria and TLR2 ligands compared to DCs from healthy controls and RA patients. DCs from psoriasis patients did not demonstrate such a dampened reaction towards mycobacteria. This impairment demonstrated by PsA DCs was associated with elevated serum CRP levels. The expression of TLR2 and other receptors known to mediate mycobacterial recognition was unaltered. The intracellular TLR(2) inhibitors SOCS3 and A20 were more highly expressed in DCs from PsA patients. PsA DCs further demonstrated up regulated levels of the autophagy-related genes ATG16L1, NOX2 and LL37; molecules implicated in the immune response against intracellular bacteria.Our findings indicate that DCs from PsA patients have a disordered immune response towards some species of (myco)bacteria. This might predicate to impaired immune responses to, and in turn impaired clearance of, these bacteria, setting the stage for the chronic inflammation of joints, entheses, skin and the gut found in PsA."}
+{"text": "Mycobacterium avium complex (MAC) clinical isolates with varying catalase activity recovered from the blood of HIV patients in terms of invasiveness and intracellular multiplicity in host cells. The catalase activity in MAC isolates was also analysed in context to CD4 counts and clinical presentation of mycobacterial disease in HIV patients.The mycobacterial catalase-peroxidases protect it from the reactive oxidative metabolites and allow its survival within the host phagocytes. We compared the virulence of Catalase activity of KatG protein of 51 mycobacterial isolates from HIV patients was determined. MAC isolate with maximum catalase activity (KatG-max) was compared to isolate having minimum activity (KatG-min) for adherence, intracellular replication and katG mRNA expression by ZN staining, colony forming units (CFU) enumeration and RT-PCR respectively in A549 and HT29 cell lines.rd day of infection (doi) [p<0.001], whereas, it was comparable at 1st doi. CFU enumeration results correlated well with the levels of katGm RNA expression.Catalase activity of mycobacterial isolates was found to be inversely related to CD4 counts and unrelated to the clinical presentation of mycobacterial disease in HIV patients. The intracellular replication of KatG-max isolate was found to be 2 fold higher than KatG-min at 3The MAC isolates having maximum catalase activity and increased katGm RNA expression was favoured for its survival and replication in the host cells. High levels of catalase activity in isolates from HIV patients with low CD4 counts suggest an important role of KatG in the establishment and progression of disseminated MAC disease."}
+{"text": "Conservation planning and the design of marine protected areas (MPAs) requires spatially explicit information on the distribution of ecological features. Most species of marine mammals range over large areas and across multiple planning regions. The spatial distributions of marine mammals are difficult to predict using habitat modelling at ecological scales because of insufficient understanding of their habitat needs, however, relevant information may be available from surveys conducted to inform mandatory stock assessments.Dugong dugong) abundance to create spatially-explicit models of dugong distribution and relative density at the scale of the coastal waters of northeast Australia . We interpolated the corrected data at the scale of 2 km * 2 km planning units using geostatistics. Planning units were classified as low, medium, high and very high dugong density on the basis of the relative density of dugongs estimated from the models and a frequency analysis. Torres Strait was identified as the most significant dugong habitat in northeast Australia and the most globally significant habitat known for any member of the Order Sirenia. The models are used by local, State and Federal agencies to inform management decisions related to the Indigenous harvest of dugongs, gill-net fisheries and Australia's National Representative System of Marine Protected Areas.We use a 20-year time series of systematic aerial surveys of dugong (In this paper we demonstrate that spatially-explicit population models add value to data collected for stock assessments, provide a robust alternative to predictive habitat distribution models, and inform species conservation at multiple scales. Ecological scales can vary from 10 s of km2 for isolated, sedentary species with small geographic ranges , to 100,000 s of km2 for migratory species . The scales of planning regions and ecological features are rarely congruent The data that inform conservation planning and the design of marine protected areas (MPAs) are primarily spatially explicit 2Marine mammals are some of the most highly dispersed species with geographic ranges up to 300,000,000 kmDugong dugon) occur in the shallow, protected coastal waters of some 40 countries and territories in the tropical and subtropical Indo-West Pacific. As the only herbivorous mammal that is strictly marine, dugongs are often used as a flagship species because of their high biodiversity and cultural values. Although dugongs are seagrass community specialists, their habitat needs are not yet sufficiently understood to predict their distribution at broad spatial scales using habitat modelling Dugongs (2) would require information on the distribution of: (1) seagrass habitat community composition; and (2) the various factors that influence the choice of seagrass species or habitats by dugongs. This information is currently unavailable for most of the habitats exploited by dugongs in northern Australia.Dugongs are of high cultural and nutritional value to Indigenous Australians and northern Australia is internationally recognised as supporting the most globally significant remaining dugong populations 2; almost half of their range in northern Australian waters from Moreton Bay in Queensland, the southern extremity of the dugong's range on the east coast (27\u00b050\u203221\u2033S), through the Gulf of Carpentaria (12\u00b013\u20328\u2033S) (2). These models have informed dugong conservation initiatives within the Great Barrier Reef World Heritage Area because they effectively delineate the spatial distribution of dugongs at the required scale Systematic aerial surveys have been used to monitor the abundance and distribution of dugong populations in northeast Australia  since th\u00b013\u20328\u2033S) . The sur\u00b013\u20328\u2033S)  to develThis paper updates and extends the spatially-explicit model of dugong distribution and relative density in the Great Barrier Reef region Marsh's group undertook systematic aerial surveys of northeast Australia in seven survey regions  approximUsing the technique of Grech and Marsh (2007) Most aerial surveys were conducted in late spring or early summer when weather and sea states provide optimum survey conditions . In highsensu Marsh and Sinclair (1989) 2) making them inappropriate to use in the spatially-explicit models which we developed at the scale of 2 km * 2 km planning units. Thus the models were based on relative rather than absolute population estimates, nonetheless, relative densities among regions should be approximately comparable All the aerial surveys estimated absolute dugong abundance by correcting sightings for perception bias  and availability bias  We corrected the spatial data from the aerial surveys for differences in sampling intensity and area sampled between surveys using equations described in Grech and Marsh (2007) As independent data on dugong abundance at the scale of northeast Australia do not exist, we used a re-substitution approach to validate the individual spatially-explicit population models International Union for Conservation of Nature and Natural Resources Red ListWe estimated dugong distribution and relative density at a planning unit of 2 km * 2 km because this scale: (1) corresponds with the scale of the aerial survey data allowing the model to account for: (a) slight changes in altitude of the aircraft (which affects transect width at the surface); and, (b) the blind area under the aircraft; and, (2) is recommended under Criterion B of the 2; medium density 0.0015<0.25 dugongs/km2; high density areas 0.25\u22640.5 dugongs/km2; and very high density areas >0.5 dugongs/km2. We included planning units with 0 dugongs/km2 to ensure that the spatial layers extended across the entire survey region , Hervey Bay (0.43 dugongs/km2), Moreton Bay (0.19 dugongs/km2) and the northern Great Barrier Reef region (0.16 dugongs/km2). The planning units with the highest relative densities were in Moreton Bay (9.0 dugongs/km2), Torres Strait (6.49 dugongs/km2), the northern Great Barrier Reef region (6.03 dugongs/km2) and Hervey Bay (4.56 dugongs/km2). The southern Great Barrier Reef region and coastal waters of the Gulf of Carpentaria had the lowest mean (<0.07 dugongs/km2) and maximum density estimates (<1.92 dugongs/km2).The average relative dugong density in the ongs/km2 . Density2; Planning units of very high and high relative dugong density in Moreton Bay and Hervey Bay were adjacent to the mainland coast and islands . In the 2; high: 12,432 km2, medium: 63,024 km2 and low: 61,800 km2  because: (1) specialised areas of high conservation value such as calving or mating areas and migratory corridors have not been identified; and (2) density estimates are regarded as robust surrogates of habitat utilization The spatially-explicit models suggest that the broad-scale patterns of dugong distribution in coastal regions of northeast Australia are determined by the physical characteristics of their seagrass habitats: exposure to wind and wave activity, tidal ranges and seabed current stress The broad-scale patterns of dugong distribution predicted by our model can assist in the identification of important dugong habitats in data-poor areas of the Indo-Pacific. It is likely that dugongs exhibit habitat preferences similar to those in northeast Australia throughout their range , coastal waters, bays and estuaries with low wave exposure Australia aims to realise its international commitments as a signatory to the Convention on Biological Diversity through the significant expansion of its existing Marine Protected Area network throughout Australia's Exclusive Economic Zone by 2012. The central component of Australia's Oceans Policy  is the development of Marine Bioregional Plans and a National Representative System of Marine Protected Areas in Commonwealth  waters. Australia's Commonwealth , State and Northern Territory governments are working together to implement this initiative. The models of dugong distribution and relative density currently inform Australia's Oceans Policy and species conservation initiatives of local and State (Queensland and Northern Territory) governments across multiple scales. In the following section, we provide specific examples of the application of the models at local, regional and national scales to demonstrate the merits of using survey data collected for stock assessment in species conservation and the design of MPAs.2). Primarily, the models assist with the development of management decisions related to the harvest of dugongs  at the scale of Torres Strait .One of the major outcomes of our modelling exercise was the improved understanding of the relative importance of the seven survey regions to dugong conservation in northeast Australia. Torres Strait has the greatest number of very high dugong density planning units when compared to the other survey regions of northeast Australia ; Table 3Hervey Bay also has a large proportion of very high and high dugong density planning units relative to its size ; Table 3Dugongs are listed as vulnerable to extinction under schedule 3 of the Queensland Nature Conservation (Wildlife) Regulation of 1994 and were one of several explicit reasons for the World Heritage listing of the Great Barrier Reef region The Australian Government is using the models of dugong distribution and relative abundance at the scale of northeast Australia  to assisMany government agencies have developed comprehensive and dedicated monitoring programmes to estimate the size and trends of marine mammal populations for stock assessment . For example, the US Marine Mammal Protection Act of 1972 and subsequent amendments mandates the use of the Potential Biological Removal technique to estimate the maximum number of animals that may be removed from a stock Figure S1Spatially-explicit population models of dugong distribution and relative density in Moreton Bay and Hervey Bay.(TIF)Click here for additional data file.Figure S2Spatially-explicit population models of dugong distribution and relative density in the southern Great Barrier Reef.(TIF)Click here for additional data file.Figure S3Spatially-explicit population models of dugong distribution and relative density in the northern Great Barrier Reef and Torres Strait.(TIF)Click here for additional data file.Figure S4Spatially-explicit population models of dugong distribution and relative density in the Gulf of Carpentaria.(TIF)Click here for additional data file."}
+{"text": "This study aims to quantify the acute exercise response to early passive and active activities in order to inform exercise prescription when designing rehabilitation programmes for the critically ill. Critical care survival is often associated with a poor functional outcome , with reThis study is a prospective randomised controlled trial with a repeated-measures crossover design. Eligible participants, requiring mechanical ventilation for 4 or more days, completed two exercise activities routinely used in early critical care rehabilitation, a passive chair transfer (PCT) and active sitting on the edge of the bed (SOEOB). The oxygen consumption and cardiovascular parameters were measured to quantify and compare the exercise response between the two activities.Data are presented as the median (interquartile range). Data for five patients have been collected, aged 68 years (23), with an ITU stay of 15 days (10.5) and duration of mechanical ventilation 8 days (12), at the point of intervention. Exercise response results are reported (Table Intensive care patients with prolonged mechanical ventilation demonstrate a higher rate of oxygen consumption when actively sitting on the edge of the bed, compared with a passive chair transfer. This may have important consequences for early mobilisation of the critically ill."}
+{"text": "Ossification of the Posterior Longitudinal Ligament (OPLL) is a condition caused by new bone developing in the posterior longitudinal ligament within the spinal canal. OPLL is a common cause of myelopathy in East Asian countries. Here, we report a case with OPLL in thoracic and lumbar spine in Kermanshah, West of Iran. A 40 years old man gradually developed lower extremities paresis with defecation or voiding difficulties. Radiographic evaluation by computed tomography (CT) and magnetic resonance imaging (MRI) confirmed the mass of ossification at the posterior aspect of the T2-T4 and T12-L1 of vertebral body with spinal cord compression. Although OPLL is a common cause of myelopathy in the East Asian countries, it should be included in differential diagnosis of myelopathy in other regions.Ossification of the posterior longitudinal ligament (OPLL), Spinal canal, Myelopathy"}
+{"text": "Sox genes encode for a group of transcription factors that share the presence of an HMG-type (high mobility group) box. This is a 79 amino acid motif that encodes their DNA binding domain. They were identified soon after the discovery of the mammalian testis-determining gene Sry, which also possesses an HMG box, and obtained their name from Sry (\u201cSox\u201d Sry-related box genes). The members of the Sox family are highly conserved among vertebrates and so far 26 different genes have been identified  and SoxB2 (Sox14 and 21) subgroups, code for a group of highly related transcription factors expressed mainly in the developing and adult Central Nervous System (CNS) in mammals , either self-renew or exit the cell cycle and differentiate. NEPs make cell fate decisions controlled by extrinsic and/or intrinsic determinants . Neuronal fates are determined around the final cell cycle of NEPs during which neural differentiation factors regulate the cell cycle either directly or indirectly. Only recently, SoxB genes have been implicated in the regulation of cell cycle. Studies in the mouse developing cortex showed that Sox1 acts to maintain the undifferentiated state of NEPs via a mechanism involving suppression of Prox1\u2013mediated cell cycle exit and neurogenesis (Elkouris et al., The transcription factors Sox1-3 have been proposed to block neuronal commitment and thus prevent differentiation (Bylund et al., Sox2 null embryos die soon after implantation, masking a potential role for Sox2 in the CNS (Avilion et al., + cortical radial identity and plasticity (Remboutsika et al., Sox2 has found itself in the position of the most celebrated of the Sox proteins due to its role in epiblast formation (Avilion et al., This review is dedicated to the memory of Prof. Larysa Pevny."}
+{"text": "Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients\u2019 age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population. Although Down syndrome (DS) was initially described in 1866 Several investigators, including ourselves have reported that adults (and children) with DS have lower bone mass, expressed as BMD, especially in the lumbar spine, compared with their peers without mental retardation or with mental retardation but without DS The Ts65Dn mouse is one of several mouse models of DS that has been developed to investigate the pathology of DS phenotypes 16)65Dn (Ts65Dn) mouse model of DS at both 3 and 24 months of age To investigate bone health in DS, we determined the skeletal phenotype of the Ts at both 3 months and 24 months of age . There w2)); bone area fraction ; cortical thickness (mm); anteroposterior and mediolateral diameters (mm). Sub-region analysis of the mid-shaft of the femur revealed that trisomy significantly decreased cortical thickness in both 3-month old  were used.Mice were treated with daily i.p. injections of 30 or 80 ug/kg PTH(1\u201334), or vehicle control, for 28 days. PTH increased whole-body BMD in both 3 month old WT and Ts65Dn mice as determined by DXA . In WT mIntermittent PTH treatment caused an approximately equivalent increase in BV/TV in both WT and Ts65Dn mice . PTH incThe observed increase in trabecular bone mass and volume was mediated by a PTH-stimulated increase in mineral apposition rate and bone formation . Osteoblex vivo bone marrow cultures, the differentiation capacity of osteoblasts and osteoclasts were impaired in Ts65Dn mice, demonstrating the cell intrinsic nature of the bone phenotype, and confirming both mesenchymal and hematopoetic lineages as targets of trisomy 21. Interestingly, and as reported by others The present study demonstrated that Ts65Dn DS mice have lower trabecular bone volume and trabecular number and higher trabecular separation in the proximal tibia and distal femur as well as decreased cortical thickness and strength compared with WT littermates. The low bone mass phenotype is consistent with the human DS population that also displays a low BMD due to decreased bone turnover Ts65Dn mice at 3-months and 24-months of age have significant decreases in trabecular and cortical bone. The BV/TV and trabecular number are significantly decreased at both ages. With the decreased number of trabeculae, there was a subsequent significant increase in trabecular spacing. Interestingly, trabecular thickness was not significantly affected, suggesting that the fundamental mechanism controlling the development of trabeculae is intact in trisomic Ts65Dn mice, but the rate at which they are generated is decreased. These results extend those of Blazek Other DS mouse models have been developed and their bone phenotype investigated The low bone mass phenotype of Ts65Dn male mice like people with DS is profound and is the result of decreased bone turnover. The decreased bone turnover is unexpected, given the hypogonadism and infertility associated with the disorder in humans ex vivo bone marrow cultures and in the histomorphometric analysis of tibias from 3-month old Ts65Dn mice. In ex vivo cultures, both osteoblast and osteoclast differentiation was significantly decreased in Ts65Dn compared with control. In vivo, osteoblast number per bone surface, osteoclast number per bone surface and bone formation rate were all significantly decreased. These observations suggest an intrinsic defect in both the mesenchymal and the hematopoetic cell lineages. While the defect in megakaryocyotopoiesis in DS has been well studied in humans and is recapitulated in the Ts65Dn mouse The defect in both osteoblast and osteoclast differentiation in Ts65Dn mice was observed in both th decade of life and are presenting in increasing numbers with low bone mass and fracture Histological evaluation of the bone marrow confirmed the megakaryocyte hyperplasia as has been reported in Ts65Dn mice and in DS patients Collectively, these observations provide evidence that the low bone mass observed in humans with DS and Ts65Dn mice is due to a cellular defect in both the hematopoietic and mesenchymal lineages, such that aneuploidy\u2019s effects on the available pool of precursor cells decreases their capacity for normal differentiation and function. Thus, fewer cells differentiating into functional osteoblasts and osteoclasts results in the accrual of lower bone mass, which is a mechanism fundamentally distinct from the high bone turnover observed in hypogonadal women and men, where increased numbers and activity of cells leads to low bone mass.In support of this idea, the Ts65Dn mice demonstrate a lifelong deficit in bone turnover, such that normal peak adult bone mass is never achieved. It is important to note that the serum bone turnover markers of control animals revealed the expected age-dependent increases in both formation and resorption markers, whereas markers in Ts65Dn mice do not increase with age and are consistently lower compared with control throughout the life of the mice. If this temporal difference in bone turnover is recapitulated in humans with DS, it would indicate that low bone turnover is sustained in DS resulting in lower bone accrual and is an area that we are actively investigating. Perhaps most importantly, our studies provide the first data to demonstrate the efficacy of a bone anabolic agent in the treatment of low bone mass in DS and call into question the routine use of bisphosphonates (which decrease bone turnover) in this patient population.Intermittent PTH therapy increases bone formation by stimulating osteoblast numbers at sites of bone remodeling, where old bone is replaced with new by the concerted efforts of both osteoclasts and osteoblasts Thus, these data provide a clearer understanding of the cellular mechanisms leading to the low bone mass in DS, suggest a new direction for treatment and provide a relevant animal model for continued studies of the skeleton in DS. Given the elevated fracture risk and rate in DS patients our data provide the rationale to consider bone anabolic therapies in DS patients with low bone mass.ad libitum and a 12-hr light:dark cycle. Only male mice were evaluated due to the decreased fertility of Ts65Dn male mice and the necessity of Ts65Dn female mice for colony maintenance. Animals were purchased at 6 weeks and aged as required. Some mice were aged and maintained at UAMS for up to 24 months.All animal handling and experimentation was performed in accordance with approved University of Arkansas for Medical Sciences (UAMS) institutional guidelines and protocols and approved by the UAMS Institutional Animal Care and Use Committee (IACUC). Ts65Dn male mice and wild type euploid littermate controls were purchased from the Jackson Laboratory . Upon arrival they were housed individually with food and water available For bone phenotyping, animals were sacrificed at 3 months and 24 months and long bones and spines harvested. Some three month old animals were injected with calcein  (administered 8 days prior to sacrifice) and alizarin red S (Sigma) or alizarin red complexone (Sigma) (administered 2 days prior to sacrifice), for subsequent determination of dynamic parameters of bone histomorphometry with an inter-label distance of 6 days as described In Ts65Dn and WT mice, serum was extracted from blood drawn at sacrifice and serum procollagen-1 N-terminal peptide (P1NP) and tartrate resistant acid phosphatase (TRAP) measured. P1NP was measured using a commercially available enzyme immunoassay (EIA) (Immunodiagnostic Systems) and TRAP using a TRAP-5b solid phase immunofixed enzyme activity assay (Immunodiagnostic Systems) according to the manufacturer\u2019s protocol.All MicroCT analyses were consistent with current guidelines for the assessment of bone microstructure in rodents using micro-computed tomography The MicroCT slices were segmented into bone and marrow regions by applying a visually chosen, fixed threshold for all samples after smoothing the image with a three-dimensional Gaussian low-pass filter  to remove noise, and a fixed threshold . Femoral cortical geometry was assessed in a 1-mm-long region centered at the femoral midshaft. The outer contour of the bone was found automatically using the built-in manufacturer\u2019s contouring tool. Total area was calculated by counting all voxels within the contour, bone area by counting all voxels that were segmented as bone, and marrow area was calculated as total area - bone area. This calculation was performed on all 25 slices (1 slice\u200a=\u200a\u223c12.5 \u00b5m), using the average for the final calculation. The outer and inner perimeter of the cortical midshaft was determined by a three-dimensional triangulation of the bone surface (BS) of the 25 slices, and cortical thickness and other cortical parameters were determined as described After MicroCT analysis, the same tibia and femora, fixed in 10% neutral-buffered formalin, were decalcified in 5% formic acid with agitation until deemed clear by the ammonium oxalate endpoint test Specimens for plastic embedding and cancellous bone histomorphometry were harvested at sacrifice and the muscle dissected away before fixation in Mallonig\u2019s fixative as we have described previously Mechanical testing was performed to determine bone strength of frozen Ts65Dn intact femora (3 month and 24 month), using standard three-point bending as we have described 6 cells per well in \u03b1-minimal essential medium (\u03b1-MEM), supplemented with 15% fetal calf serum, and 10\u22128 M 1,25-dihydroxyvitamin D3 2D3 in quadruplicate wells per treatment. Cells were fed every 3 days with half-volumes of medium, until day 14, when cells were fixed and stained with tartrate resistant acid phosphatase (TRAP) to facilitate determination of the number of TRAP-positive multinucleated (3 or more nuclei) cells formed per well.Bone marrow cells were harvested from femurs for osteoclastogenic culture as previously described 5 cells/cm2 on six-well tissue culture plates (Becton Dickinson Labware) osteoblast medium (\u03b1-MEM +15%FBS containing 10 mM BGP and 50 \u00b5M ascorbic acid). The total number of mesenchymal progenitors recruited into the osteoblastic lineage was measured by alkaline phosphatase-positive staining for colony forming unit-fibroblast (CFU-F) at day 10. Replicate cultures were fed every 3 days with half-volumes of medium, until day 28, when cells were fixed and minerals stained with Alizarin Red to facilitate determination of the number of bone nodules representing CFU-osteoblastic (CFU-OB) formed per well For osteoblastogenesis, bone marrow cells were harvested from femurs and seeded in triplicate at 2.5\u00d710All data were analyzed by either Student\u2019s t-test or one way ANOVA with post-hoc analyses by Bonferroni post-hoc test as appropriate. Parametric data are presented at mean \u00b1 SEM. Differences with P values <0.05 were considered statistically significant and are reported as such. The SigmaStat (SPSS Science) software package was used for all statistical analysis.Figure S1Age-related bone phenotype in Ts65Dn mice. (A) Micro CT reconstructions of proximal tibia and femur from 3-month (left column) and 24-month (right column) old WT (top) and Ts65Dn (bottom) mice. Low bone volume and cortical thinning is evident. (B). Paraffin-embedded decalcified histological sections of proximal tibia from 3-month (left column) and 24-month (right column) old WT (top) and Ts65Dn (bottom) mice stained with H&E. The expected age-related decrease in trabecular bone is observed in both WT (top) and Ts65Dn (bottom), however, the expected increase in marrow fat is observed in WT (top) but not Ts65Dn (bottom). In contrast, Ts65Dn mice reveal the reported elevation in marrow megakaryocyte number (TIF)Click here for additional data file.Figure S2Decreased cortical bone parameters of 24-month old Ts65Dn mice. Determination of femoral midshaft cortical parameters from Micro CT reconstructions of mid shaft femur shows significant decreases compared to WT in (A) cortical cross sectional area, (B) total cross sectional area, (C) periosteal perimeter, (D) Peak load (load tolerated at the breaking point adjusted for bone size), (E) Stiffness (deformation tolerated before breaking). Open bars WT; solid bars Ts65Dn. *, p<0.05 vs. WT control.(TIF)Click here for additional data file."}
+{"text": "The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders. It was discovered based on its sequence similarity to other proteins belonging to this receptor family  animals administered a PTH2R antagonist as discussed below.in situ hybridization histochemistry  and dopamine neurons in the arcuate nucleus , hotplate tests were performed before and after an inescapable foot shock, used as the stressful stimulus  or saline) while no differences were observed between groups in the number of closed arm entries or total arm entries, suggesting an anxiolytic-like effect of TIP39  neurons, whose activity is suppressed during lactation. In addition, the TIP39-PTH2R neuromodulator system might also play a role in conveying the effect of suckling on other systems adapted in the postpartum period. PTH2Rs in the preoptic area, the lateral septum, and the periaqueductal gray could be involved in the control of maternal behaviors Dobolyi, . EmotionThere is limited information available showing that TIP39 neurons are activated in stress situations. At present, only the effects of an h-long high intensity noise stress have been reported. Medial paralemniscal and posterior intralaminar TIP39 neurons demonstrate Fos induction together with CRH neurons in response to noise stress, suggesting that TIP39 neurons could be involved in the transmission of acoustic stress derived information to CRH neurons in the PVN (Palkovits et al., c-fos in some PVG neurons (Kiyohara et al., c-fos expression in the PVG significantly outlasts the cold exposure (Miyata et al., Cold exposure but not warm ambient temperature induced The PVG is a site of stimulation-induced analgesia (Rhodes and Liebeskind, via the facilitation of copulatory behavior by current injection into the area (Shimura and Shimokochi, Fos expression following ejaculation (Wang et al., The TIP39-PTH2R neuromodulator system is present in several brain areas that are activated in males following mating (Sachs and Meisel, c-fos expression in the PIL but not in the PVG in response to reunion with their litter (Cservenak et al., Another reproductive influence reaching TIP39 neurons in the PIL was reported in mother rats. Dams deprived of their pups for a day demonstrated 2+ levels (Goold et al., via presynaptic excitation of their afferents (Dimitrov et al., in situ hybridization histochemistry (Figure via potentiation of excitatory inputs to inhibitory interneurons acting on the AVP and dopaminergic neurons, respectively.There are no indications at present that TIP39 would have any action apart from activating the PTH2R. The PTH2R elevates cAMP and in some cells also increases Cay Figure . In othey Figure . Thus, tThe TIP39-PTH2R neuromodulator system may play an important role in the regulation of several different aspects of neuroendocrine functions. TIP39 neurons in the PVG may be stimulated by stress inputs compromising the homeostasis of the animal while TIP39 neurons in the PIL may be stimulated by various reproductive events Figure . AdditioThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Drosophila are remarkably conserved. As IIS pathway governs growth and development, metabolism, reproduction, stress response, and longevity; temporal, spatial, and nutrient regulation of dilps encoding Drosophila insulin-like peptides (DILPs) provides potential mechanisms in modulating IIS. Of eight DILPs (DILP1\u20138) identified, recent studies have furthered our understanding of physiological roles of DILP2, DILP3, DILP5, and DILP6 in metabolism, aging, and responses to dietary restriction (DR), which will be the focus of this review. While the DILP producing IPCs of the brain secrete DILP2, 3, and 5, fat body produces DILP6. Identification of factors that influence dilp expression and DILP secretion has provided insight into the intricate regulatory mechanisms underlying transcriptional regulation of those genes and the activity of each peptide. Studies involving loss-of-function dilp mutations have defined the roles of DILP2 and DILP6 in carbohydrate and lipid metabolism, respectively. While DILP3 has been implicated to modulate lipid metabolism, a metabolic role for DILP5 is yet to be determined. Loss of dilp2 or adult fat body specific expression of dilp6 has been shown to extend lifespan, establishing their roles in longevity regulation. The exact role of DILP3 in aging awaits further clarification. While DILP5 has been shown associated with DR-mediated lifespan extension, contradictory evidence that precludes a direct involvement of DILP5 in DR exists. This review highlights recent findings on the importance of conserved DILPs in metabolic homeostasis, DR, and aging, providing strong evidence for the use of DILPs in modeling metabolic disorders such as diabetes and hyperinsulinemia in the fly that could further our understanding of the underlying processes and identify therapeutic strategies to treat them.The neuroendocrine architecture and insulin/insulin-like signaling (IIS) events in  Drosophila, eight insulin-like peptides (DILPs) and one insulin receptor (DInR) are found. DILPs 1\u20138 have been identified mostly through their sequence homology to the mammalian insulin and the typical B-C-A domain structure as observed in mammalian insulin  in the brain has provided a physiological link between those two major tissues governing nutrient sensing, metabolism, and aging  pathway governs growth and development, metabolism, reproduction, stress response, and longevity. In Drosophila insulin-like peptide genes (dilp1\u20137) with diverse temporal and spatial specific expression patterns  and several neurons in the brain  constructs in their fat body similar to the levels observed in dSir2 RNAi flies , short neuropeptide F (sNPF) modulates metabolism and lifespan revealed an up-regulation of dilp1 and dilp2 mRNA as the result of sNPF overexpression accompanied by increased IIS in the periphery , a member of Drosophila E3 ubiquitin ligases and adaptor proteins, negatively regulates the expression of brain dilps. Neuronal and IPC-specific knockdown of dcbl results in up-regulation of dilps 2, 3, 5 whereas the Epidermal growth factor receptor (EGFR) signaling pathway mediates this regulatory effect of dCbl only on dilps 2 and 3. Thus, a likelihood of other mediators for dilp5 is speculated  play a prominent role in regulating insulin secretion in \u03b2-pancreatic cells  signaling -producing corpora cardiaca (CC) cells are neurosecretory cells that function to regulate metabolic processes in the fly (Rulifson et al., dilp2 overexpression strongly supported the notion that loss of DILP2 was responsible for the phenotypes (Rulifson et al., The first set of compelling evidence demonstrating the functional extent of DILPs in controlling growth, development, and glucose homeostasis was generated by the destruction of IPCs. Ablation of IPCs during the early larval stage results in severe developmental delay with a reduction of both cell numbers and body size accompanied by an increased level of circulating sugars suggesting a diabetic-related phenotype (Rulifson et al., daf-2, a gene encoding the insulin receptor homolog in C. elegans nearly doubled the lifespan of the organism (Kenyon et al., Drosophila homolog of the insulin receptor substrate CHICO similarly render cell non-autonomous effects in lifespan extension as the result of reduced IIS (Clancy et al., The role of IIS pathway in aging was first discovered when mutations of dilps and DILP2 possesses the highest homology to the mammalian insulin with a 35% identity in protein sequence (Brogiolo et al., dilp2 is associated with lifespan extension under several conditions. First, activation of dFOXO in the pericerebral fat body extends lifespan with an accompanied reduction in dilp2, but not in dilp3 or dilp5 mRNA levels (Hwangbo et al., dilp2 is associated with the extension of lifespan observed in those flies (Wang et al., dilp2 transcript levels, again indicating that the reduction of dilp2 expression was closely associated with extended longevity under those genetic conditions (Bauer et al., dilp2 expression and increased lifespan, direct modulation of dilp2 levels was needed to assess the causal relationship between dilp2 expression and lifespan control. To this end, surprisingly, while causing a severe reduction of dilp2 transcripts, targeted knockdown of dilp2 in IPCs did not result in any lifespan extension (Broughton et al., dilp3 and dilp5 expression was observed in those flies raising the possibility that a compensatory mechanism exists to modulate overall dilp expression in the IPCs. However, this compensatory increase in dilp3 and dilp5 expression could not completely account for the lack of lifespan extension in dilp2 knockdown flies as a similar increase of dilp3 and dilp5 transcripts was observed in long-lived dilp2 null mutant flies and increased dilp5 expression levels in long-lived dilp2\u20133 mutants (Gronke et al., dilp2 knockdown elicits additional genetic alterations neutralizing the effect on lifespan associated with reduced dilp2 transcripts. The extended lifespan measured in dilp2 null mutants, however, confirms a major role of DILP2 in longevity control. The absence of any change in lifespan in flies with a dilp3 deletion is intriguing as both dilp2 and dilp5 transcript levels are lowered in those flies (Gronke et al., dilp transcript levels and lifespan effects in dilp2, dilp2\u20133, and dilp3 null mutants requires further clarification with measurements of DILP peptide levels as possible compensatory mechanisms to modulate IIS and lifespan regulation. An involvement of DILP3 in longevity control is worth further investigation, however as dilp3 transcript levels appeared to be specifically reduced in long-lived flies with increased mitochondrial uncoupling in adult IPCs (Fridell et al., dilp5 null mutant appeared to have no effect on lifespan under standard diet (Gronke et al., dilp5 levels are moderated in DR-mediated lifespan extension (Min et al., dilp6 loss-of-function mutation neither had any effect on adult Drosophila survival nor on any compensatory increase in the expression of other dilps (Gronke et al., dilp6 in the adult abdominal fat body significantly extends lifespan in females in a diet-dependent manner and negatively affects expression of dilp2 and dilp5, whereas a modest effect in survival is observed when dilp6 is expressed in the pericerebral fat body. This study also shed light on the fact that the longevity effect of dFOXO when overexpressed in the pericerebral fat body requires dilp6 (Bai et al., dilp mutants has confirmed lifespan extension as the result of dilp2 deficiency suggesting a major role of DILP2 in modulating IIS. On the other hand, targeted expression of dilp6 in the adult fat body results in profound longevity and metabolic consequences that underlies its role in lifespan regulation.A significant amount of interest has been bestowed upon DILP2 as its transcript is most abundantly expressed among all dilp mutants have paved the way. IPC ablated flies exhibit high levels of trehalose, lipid and glycogen stores, accompanied by increased stress resistance (Broughton et al., dilp2 loss-of-function mutant with no change in lipid or glycogen levels (Gronke et al., dilp 1\u20134 loss of function mutants were starvation resistant recapitulating the role for dilp2 in starvation resistance (Gronke et al., dilp2 null mutants nor dilp 2\u20133, 5 deletion mutants, created by homologous recombination, were resistant to starvation (Gronke et al., dilp2 null mutants. A putative role for DILP2 in response to oxidative stress was discovered in the context of JNK signaling upon oxidative stress where dilp2 expression is repressed in IPCs (Wang et al., dilp2 RNAi hypomorphs (Broughton et al., dilp2 loss-of-function mutants (Gronke et al., dilp6 over expression in the abdominal fat body exhibit metabolic phenotypes reminiscent of those seen as a consequence of reduced IIS (Bai et al., dilp6 loss-of-function mutants only had high stored lipid levels revealing its specific role in lipid storage (Gronke et al., To aid a better understanding of the significance of DILP2 and DILP6, physiological alterations that accompanied lifespan extension in respective dilp3 or dilp5 single mutants were neither resistant to starvation or oxidative stress nor was there any change in their trehalose, glycogen, or lipid levels (Gronke et al., dilp3 overexpressors play a role in regulating triglyceride levels (Varghese et al., Unlike DILP2 and DILP6, an involvement of DILP3 and DILP5 in any physiological feature that plays a part in lifespan regulation has not been identified. Drosophila. While the exact molecular mechanisms behind DR-mediated lifespan extension are yet to be completely elucidated, several molecular pathways have emerged as important players involved in DR responses (Narasimhan et al., C. elegans, depending upon the methods of DR, lifespan extension associated with DR is largely independent of IIS (Kaeberlein et al., Drosophila (Clancy et al., chico mutants did not respond to optimal DR for additional lifespan extension indicating an overlap between IIS and DR (Clancy et al., dFOXO mutants remained sensitive to DR thus suggesting that DR acts independently of IIS (Min et al., Drosophila in order to reconcile discrepant findings as well as pinpoint a role of IIS in DR (Tatar, Through dilution of nutrient content, DR is a robust intervention that has been shown to extend lifespan in R Tatar, .Drosophila are shown to extend lifespan with changes in dilp5 mRNA levels but not dilp2 or dilp3 levels (Min et al., dilp5 mRNA and DILP5 protein levels are down-regulated in wild type flies under a yeast DR diet where only yeast is diluted while keeping carbohydrate levels constant (Broughton et al., There is emerging evidence on the role of IPCs in lifespan extension through DR, as those neurosecretory cells appear to respond to nutrient changes (Broughton et al., dilp5 knocked down by a UAS-dilp3RNAi construct that repressed expression of dilps 2, 3, and 5 and blocked the nutrient-dependent expression of dilp5, exhibited a normal response to DR under a yeast DR regime implying that DR-mediated lifespan extension works independently of DILP5 (Min et al., dilp6 in the fat body lowers dilp2 and dilp5 expression as well as the respective hemolymph peptide levels, the lifespan of dilp6 overexpressors was similar to the controls under a yeast restricted diet corroborating with the evidence that DR works independently of dilp5 and DILP5 (Bai et al., Flies with dilp5 null mutant flies that displayed a normal DR response also exhibited a compensatory up-regulation of dilp2 mRNA when raised on food with high yeast concentration while dilp3 mRNA levels were up-regulated in these flies raised on food with relatively low yeast concentration (Gronke et al., dilp5 loss-of-function flies raised on yeast DR diet. Supporting evidence for the involvement of DILPs in DR, if not a direct role, was presented when dilp 2\u20133, 5 deletion mutant flies (Gronke et al., per se but whose activity has shown to modulate DR response when over-expressed (Giannakou et al., dilp5 is modulated under DR, this change in expression could simply be a response associated with dietary alterations but does not trigger the longevity effect of DR. Further clarification is required to definitively assign a physiological role of DILP5, if any, in DR response.However, Drosophila homolog of IGF-binding protein, Imp-L2 is shown to bind to DILP2 (Honegger et al., dilps have confirmed that loss of dilp2 and over-expression of dilp6 is sufficient to extend lifespan (Gronke et al., Drosophila as a model to study cross talk between the nutrient sensing fat body and the neurosecretory IPCs has shed significant insight into a systemic control of DILP activities as the result of communication between those two tissues tightly associated with metabolism. The studies highlighted in this review have underscored the importance of measuring DILP levels in order to substantiate and validate their functional significance. Specifically, measuring circulating DILPs in the hemolymph should provide most relevant assessment on secreted DILP levels and their systemic effects (Bai et al., DILPs are involved in a myriad of physiological processes ranging from growth (Brogiolo et al., dilps 1\u20135 mimics phenotypes seen in type 1 diabetes (Rulifson et al., dilp levels in modeling type 2 diabetes (Musselman et al., dilps in Drosophila, metabolic disorders such as diabetes, hyperinsulinemia, or those affecting glucose homeostasis can be modeled in this genetic organism. These approaches will likely further characterize the molecular mechanisms behind these disorders, discover drug targets, and screen potential therapeutic modes to treat these disorders. Apart from disease models, emerging research has revealed an involvement of DILPs in stem cell biology including stem cell proliferation (LaFever and Drummond-Barbosa, dilp8 in tumor eye discs that responds to signals from peripheral tissues to mediate their growth and development has further strengthened Drosophila as a model for investigating mechanisms underlying inter-organ communication and demonstrated a role for DILP8 in cancer biology (Garelli et al., Drosophila through diverse mechanisms that are being unraveled.Ablation of IPCs or deletion of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This study evaluated the potential of the NAVIGATOR (Applied Physiology) haemodynamic monitor to improve consistency of cardiovascular assessments amongst ICU members with different levels of expertise and experience.n = 20) post cardiac surgery were monitored by NAVIGATOR to display heart efficiency (Eh), mean systemic filling pressure (Pms) and vascular resistance (SVR) against targets for mean arterial pressure and cardiac output set by the clinical team. Four categories of staffparticipated: nine consultants (C), eight senior registrars (SR), nine registrars (R) and 11 nurses (N)  and were asked to score Eh, Pms, and SVR ranging (discrete steps of one) from -5  to 0  to 5  first without (BLIND) and then given (OPEN) access to the NAVIGATOR display. Recommendations for therapeutic interventions were noted. Agreement , disagreement (median and interquartile range of steps) and therapeutic agreement  were recorded and analysed for statistical difference BLIND versus OPEN .Patients (Eh was commonly overestimated, Pms commonly underestimated with no clear trend for SVR. Agreement amongst all categories of staff increased and disagreement score decreased for Eh, Pms and SVR Table  comparinThe assessment of heart function, intravascular filling and resistance state in postoperative cardiac patients was made significantly more consistent amongst different ICU staff members using the NAVIGATOR haemodynamic monitor. Such enhanced consistency could potentially make the haemodynamic management more effective with improved clinical outcomes."}
+{"text": "Early diagnosis of macrophage activations syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) may be challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. However, the diagnostic value of the guidelines for hemophagocytic lymphohistiocytosis (HLH) (1) or sJIA-associated MAS (2) has seldom been examined.To investigate the sensitivity and specificity of diagnostic guidelines for HLH and sJIA-associated MAS in patients with sJIA who developed MAS.The study sample included 155 children with sJIA who had MAS (diagnosed and treated as such by the attending physician) and 2 control groups with potentially \u201cconfusable\u201d conditions, including active sJIA without MAS (n=303) and a systemic febrile infection requiring hospitalization (n=191). Diagnostic guidelines for HLH and sJIA-associated MAS were applied to all MAS and control patients. Because no patient had NK-cell activity and soluble CD25 determination available and bone marrow aspirate was performed in only a few patients, these 3 criteria were excluded from HLH guidelines. HLH criteria were, therefore, met when at least 4 of the 5 remaining variables were present. sJIA-associated MAS criteria were met when at least 2 laboratory criteria or at least 1 laboratory criterion and 1 clinical criterion were present. Sensitivity and specificity of guidelines in discriminating patients with MAS from control patients were assessed.The table shows the comparison of sensitivity and specificity of diagnostic guidelines.The diagnostic guidelines for sJIA-associated MAS revealed strong sensitivity and specificity, whereas HLH guidelines were highly specific, but lacked sensitivity. Sensitivity of HLH was mostly hampered by the excessive stringent threshold for cytopenia and hypofibrinogenemia, and the infrequent occurrence of splenomegaly in patients with MAS."}
+{"text": "Ischemic brain injury due to stroke and/or cardiac arrest is a major health issue in modern society requiring urgent development of new effective therapies. The use of appropriate animal models is essential to study the mechanisms of ischemia-induced injury and neuroprotection. The goal of our study was to establish a reliable and reproducible model of brain ischemia in pigs  for further research.in vivo SDF videomicroscopy) and histological structure (light microscopy) of brain tissue in healthy control animals and after 3 hours of brain ischemia (three different models).Eighteen pigs (18 to 22 kg) were anesthetized and randomly assigned to the one of the following groups: 1 - control, 2 - unilateral carotid occlusion, 3 - bilateral carotid occlusion, 4 - bilateral carotid occlusion + hypotension (MAP 40 to 50 mmHg). In order to investigate the effects and mechanisms of cerebral ischemia, we assessed the mitochondrial respiration (high-resolution respirometry), microcirculation . Mitochondrial respiration rates after addition of atractyloside and cytochrome c were the same in all experimental groups, suggesting that intactness of mitochondrial outer membrane was not affected by cerebral ischemia. Microcirculatory and histological alterations also demonstrated increasing derangement and reversible structural changes after bilateral carotid occlusion and vascular occlusion combined with systemic hypotension.LEAK respiration  was not affected by ischemia in any model. The OXPHOS capacity with pyruvate + malate as substrates decreased by 20% and 79% compared to the control level after bilateral carotid artery occlusion and bilateral carotid occlusion + hypotension, respectively, resulting in the decrease of RCI (ADP/PM) by 14% and 73%. The OXPHOS capacity with succinate as substrate remained constant after unilateral carotid artery occlusion but decreased by 53% after bilateral carotid artery occlusion and hypotension compared to the control level ."}
+{"text": "Objectives. To evaluate the feasibility of implementing a statewide children with special health care needs (CSHCN) program evaluation, case management, and surveillance system using a standardized instrument and protocol that operationalized the United States Health and Human Services CSHCN National Performance Measures. Methods. Public health nurses in local public health agencies in Washington State jointly developed and implemented the standardized system. The instrument was the Omaha System. Descriptive statistics were used for the analysis of standardized data. Results. From the sample of CSHCN visit reports (n = 127), 314 problems and 853 interventions were documented. The most common problem identified was growth and development followed by health care supervision, communication with community resources, caretaking/parenting, income, neglect, and abuse. The most common intervention category was surveillance (60%), followed by case management (24%) and teaching, guidance, and counseling (16%). On average, there were 2.7 interventions per problem and 6.7 interventions per visit. Conclusions. This study demonstrates the feasibility of an approach for statewide CSHCN program evaluation, case management, and surveillance system. Knowledge, behavior, and status ratings suggest that there are critical unmet needs in the Washington State CSHCN population for six major problems. Children with special health care needs (CSHCN) are at increased risk for poor health outcomes . The CSHThe Maternal Child Health Bureau (MCHB) defines CSHCN as \u201cthose who have or are at increased risk for a chronic physical, developmental, behavioral, or emotional condition and who also require health and related services of a type or amount beyond that required by children generally\u201d . The MCH Identifying health care problems experienced by CSHCN and their families provides information about the larger service system, while a successful system of services results in high levels of child and family health and well-being . Partner Programs that address the unique needs of CSCHN have long been a component of the public health system . Public The adoption of electronic health records and public health information systems varies across jurisdictions in the United States . Many loThe objective of this study was to evaluate the feasibility of implementing a state-wide case management, surveillance, and program evaluation system for CSHCN program using a standardized Omaha System protocol and visit report. This paper reports preliminary data from the first four months after the implementation of the standardized data collection protocol.The University of Minnesota Institutional Review Board and State of Washington Institutional Review Board approvals were obtained for this study. All local public health agencies in Washington State were invited to a statewide training on the data collection system (September 2010) and to participate in the data collection starting November 2010. The data collection period for this study ended in February 2011. Visit reports were submitted to State of Washington Department of Health CSHCN officials for program evaluations by 25 of the 35 local agencies during this time period. The Department of Health entered the deidentified data into a spreadsheet and provided the spreadsheet to the research team for analysis . The Omaha System  was seleThe Problem Classification Scheme is used to identify and classify health-related issues and includes 42 problems. Problems are uniquely identified by distinctive definitions and signs and symptoms (s/sx). The Intervention Scheme is used for addressing the problems which are described using the four-level Intervention Scheme. The four terms of the Intervention scheme are: problem from the Problem Classification Scheme, category (action term), target (defined term that further specifies the intervention), and care description  [The Problem Rating Scale for Outcomes is used to measure client knowledge, behavior, and status (KBS) related to each client problem. KBS ratings are documented using a Likert-type ordinal scale from 1 (lowest) to 5 (highest). The knowledge scale measures what the client understands and knows. The behavior scale measures the appropriateness of client actions. The status scale describes the level of severity of client sign and symptoms . The defThe State of Washington Department of Health together with PHNs serving CSHCN sought to develop a uniform CSHCN evaluation protocol including the development of practice standards and assessment guidelines. The purpose of their project was to generate data for overall quality improvement and outcomes reporting. They created the evaluation protocol in response to three important trends: 1) the need to respond to federal maternal-child health national performance measures, (2) the fact that many of the public health agencies had the electronic capacity to collect standardized data, and (3) many of the agencies were using the Omaha System for other maternal-child health programs . Title V the needn = 127). The client demographics were excluded from analysis because of Washington State data deidentification protocols. The only known characteristics of the sample were that the CSHCN who received PHN visits qualified for services through the HHS Title V CSHCN definitions and criteria. There were CSHCN visit reports , 314 problems and 853 interventions were documented. The most common problem identified was growth and development followed by health care supervision, communication with community resources, caretaking/parenting, income, neglect, and abuse. The most common intervention category was surveillance (60%), followed by case management (24%) and teaching, guidance, and counseling (16%). On average, there were 2.7 interventions per problem and 6.7 interventions per visit. The mean KBS ratings for each problem are reported in  From the visit reports (n = 80), the most common s/sx were abnormal results of developmental screening tests (40%), inadequate achievement/maintenance of developmental tasks (40%), age-inappropriate behavior (30%), and abnormal weight/height/head circumference in relation to growth/age standards (23%).  For the growth and development problem (n = 57), the most common s/sx were inability to coordinate multiple appointments/treatment plans (23%), inadequate source of health care (21%), inadequate treatment plan (21%) fails to obtain routine/preventative health care (18%), inconsistent source of health care (11%), fails to return as requested by health care provider (9%), and fails to seek care for symptoms requiring evaluation/treatment (7%).  For the health care supervision problem (n = 57), the most common s/sx were unfamiliar with options/procedures for obtaining services (58%), language, cultural, educational, transportation barriers (38%), difficulty understanding roles/regulations of service providers (36%), inability to communicate concerns to provider (24%), dissatisfaction with services (20%), limited access to care/services/goods (14%), and inability to use/have inadequate communication devices/equipment (2%).  For the communication with community resources problem (n = 48), the most common s/sx were difficulty providing physical care/safety (33%), difficulty providing cognitive learning experiences and activities (33%), difficulty providing preventative and therapeutic health care (31%), expectations incongruent with the stage of growth and development (19%), difficulty providing emotional nurturance (17%), dissatisfaction/difficulty with responsibilities (15%), difficulty interpreting or responding to verbal/nonverbal communication (15%), and neglectful or abusive (4.2%).  For the Caretaking/parenting problem (n = 45) were low/no income (78%), ability to buy only necessities (33%), uninsured medical expenses (18%), difficulty buying necessities (18%), and difficulty with money management (11%).  The most common s/sx of the income problem (n = 18), the most common s/sx were cluttered living space (44%), structural barriers (11%), homelessness (11%), structurally unsound (6%), inadequate heating/cooling (6%), steep, unsafe stairs, (6%) inadequate/obstructed exits and entries (6%), presence of lead based paints (6%), and unsafe equipment/wiring (6%).  For the residence problem (n = 12), the most common s/sx were of the signs and symptoms documented in the neglect problem included inadequate/delayed medical care (25%), included lacks necessary supervision (17%), while lacks adequate physical care (8%), lacks emotional support (8%).For the neglect problem . The use of the CSHCN visit reports will generate large data sets that will enable further evaluation of the effectiveness of PHN interventions for these problems. Previous studies have described intervention tailoring and effectiveness for high risk families \u201321. Furt The use of the Omaha System enabled the aggregation of standardized CSHCN data for program evaluation. Assessments and intervention data from 25 of 35 local health jurisdictions were included in this study. The 127 visit reports were submitted to the Department of Health on the paper visit report forms. Data from electronic documentation of CSHCN assessments and interventions were not included in this study but will be available in the future. The interoperability of electronic systems continues to be a challenge. It is essential for state and local health jurisdictions, software vendors, and policy makers to work together to achieve the goals of standardized, interoperable systems to support uniform data collection for program evaluation and research.The results of this study will be used by the Washington State CSHCN program to focus nursing activities on the problems most likely to be encountered by PHNs serving the CSHCN population. Additionally, these results will be used to further refine the program evaluation process.National, state, and local officials have a responsibility to develop, support, and maintain CSHCN programs , 22. Pub With all research using large observational data sets, limitations of the data include observer bias and fidelity to documentation procedures. While the sample of 127 clients from 25 local health jurisdictions demonstrates the feasibility of the approach, bias toward submitting forms for clients with the greatest need may exist. This limitation is supported by the PHN interpretation of the findings reported in Section 5.0. Therefore, alternative explanations for the findings must be considered. In this study, many of the local health jurisdictions started to use the Omaha System for the CSHCN at the beginning of the data collection period. Documentation quality was supported by peer training and the use of KBS rating guide supplements. However, no evaluation of documentation quality was included in the program evaluation protocols. Further research is needed to create quality assurance measures that can be implemented as an integral part of program evaluation.This study demonstrates the feasibility of a structured approach to case management, surveillance, and program evaluation for CSHCN using a standardized terminology. The use of the Omaha System facilitated uniform data collection of client assessments and services across 25 of 35 local health jurisdictions in the first four months of the evaluation. Preliminary findings suggest that critical needs existed among CSHCN in Washington State. In the future, larger data sets will be used to evaluate the quality of PHN services, inform public policy, and improve the health CSHCN and their families."}
+{"text": "A number of studies have outlined mechanisms by which mycoplasma infection may promote allergic lung inflammation. In addition, there is increasing evidence from human studies suggesting that mycoplasma infection contribute to asthma exacerbations, and severity with the change of cytokines. The present study evaluated the change of serum levels of eosinophil count, eosinophil cationic protein, and interleukin-5 in atopic children with Mycoplasma pneumonia infection.We recruited 145 children including 45 atopic children with mycoplasma pneumonia (Group 1), 39 non-atopic children with mycoplasma pneumonia (Group 2), 35 children with viral pneumonia (group 3), 26 non-atopic children with viral pneumonia with mycoplasma infection (Group 4). The change of total eosinophil count, serum levels of interleukin (IL)-5, eosinophil cationic protein were measured at admission and at recovery for each group by using commercial ELISA.The serum level of IL-5 at admission was increased at recovery in group 1 . However, Buserum eosinophil cationic protein concentrations were increased at clinical recovery compared to the mean serum concentration at admission .Mycoplasma infection may be associated with the mechanism by which the Mycoplasma pneumoniae contribute to the development of airway hypersensitivity.The outcomes of the present study implied changes of eosinophil and its mediators during"}
+{"text": "The aims were to assess: (i) how the instruments were used in practice; (ii) which items of resource use were most frequently measured using patient-recall; and (iii) how estimates compared if more than one method of data collection was used for the same resource itemsWe conducted a review of articles citing trial-related resource use measures catalogued in the Database of Instruments for Resource Use Measurement  used an instrument derived from Beecham and Knapp\u2019s Client Service Receipt Inventory or a variation thereof (81/143). Most measures relied on patient- or proxy-recall (126/146) generally administered during researcher interviews. Use of primary and secondary care was the most widely reported items of resource use (136/146). Twelve studies compared more than one method of data collection for the same resource items and 8/12 showed good correlation between medical records and patient/carer recall or at least indicated one could routinely validate the other. No single administration method was deemed superior.Patient interviews are the most common method of questionnaire administration but studies lack clarity on how they are conducted. Results indicate good precision and accuracy in recall questionnaire use; however, concerns about recall bias still exist."}
+{"text": "Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices. Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder characterized by upper motor neuron (UMN) and lower motor neuron (LMN) degeneration The UMN involvement in ALS cannot be easily established based on the clinical ground because of the confounding effect of LMN involvement. The UMN damage has initially been explored mainly in the corticospinal tract using conventional Magnetization Transfer Imaging (MTI) is a MR technique capable to explore the microstructure of the cerebral cortex in several neurodegenerative diseases In order to explore the topographical distribution of VBM and MTI changes in the cerebral cortex of ALS patients we performed a cross sectional study which included voxel based analysis (VBA) of T1 weighted images and MT ratio as well as a multimodal image analysis aimed to ascertain whether MT changes occur independently of regional volume loss.We examined 18 consecutive right handed ALS patients  and 18 right handed healthy controls . Age and gender between groups were not significantly different (Mann-Withney U test p\u200a=\u200a0.07 for age and Pearson Chi-square p\u200a=\u200a0.17 for gender). All patients had definitive ALS diagnosis according to the revised El Escorial criteria MR data were acquired on a 1.5 T scanner  with high performance gradients , equipped with an 8-channel head coil with ASSET-technology.A high-resolution 3D spoiled gradient recalled (SPGR) sequence (repetition time (TR)/echo time (TE)\u200a=\u200a28 ms/5 ms, flip Angle 40\u00b0, number of excitation 0.75, field of view (FOV) 240 mm, 192\u00d7192 matrix, 124 oblique-sagittal slices 1.5 mm thick, null gap) was acquired with (Sat) and without (No-Sat) the magnetization transfer (MT) saturation pulse. The MT pulse was a 1200 Hz off-resonance pulse.The VBM analysis was carried out by the FSL-VBM optimized protocol MT image processing was performed as described in a previous work In order to exclude the possibility that differences found in voxel-wise MTr analysis were due to brain atrophy in ALS patients compared to healthy subjects, we performed a multimodal image analysis In order to establish a correlation among clinical variables and VBM or MTr changes, ALSFRS score, MRC for upper limb, MRC for lower limb, disease duration and upper motor neuron sign score was inserted as covariate variables within different GLM design matrix.Statistical maps were superimposed onto Anatomical Automated Labeling (AAL) Atlas The research was conducted according to the principles expressed in the Declaration of Helsinki. The study was approved by the Ethics Commitee of Azienda Ospedaliera Universitaria Pisana, Pisa, Italy. Written informed consent was obtained from all the study partecipants.Results of the between group VBM analysis revealed several clusters of reduced cortical GM in ALS patients compared to healthy controls (p<0.05 FWE corrected for multiple comparisons). They were located in the superior, middle and inferior frontal gyri , in the supplementary motor area (AAL 20) and in the temporal lobe (AAL 85) . These rResults of the between group MTI analysis revealed that the MTr values were significantly lower in ALS patients than in the healthy controls in the following cortical regions: superior, middle and inferior frontal gyrus , gyrus cinguli , supplementary motor area , insula  and temporal lobe  .Results of the between group regional MTI analysis corrected for atrophy revealed that the MTr values were significantly lower in ALS patients than in the healthy controls in the superior, middle and inferior frontal gyri , in the gyrus cinguli , in the supplementary motor area , in the insula  and in the temporal lobe  .No cluster of significant association between atrophy or MTr changes and clinical scales was detected in the respective statistical maps.ALS is emerging as a multi-system disease involving several frontal-temporal structures beside motor structures and functions In order to compare the spatial distribution of atrophy and MTr changes in ALS we adopted in the present study a voxel based approach of MT data Since a region specific MTr decrease in the sensory motor cortex is observed with advancing age Although we do not know the exact meaning of the reduced MTr in the cerebral motor-related and extra-motor cortex of ALS patients, the rate of MT effect depends on the surface chemistry and the biophysical dynamics of the macromolecules, as well on the concentration of macromolecules and water The neuronal loss and degeneration in the V layer of the cortex into the precentral gyrus is considered the pathological hallmark of the UMN involvement in ALS In the present study the voxel-wise analysis of GM volume, MTr and MTr data corrected for regional atrophy failed to show any structural abnormality in the precentral gyrus of ALS patients. This result may reflect both the fact that the pathological changes in primary motor cortex of ALS patients are subtle On the other hand our and other studies showed clusters of atrophy and MTr changes in motor-related area. Clusters of decreased MTr independent of cortical atrophy were observed in the premotor cortex particularly in the superior, middle frontal gyri pertaining to the fronto parietal circuit At multimodal image analysis, the MTr decrease in prefrontal and temporal cortex of our ALS patients survived correction for local atrophy indicating that the microstructural changes exist beyond the areas of cortical atrophy. This interpretation is supported by the observation that MTI can detect microstructural changes in cortical areas unaffected by atrophy also in patients with Alzheimer disease (AD) A longitudinal evaluation of VBM and MTr data could be a further fundamental step in evaluating their spatial and temporal relationship in the progression of motor and cognitive functions in ALS and is currently under way.We recognize as main limitation of our work that we did not obtain a detailed neuropsychological profile of our patients. This hinders investigation of the relationship between behavioural and cognitive functions and regional volume or MTr of the cortical GM in specific brain structures VBM and MTI reveal regional atrophy and microstructural changes of the cerebral cortex in ALS involving not only motor-related areas but also frontotemporal cortices.MTr reduction occurs in non atrophic cortical areas suggesting that microstructural degenerative phenomena can extend beyond the tissue loss in ALS.Table S1Demographic and Clinical data.(DOC)Click here for additional data file.Table S2VBM results: clusters of cortical atrophy.(DOC)Click here for additional data file.Table S3MT Imaging results: clusters of reduced MT ratio.(DOC)Click here for additional data file.Table S4MT Imaging results: clusters of reduced MT ratio adjusted for atrophy.(DOC)Click here for additional data file."}
+{"text": "A number of human diseases such as obesity and diabetes are associated with changes or imbalances in the gut microbiota (GM). Laboratory mice are commonly used as experimental models for such disorders. The introduction and dynamic development of next generation sequencing techniques have enabled detailed mapping of the GM of both humans and animal models. Nevertheless there is still a significant knowledge gap regarding the human and mouse common GM core and thus the applicability of the latter as an animal model. The aim of the present study was to identify inter- and intra-individual differences and similarities between the GM composition of particular mouse strains and humans.A total of 1509428 high quality tag-encoded partial 16S rRNA gene sequences determined using 454/FLX Titanium (Roche) pyro-sequencing reflecting the GM composition of 32 human samples from 16 individuals and 88 mouse samples from three laboratory mouse strains commonly used in diabetes research were analyzed using Principal Coordinate Analysis (PCoA), nonparametric multivariate analysis of similarity (ANOSIM) and alpha diversity measures. A reliable cutoff threshold for low abundant taxa estimated on the basis of the present study is recommended for similar trials.Distinctive quantitative differences in the relative abundance of most taxonomic groups between the examined categories were found. All investigated mouse strains clustered separately, but with a range of shared features when compared to the human GM. However, both mouse fecal, caecal and human fecal samples shared to a large extent not only representatives of the same phyla, but also a substantial fraction of common genera, where the number of shared genera increased with sequencing depth. In conclusion, the GM of mice and humans is quantitatively different (in terms of abundance of specific phyla and species) but share a large qualitatively similar core. Shifts in the composition, known as dysbiosis, of the human GM have in several studies been associated with diseases such as allergies Rodents are the mammalian model most extensively used to investigate the relationship between GM and health and disease. The reason for the popularity of mouse models is their well explored genetic and relatively close physiological similarity with humans and the ability to control a wide range of environmental factors which reduces variation in the baseline gut microbiota between individual study objects Lachnospiraceae family have been suggested as possible biomarkers to help predict predispositions to inflammatory bowel disease Many GM related disorders have been linked with bacterial dysbiosis on a higher taxonomic level proving the usefulness of sequencing the GM to e.g. phylum and family level. For example, Turnbaugh et al. showed that a switch from a low fat to a high fat, high sugar diet in mice, which was associated with obesity, lowered the Bacteroidetes/Firmicutes ratio in the gut within one day However, the usefulness of mice models for such studies would to a large extent also depend on similarities in their GM profiles at genus or species level with humans. The aim of the present study was therefore to demonstrate inter- and intra-individual differences and similarities between the GM composition of three laboratory mouse strains commonly used in research in chronic inflammatory diseases with those of humans based on more than 1.5 million high quality sequences of partial 16S rRNA gene verified with tag-encoded 454/FLX Titanium (Roche) pyro-sequencing.A total of 88 mice and 128 human  GM profiles determined using tag-encoded 16S rRNA gene 454/FLX Titanium (Roche) pyro-sequencing were included in the study . All samAll animal experiments were carried out in accordance with the Council of Europe Convention European Treaty Series (ETS) 123 on the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes, and the Danish Animal Experimentation Act (LBK 1306 from 23/11/2007). The study was approved by the Animal Experiments Inspectorate, Ministry of Justice, Denmark.Human specimens used in this meta-analysis come from the independent study that was approved by The Scientific Ethics Committee of Capital Region, Denmark (reference H-4-2010-137). Written informed consent was obtained from volunteers prior to recruitment.http://www.drive5.com/usearch/). The representative sequences from each cluster were aligned with pyNAST (http://qiime.org/pynast/) and subjected to the Ribosomal Database Project (RDP)-based 16S rRNA gene annotation. For intra-individual assessment all mouse and 16 human samples from the control group were subsampled to an equal number of reads per individual (4500 reads per sample which constitutes to 85% of the second most indigent sample in the dataset). For inter-group comparison the reads were merged according to host (mouse strain/human) and subsampled to an equal number of sequences per category, respectively 80000 reads for mice strains comparisons and 600000 reads for similarity assessment between mice and humans. Both numbers constitute approximately 85% of the least numerous category. Alpha diversity measures such as rarefaction curves based on the estimated species number (97% sequence identity threshold), Chao1 and Shannon indexes were calculated for OTU tables that were unified to 4000 (first most indigent sample) sequences per sample.The dataset was analyzed using the Quantitative Insight Into Microbial Ecology (QIIME) open source software package In order to investigate the influence of the sequencing method into variance between categories, which is caused mostly by the low abundant taxa, a set of 16 samples each sequenced in 4 independent runs were compared within their quadruplicates. A set of 1000 subsampled OTU-tables was generated for each sample (3000 reads per sample). Low abundant taxa were removed until taxa similarity of all replicates within a given sample crossed 99%. An average, minimum cutoff value was therefore calculated based on 16000 subsampled OTU tables using an in-house Matlab (Mathworks) script.Principal Coordinate Analysis (PCoA) plots were generated with the Jackknifed Beta Diversity workflow based on 10 distance metrics calculated using 10 subsampled OTU tables. The -e value (number of sequences taken for each jackknifed subset) was set to 85% of the sequence number within the most indigent sample. Analysis of similarities (ANOSIM) was used to evaluate group differences using weighted and unweighted uniFrac distance metrics that were generated based on rarefied (4500 reads per sample) OTU tables. The relative distribution of the GM genera registered in 88 mouse and 16 human samples was calculated for unified, summarized at the genus level OTU tables.http://metastats.cbcb.umd.edu). From each group 14 samples  were randomly chosen and combinations of group pairs were tested using 1000 permutations . The relationship between sequencing depth and shared GM, classified into phylum and genus level, between mice and humans was plotted based on multiple subsampled OTU tables composed of two categories collecting 794988 human and 714440 mouse GM 16S rRNA gene reads. Simulation of each sequencing depth was repeated 100 times and an average proportion of shared taxonomic groups between the two categories were calculated (abundance threshold for unshared taxa\u200a=\u200a0.19%).Differences in taxa abundances at phylum and genus level between categories were verified with Metastats (http://www.cytoscape.org/).A network presenting shared genera between categories was prepared for normalized OTU tables (600000 reads per category) after filtering the low abundant OTUs (abundance threshold for unshared taxa\u200a=\u200a0.19%) using the make_otu_network.py script (QIIME). The visualization of the OTU-networks was performed with an open source platform \u2013Cytoscape  yielded 1753858. After removing chimeric sequences a total of 1509428 reads remained, meaning that the ChimeraSlayer algorithm Alpha diversity assessment using rarefaction curves revealed that the fecal GM of the BALB/c mice is the most rich in OTUs (species-level). The average Chao1 index calculated for 4000 reads per sample was 2.5\u20135 times higher in this group compared with other groups . SpeciesobLep/J groups where age was the only varying factor were only partially separated . The three remaining mouse strains were either devoid of bacteria from this phylum, or the bacteria were below the detection limit.All reads used in this study were classified into 9 phyla after applying the abundance threshold (0.19%), with one phylum noted as unclassified . GeneralAlistipes (12%), while in human specimens \u2013 Roseburia (12%) and unclassified genus representing the Clostridiales order (10%) were the dominating genera.The relative abundance of genera depicted for all samples individually shows explicit alterations between studies with the human specimens being the most conspicuous category . In totaMetastats analysis revealed widespread differences in the bacterial relative abundance at both phylum  and genuobV-Lep/J pups  and the NOD group was not detected in the adult B6. obV-Lep/J counterparts (examined in the age of 16 weeks), nor in any of the BALB/c mice. The Akkermansia genus which is the only representative group of the Verrucomicrobia phylum, was therefore the reason of discrepancies on both the phylum . The similarity of the collective mouse and human microbiomes without the abundance threshold was correspondingly 40% and 57% lower at the phylum and the genus level  comparedIn Laboratory mice are commonly used as experimental models for diseases such as diabetes Qualitative and quantitative-based analysis of the three mouse strains fecal GM compared with the mice caecal and human fecal GM (PCoA and ANOSIM) disclosed significant separation of all microbial profiles. The composition of the GM has previously been shown to be influenced by multiple factors including environment and host genetics Diet is an environmental factor known to strongly influence GM composition Early priming of bacterial colonization during early life may also influence GM and immunity later in life Lastly, for adult humans and mice the influence of age on the GM profiles seems to be minor as neither human samples collected from patients at different age (18\u201350 years) nor NOD mice analyzed at different ages (14\u201330 weeks) clustered according to age. This supports the high level of GM composition stability in adult individuals which was previously documented among humans and mice Although innovations in high throughput sequencing techniques offer insight into microbial communities at an hitherto up-preceded level of details one need to be aware of constrains that comes with it, for example: sequencing depth, reads error  rate and length or analysis methods In the present study the Firmicutes fraction was more abundant than the Bacterioidetes in most fecal and caecal samples, except for the BALB/c fecal samples, which showed an inverted proportion of these two phyla. Human fecal samples had relatively more Firmicutes and less Bacteriodetes compared to most mouse fecal and caecal samples. This is in accordance with earlier studies reporting that the majority of bacteria in the gut are members of these two phyla and that in mice the Firmicutes fraction seems to be much larger than the Bacteriodetes fraction As seen from Prevotella genus has been found to be inversely correlated with body weight gain, cholesterol accumulation, insulin resistance and diet-induced adiposity Odoribacter genus which relative abundance was recently shown to be increased in the caecum of mice exposed to grid floor induced stress obLep/J group that on the other hand were lacking members of the Akkermansia genus. Akkermansia muciniphila has been suggested to possess anti-inflammatory properties as it was found to be present in lower levels in humans suffering from inflammatory bowel disease compare to the healthy control group For example, the vs. humans) using 0.6 million reads per category disclosed 89% similarity between mouse and human GM genera, with 9 genera being unique for human samples and not detected in any of the three mice strains (abundance threshold 0.19%). Among these 9 genera were Faecalibacterium from the Ruminococcaeae family and Asteroleplasma from phylum Tenericutes that both have been suggested as possible indicators of a healthy human GM since disturbances in the relative distribution of common species from these genera have been linked with the etiology of Crohn\u2019s disease (CD) and ulcerative colitis (UC) Megasphera genus was also unique for humans not being detected in any of the three mouse strains. Megasphera spp. have been imputed to support the growth of colonic mucosa Mistsuokella genus has recently been identified as a GM member of lean as well as obese Indians Faecalibacterium and Dialister but also Sutterella from the Proteobacteria phylum showed poor establishment after transplanting them from human into mice GI tracks Pairwise comparison  and mouse (blue node) categories generated for normalized OTU tables (600000 reads per category) after filtering the low abundant OTUs  using the make_otu_network.py script (QIIME). The visualization of the OTU-networks was performed with an open source platform \u2013Cytoscape .(PDF)Click here for additional data file.Figure S2Number of GM phyla and genera shared between given categories using raw data. Number of taxonomic labels shared between given mice strains using raw data where no abundance threshold was used (A) on the genus level and (B) on the phylum level. 80000 high quality 16s rRNA reads used to represent the GM of each mouse strain were annotated to the Ribosomal Database Project  database. (C) Number of phyla and genera shared between collated categories of humans and mice using raw data (600000 reads per category). Labels \u201cBALB/c (f)\u201d, \u201cBALB/c (c)\u201d, \u201cB6.V-obLep/J (16)\u201d and \u201cB6.V-obLep/J (8)\u201d stand for the gut GM of BALB/c mice determined using fecal and caecal samples and B6.V-obLep/J mice using fecal specimens sampled in 16 and 8 weeks of age respectively.(PDF)Click here for additional data file.Table S1The relative distribution of bacterial genera among categories. The relative distribution of the gut microbial genera among single human  and five mouse groups . The abundance threshold within at least one of the category was set to 0.19%.(PDF)Click here for additional data file.Table S2Differences in the relative abundance of gut microbial phyla between categories. Differences in the gut microbial phyla relative distribution verified using Metastats (http://metastats.cbcb.umd.edu) for all combinations of categories. Each pairwise comparison was performed based on 1000 permutations .(PDF)Click here for additional data file.Table S3Differences in the relative abundance of gut microbial genera between categories. Differences in the gut microbial genera relative distribution verified using Metastats (http://metastats.cbcb.umd.edu) for all combinations of categories. Each pairwise comparison was performed based on 1000 permutations .(PDF)Click here for additional data file."}
+{"text": "Dear Editor,Vagal paragangliomas are uncommon tumors of the parapharyngeal space, approximately 200 cases having been reported. They ariThe other manifestations are hoarseness and less commonly dysphagia, palatal weakness and tongue hemi-atrophy.4] Press Press4] A 37 years old farmer presented with hoarseness and left cervical mass beyond mandible angle. He did not claim of another symptom, on physical examination a firm mobile 2x2 cm mass was moving horizontally. Before treatment planning, we found left vocal cords paralyzed and CT scan demonstrated a heterogenous lesion next to the carotid bifurcation . PlanninThe normal carotid body is a small mass of neurovascular tissue located bilaterally in the medial valley of the carotid artery bifurcation. Although the term \"tumor\" has historically been assigned to these masses, they are not carcinomas, and the neoplastic process is actually hypertrophy of the carotid body tissue.The four main locations of glomus tissue within the head and neck are: (a) The carotid bifurcation (carotid body tumor), (b) The inferior ganglion region (ganglion nodosum) and cervical portion of the vagus nerve , (c) The jugular bulb region (glomus jugulare) and (d) The middle ear cavity (glomus tympanicum). ParagangChallenging options about surgical versus radiation treatment continues, advocating radiation for small lesions,9] and s and s9]"}
+{"text": "Nosocomial infection is a constant concern in the obstetric and surgical practice in both developing countries than in developed countries.To assess knowledge, attitudes and practices of the staff of maternity services in the prevention of nosocomial infection in three community health centers in Bujumbura.A qualitative survey was conducted using a standardized questionnaire over 2 months with 76 health workers from three maternity wards of health facilities in the vicinity of all categories. Data collection consisted of two parts: first assessment of knowledge through a questionnaire and also the observation of attitudes and practices of personal hygiene.It was noted: In knowledge: Knowledge of the exact def-inition of nosocomial infection: 75% (doctors), modes of transmission of infection (manu-portage): 50%, hygiene protocols: 25%, and procedures decontamination of contaminated equipment: 16%. At the observation of practices:Compliance with hand washing before and after childbirth: 50% Use of alcohol-based solutions: 20%, antiquated equipment sterilization: 80% Compliance with the sterilization of equipment: 25% Circulation in delivery rooms disorganized: 100%, perceived risk of blood contamination (uterus): 75%, biomedical waste collected and decontaminated evil: 80%, existence of incinerators: 33.3% and participation in training in personal hygiene: 50%.There is a high risk of infectious contamination in maternity services studied for both the staff and for parturient and their newborns.None declared."}
+{"text": "This study assessed the feasibility and acceptability of utilising insecticide treated plastic sheeting (ITPS) as a malaria control intervention in Papua New Guinea (PNG).\u00ae ITPS was installed in 40 homes across four study sites representing a cross section of malaria transmission risk and housing style. Structured questionnaires were completed at the time of ITPS installation (n=40) and at four weeks post installation (n=40) with the household head. Similarly, focus group discussions (FGDs) with the male and/or female household heads were completed at installation (n=5) and four week follow-up (n=4).Zero Vector\u00ae ITPS was successfully installed in a range of homes employing traditional and/or modern building materials in PNG. The ITPS installations remained intact over the course of the four week trial period and were highly acceptable to both male and female household heads. No dissatisfaction with the ITPS product was reported at four week follow-up; however, the installation process was time consuming, participants reported a reduction in mosquito net use following ITPS installation and many participants expressed concern about the longevity of ITPS over the longer term.ZeroVector\u00ae ITPS installation is feasible and highly acceptable in a diverse range of PNG contexts and is likely to be favourably received as a vector control intervention if accessible en masse. A longer-term evaluation is required before firm policy or public health decisions can be made regarding the potential application of ITPS in the national malaria control program. The positive study findings suggest a longer-term evaluation of this promising malaria control intervention warrants consideration.ZeroVector"}
+{"text": "Despite the introduction of more aggressive systemic therapies for the management of rheumatoid arthritis (RA) MTP joint pain & deformity is commonly reported. Previous research has proposed that articular damage in the forefoot of patients with RA is probably caused by synovitis leading to destruction of the bone & soft tissues, which might result in the failure of a complex ligamentous system & the dynamic effect of displacement of the plantar plates (PP).In 24 patients with RA the more symptomatic forefoot was imaged using MRI, high-resolution ultrasound (HRUS) & conventional radiography (CR). The MRI & HRUS images were assessed to determine inflammation & damage at the MTP joints, the presence or absence of the PP & to identify tears of the PP & their location. CR was used to determine radiographic progression at the MTP joints.17 females and 7 males (mean (SD) age of 55.5 (10.5) years, disease duration 10.6 (8.6) years & forefoot pain score was 43.4 (27.9)) took part.Tears were not identified on HRUS. The Larsen score on the index foot correlated with the absence of PP viewed using both MRI  & HRUS . MRI synovitis was not related to PP absence on either MRI  or HRUS  but there was good correlation between MRI bone oedema & the number of absent PP visualised using MRI  & HRUS . There was also a strong correlation between MRI imaged bone erosion & PP absence confirmed using both MRI  & HRUS .In agreement with existing literature, this current study demonstrates that pain & deformity at the MTP joints is highly prevalent despite good disease control. The findings indicate that PP failure is associated more with damage at the lesser MTP joints than active synovitis in patients with RA. Longitudinal follow-up of patients with RA & forefoot pain is required to establish the relationship between local inflammation, disease activity, impairment & structural changes, & identify factors that precede & result in PP pathology."}
+{"text": "The endothelial glycocalyx is a recently discovered structure at the luminal side of blood vessels consisting of proteoglycans and glycosaminoglycans, which play an important role in vascular barrier function and cell adhesion. Due to its vulnerability, the endothelial glycocalyx may easily be altered by hypoxia , TNF\u03b1 22, oxidizn = 10), severe sepsis (n = 9) and septic shock (n = 18) as defined by the members of the ACCP/SCCM Consensus Conference Committee  by ELISA technique and polymorphonuclear leukocyte (PMN) function by flow cytometry in eight healthy volunteers (HV) and 37 patients who were prospectively enrolled within 24 hours of onset of signs of infection, if they met the criteria for sepsis n = 0, severeP < 0.05; Figure Plasma levels of the glycocalyx components were significantly higher in septic patients than in healthy volunteers and even more pronounced in patients with severe sepsis and septic shock (all Elevated plasma levels of hyaluronan, syndecan and heparan sulfate are suggestive of a glycocalyx shedding from endothelium with increasing sepsis severity. This process might contribute to the vascular dysfunction and development of edema in septic patients."}
+{"text": "The aim of the study is identification of correlations between the serum concentrations of iron and the risk of breast cancer among female BRCA1 mutations carriers and unselected breast cancer patients.The first group (99 triplet) selected for the trial were Polish women, positive for at least one of three founder mutations in BRCA1 gene dominating in Poland . Serum was collected at the time of breast cancer diagnosis. Persons with detected tumor were considered as cases and the others were considered as controls. One case and two controls were paired regarding many criteria  to achieve the maximum of similarity between them.The subjects of the second group (28 triplet) selected for the trial were Polish women, positive for at least one of three founder mutations in BRCA1 gene. Serum was collected 1-2 years before breast cancer diagnosis. One case and two controls were matched for year of birth, past history of cancer, adnexectomy status and cigarettes smoking to achieve the maximum of similarity between them.The subjects of the third group were unselected cancer for the trial were Polish women. Serum was collected during breast cancer diagnosis before treatment. One case and one control were matched for year of birth (+/- 3 years), number and location of cancer among I\u00ba relatives, smoking-the number of pack years (+/- 10%), adnexectomy status, CHEK2 mutation.The proportion of cases and control in the first quartile was taken as a reference to calculate the odds ratio, confidence interval and p-value of the multivariate conditional logistic regression.The iron was quantitatively measured by ICP-MS (Inductively Coupled Plasma Mass Spectrometry), .This study shows that concentration levels of iron in blood serum are a strong factors associated with an additionally increased risk of breast cancer among BRCA1 mutation carriers and unselected breast cancer patients.For iron concentration in BRCA1 carriers (serum collected at the time of breast cancer diagnosis) all quartiles above the first one had a decreased risk of breast cancer. The results are shown in Table For iron concentration in BRCA1 carriers (serum collected 1-2 years before breast cancer diagnosis) the last quartile had a decreased risk of breast cancer. The results are shown in Table Individuals classified in the III and IV quartile had lower risk of breast cancer however results were statistically insignificant.The strongest result and lowest cancer risk was for Fe > 1350 \u03bcg/l For iron concentration in unselected breast cancer patients (serum was collected during breast cancer diagnosis before treatment) all quartiles were statistically insignificant. The results are shown in Table Individuals classified in the III quartile had lower risk of breast cancer however results were statistically insignificant.The strongest result and lowest cancer risk was for Fe > 1000 \u03bcg/l .For iron concentration in unselected breast cancer patients (serum was collected during breast cancer diagnosis before treatment) before 55 years old, third quartile had a decreased risk of breast cancer. The results are shown in Table Individuals classified in the III quartile had lower risk of breast cancer ;The strongest result and lowest cancer risk was for Fe concentration higher than 987 \u03bcg/l (III quartile) ; max 1285 \u03bcg/l (III quartile)"}
+{"text": "Inflammation is a vital process induced by microbial infection or tissue injury. The main function of inflammation is to resolve the infection or repair the damage and return the body to a state of homeostasis. Acute inflammation can induce signals that result in two main functions: 1) initiation of an inflammatory cascade that helps limits the infection and 2) activation of the immune response. In this study we determined the impact of the nature and magnitude of acute inflammation on the host anti-tumor activity against Ehrlich Ascites cancer cell (EAC) line as a model system which forms either peritoneal ascites upon intraperitoneal injection.Different inflammatory signals, including agonists for toll-like receptor (TLR) 2 (zymosan) and TLR3 agonist (poly (I:C) or its clinical grade Hiltonol\u00ae), complete Freund's adjuvant (CFA), and incomplete Freunds Adjuvant (IFA), and BCG from Bacillus calmatte (TLR9 agonist) were used to induce acute inflammation 1 day after i.p. challenge with EAC.We found that Hiltonol\u00ae, poly (I:C), IFA, CFA, and BCG induced inflammatory cells associated with anti-tumor activity that resulted in significant decrease in the tumor growth measured by the total number of tumor cells after 7 days of tumor challenge. Of interest, among the test TLR agonists both poly(I:C) and Hiltonol\u00ae (TLR3 agonist) showed the highest anti-tumor effects.Provision of the proper inflammatory signal with optimally defined magnitude and duration during cancer growth will induce inflammatory cells with potent anti-tumor responses leading to significant decreases in tumor growth."}
+{"text": "Studies investigating the outcome of conservative scoliosis treatment differ widely with respect to the inclusion criteria used . While tA PubMed and (incomplete) hand search for outcome papers on PT has been performed in order to detect study designs and inclusion criteria used.Real outcome papers (start of treatment in immature samples / end results after the end of growth) have not been found. Some papers investigated mid-term effects of exercises, most were retrospective, few prospective  and someAn agreement of the scientific community on common inclusion criteria for future studies on PT is necessary. We would suggest the following: (1) girls only, (2) age 10 to 13 with the first signs of maturation (Tanner II), (3) Risser 0-2, (4) risk for progression 40 \u2013 60% according to Lonstein and Carlson.A SOSORT consensus paper following a 3-step Delphi process seems necessary in order to establish the inclusion criteria for future studies on PT."}
+{"text": "Disseminated intravascular coagulation (DIC) is observed after not only sepsis but also trauma. DIC is associated with concomitant activation of coagulofibrinolytic disorder and systemic inflammation with endothelial dysfunction and microvascular permeability. The angiogenic factors, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), and their receptors, play crucial roles in angiogenesis and microvascular permeability. The aim of the study was to assess: the relationship between angiogenic factors, their soluble receptors and organ dysfunction associated with DIC precipitated by severe trauma; and the effects of DIC-induced platelet consumption, thrombin generation and tissue hypoxia on the expression of these factors and receptors.Fifty-seven patients with severe trauma were divided into two subgroups: 30 DIC patients and 27 non-DIC patients. The serum levels of angiogenic factors were measured on admission (day 1), day 3, and day 5. We compared serum levels of these angiogenic factors between with and without DIC groups and evaluated their predictive value for organ dysfunction and outcome.DIC patients showed higher Sequential Organ Failure Assessment (SOFA) scores, soluble fibrin and lactate levels. The serum levels of VEGF, Ang1, and the sTie2 levels were lower in the DIC patients than the non-DIC patients. The serum levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio in the DIC patients were higher than in those without DIC. The sVEGFR2 levels showed no statistically significant difference between the patients with and without DIC. The levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio correlated with the SOFA score. In particular, sVEGFR1 and Ang2 were independent predictors of an increase in the SOFA score. The lactate levels independently predicted increases in the levels of sVEGFR1 and Ang2 and platelet consumption also independently predicted the increase in Ang2 levels in severe trauma patients with DIC.Angiogenic factors and their soluble receptors, particularly sVEGFR1, play pivotal roles in the development of organ dysfunction in DIC associated with severe trauma. The DIC-induced tissue hypoxia and platelet consumption plays crucial roles in inducing sVEGFR1 and Ang2, and in determining the prognosis of the severity of organ dysfunction."}
+{"text": "Molecular epidemiologic findings suggest an ancient focus of TB. Mycobacterium tuberculosis in India is largely unknown. A collection of 91 isolates originating from 12 different regions spread across the country were analyzed by genotyping using 21 loci with variable-number tandem repeats (VNTRs), by spoligotyping, by principal genetic grouping (PGG), and by deletion analysis of M. tuberculosis\u2013specific deletion region 1. The isolates showed highly diverse VNTR genotypes. Nevertheless, highly congruent groupings identified by using the 4 independent sets of markers permitted a clear definition of 3 prevalent PGG1 lineages, which corresponded to the \"ancestral\" East African\u2013Indian, the Delhi, and the Beijing/W genogroups. A few isolates from PGG2 lineages and a single representative of the presumably most recent PGG3 were identified. These observations suggest a predominance of ancestral M. tuberculosis genotypes in the Indian subcontinent, which supports the hypothesis that India is an ancient endemic focus of TB.Although India has the highest prevalence of tuberculosis (TB) worldwide, the genetic diversity of  Mycobacterium tuberculosis, its main causative agent, is widely disseminated and is one of the most successful human pathogens today, with 2 billion persons infected. Most of the disease's effects are now concentrated in countries with few resources; India has the highest number of cases (Tuberculosis (TB) in humans has been described since ancient times. M. tuberculosis  of genetic elements named mycobacterial interspersed repetitive units (MIRUs)  were used to assess consistency of the genetic relationships obtained by VNTR typing and spoligotyping at a broader evolutionary level. SNPs in the katG and gyrA genes classify M. tuberculosis isolates into 3 principal genetic groups (PGGs) thought to have evolved sequentially from group 1 to group 3  according to the previously described method . MIRU-VNTR profiles were compared to each other by using the neighbor-joining algorithm. For spoligotypes, the Jaccard index was calculated to allow for the construction of a dendrogram by using the unweighted pair-group method with arithmetic averages. The spoligotypes were compared to fingerprints in an international database , X (1 case), and T (8 cases) spoligotype families were detected among the isolates of the PGG2/3group. The single PGG3 isolate (ICC399) had a T spoligotype, which includes both PGG2 and PGG3 strains   groups. This correlation, also seen in previous studies on isolates from Singapore  has been observed in southern India (,,The few previously identified TbD1+ strains were isolated from patients from East Africa and South Asia. These strains have low copy numbers of IS India ,,. Also co India ,,.6110 distribution (6110 low copy-number fingerprints and of known spoligotypes (,6110 (The prevalence of these low-copy-number strains in regions of such high endemicity has raised the question of the true extent of genetic variation beyond their restricted ISgotypes ,. Moreove,,In addition to the TbD1+ isolates, 2 other major PGG1 families were well represented in this Indian collection. They were qualified as modern groups by their TbD1\u2013 status. The recently identified Delhi type (M. tuberculosis ancestral strains and the relatively poor representation of the most recent lineages in this Indian collection lend support to the hypothesis that India is a relatively ancient endemic focus of TB (M. tuberculosis complex, subsequent to the recently proposed emergence of tubercle bacilli in eastern Africa millions of years ago (The predominance of"}
+{"text": "We reviewed neuromedin U (NMU) and neuromedin S (NMS) involvement in the regulation of the hypothalamo\u2013pituitary\u2013adrenal (HPA) axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are also expressed in the HPA axis and progress in molecular biology techniques provided new information on their actions within this system. Several lines of evidence suggest that within the HPA axis NMU and NMS act at both hypothalamic and adrenal levels. Moreover, new data suggest that NMU and NMS are involved in central and peripheral control of the stress response. Bombesin-like neuromedins\u2014neuromedin B (NMB) and neuromedin C (NMC)  and neuromedin L (NML)  , for which no substantial homology with other known neuropeptides was found  and its anorexigenic action have enhanced interest in physiological role of NMU and NMS  and the other 8 (NMU8) amino acid residues   gene, on the other hand, was identified based on its sequence similarity with NMUR1  NMU-like immunoreactivity was observed in perikaria of the dorsal nucleus of the hypothalamus and the caudal part of the infundibulum . In the rat hypothalamus expression of NMS gene was nearly 3-fold higher than that of NMU gene  and protein (dot blot method) were identified in 2000  injection of NMU demonstrated a strong increase in Fos-immunoreactive nuclei in the PVN and supraoptic nucleus (SON) of the rat hypothalamus  release by rat hypothalamic explants NMU also regulates HPA axis in birds. Icv administration of NMU in chicks significantly upregulated mRNA expression of CRH in the hypothalamus  blood ACTH level remained unchanged  into hemiadrenalectomized rats did not significantly change corticotropin levels  resulted in a dose-dependent increase of plasma ACTH concentrations, an effect significantly reduced by pretreatment with anti-NMU IgG  and a sustained (24 h) elevation of plasma corticosterone concentration  NMU activates CRH containing neurons and stimulates CRH secretion, which in turn triggers pituitary ACTH and adrenal corticosterone/cortisol secretion. In this regard it is not astonishing that NMU and NMS are involved in central and peripheral control of the stress response. These studies were initiated by Hanada et al.  who obseStress related behavior induced by icv NMU or NMS administration was also observed in cattle  glycol (PEG) (\u201cPEGylation\u201d) may be helpful in these attempts (Ingallinella et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Aortic valve stenosis (AVS) is the most common valvular disease. Its evaluation is of growing interest because of its increasing incidence with the aging population. Previous studies demonstrated the usefulness of Phase-Contrast Magnetic Resonance (PCMR) images in the evaluation of AVS. However, because of the lack of automated methods for PCMR data analysis, this technique remains time-consuming and operator-dependent.Therefore, the aims of this study were 1) to develop a semi-automated method for aortic flow analysis from PCMR images, and 2) to evaluate several approaches of aortic valve area (AVA) estimation.2) and 12 healthy subjects  who had the same day a trans-thoracic echocardiography (TTE) and PCMR acquisitions at the levels of the aortic valve and the left ventricle outflow tract (LVOT). PCMR data analysis included a semi-automated segmentation, based on pixels connectivity in terms of velocity sign, to delineate the aortic flow on all systolic frames, as well as a functional parameters extraction from aortic velocity and flow rate curves such as aortic maximal velocity (VmaxAo) and AVA. AVA was calculated using: 1) Hakki\u2019s formula which is a simplification of Gorlin\u2019s formula, resulting in AVA1= cardiac output divided by \u221asystolic pressure gradient, 2) the continuity equation with the most pertinent method found in previous studies in PCMR resulting in AVA2 = LVOT stroke volume (LVOT SV) divided by aortic valve velocity time integral (VTIAo), and 3) the continuity equation with another approach previously described in echocardiography but never used in PCMR. It resulted in AVA3= LVOT peak Flow rate (QLVOT) divided by VmaxAo . Hakki\u2019s formula underestimated the AVA with regard to TTE in the absence of severe stenosis. AVA3 provided the best results .The LVOT and aortic flows were successfully delineated on all phases for all subjects. Comparison of PCMR and echocardiographic Vmaxts Table  in termsOur semi-automated approach for AVS evaluation from PCMR provided reproducible velocity measurements and AVA estimates in good agreement with echocardiographic values, and were able to characterize the severity of AVS."}
+{"text": "Rheumatoid arthritis (RA) is a prototypic autoimmune disease characterized by a prominent humoral autoimmunity. Of particular relevance is the local production of autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies in the inflamed synovial tissue. The mechanisms underlying break of B cell tolerance and local autoantibody production remains poorly understood. This study was conducted in order to identify cellular and molecular pathways implicated in RA-specific humoral autoimmunity.Synovial tissue samples were obtained by arthroscopy from untreated individuals with RA (n=33) and inflammation matched SpA controls (n=58). Gene expression profiling was performed on tissue samples of patients with established arthritis using 44K Whole Genome Human microarrays (Agilent). Top differentially expressed genes were validated on three independent cohorts by Taqman based RT-qPCR and immunohistochemistry. Collagen-induced arthritis (CIA) and Experimental autoimmune encephalomyelitis (EAE) experiments were conducted using Bob1 knockout mice and their littermate controls.\u2212/\u2212 mice were fully resistant to CIA induction compared to their wild-type littermates. This remarkable protection from CIA is explained by failure to produce pathogenic anti-collagen autoantibodies in the absence of Bob1. In contrast, Bob1\u2212/\u2212mice were susceptible to MOG protein induced EAE and incidence and severity of clinical disease were not altered in these mice comparing to wild-type littermates, suggesting that absence of Bob1 does not impact on antigen-presentation/costimulatory capacity of B cells.Microarray screening for genes differentially expressed in the inflamed synovium, the key target of the disease process in RA, revealed a prominent and disease-specific B cell/plasma cell signature with the B cell-specific transcriptional co-activator Bob1 and its transcriptional target BCMA among the most upregulated genes. Validation by RT-qPCR on two independent cohorts representing early and established arthritis confirmed microarray data and demonstrated elevated expression of Bob1 and BCMA not only in established RA, but also at the early phase of the disease. Quantitative evaluation of immunohistochemical stainings of synovial tissue with monoclonal antibody for Bob1 revealed significant increase in Bob1 positive cells in RA synovium (p<0.01). Next we determined whether lack of functional Bob1 modifies disease onset or severity in CIA. Interestingly, the results showed that Bob1The specific increase in Bob1 expressing cells in RA synovitis and the resistance of Bob1-defecient mice to development of CIA indicate that Bob1/BCMA axis may contribute to humoral autoimmunity in RA. The relationship between an aberrant Bob1 expression and the break of peripheral tolerance in RA is currently under investigation."}
+{"text": "We investigated the effects of dorsal root stimulation (flexor related dL2 and extensor related dL5) on fictive locomotion evoked pharmacologically (by 5-HT+NMDA+DA) in the isolated neonatal mouse spinal cord. In our experiments, electrical stimulation produced a wide variety of effects depending on stimulation frequency, intensity, and the drug concentrations used. At stimulation intensities near threshold we were able to produce phase advances and delays that resolved within a single step cycle. During these single-cycle alterations we observed different effects after stimulating dL2 and dL5. Stimulation of dL2 during ipsilateral extension typically produced an early onset of the next flexion and termination of current extension in the ipsilateral activity with or without rhythm disturbances on the contralateral side of the cord (subject to drug concentrations and stimulus intensity). These disturbances represented a true phase resetting characterized by a full flexor phase expression independent of ending the stimulation producing the disturbance. In contrast, stimulation of dL5 often produced a complex bilateral effect starting from a brief activation of ipsilateral extension (for the stimulus duration) with a corresponding reduction in the flexor activity followed by a reactivation of ipsilateral flexor activity (a full second burst that could represent a rebound evoked by end of stimulation) and then by an enhanced next extensor burst. Our results were consistent with the previously proposed two-level architecture of the spinal central pattern generator (CPG) consisting of a top-level rhythm generator (RG) and pattern formation (PF) circuits ,3. The a"}
+{"text": "ERBB2. In this review, we will focus on the functional role of these somatic mutations that cause ERBB2 receptor activation. We will additionally discuss the current preclinical and clinical therapeutic strategies for targeting mutationally activated ERBB2.Despite the ongoing \u201cwar on cancer,\u201d cancer remains one of the major causes of human morbidity and mortality. A new paradigm of targeted therapies holds the most promise for the future, making identification of tumor-specific therapeutic targets of prime importance. ERBB2/HER2, best known for its role in breast cancer tumorigenesis, can be targeted by two types of pharmacological manipulation: antibody therapy against the extracellular receptor domain and small molecule compounds against the intracellular tyrosine kinase domain. Aberrant activation of ERBB2 by gene amplification has been shown to participate in the pathophysiology of breast, ovarian, gastric, colorectal, lung, brain, and head and neck tumors. However, the advent of next-generation sequencing technologies has enabled efficient identification of activating molecular alterations of  Rising incidences of neoplasia worldwide are estimated to translate into 13 million cancer deaths by 2030 , HER3/ERBB3, and HER4/ERBB4  amplification and overexpression, (ii) molecular alterations of the receptor, and (iii) inhibition of phosphatase activity  revealed more rapid and acute activation of different signaling pathways compared with the full-length receptor and the 648-CTF fragment   was demonstrated to be active in patients with breast cancer who had progressed on trastuzumab therapy  were found to respond to neratinib  in lung epithelium revealed that the combination of afatinib and an mTOR inhibitor (rapamycin) were effective in mediating tumor shrinkage , a second irreversible inhibitor of EGFR and ERBB2, was demonstrated in Ba/F3 cells expressing an ERBB2-mutant with an insertional mutation at codon 776 and in transgenic lung cancer models , a third irreversible pan-ERBB inhibitor, is currently under clinical investigation due to promising preclinical studies  or with other targeted therapies  present valid options to combat ERBB2-driven oncogenesis.in vitro and in vivo experiments (Garcia-Garcia et al., Recent clinical data showed a significant overall survival benefit of patients with heavily pretreated metastatic ERBB2-positive breast cancer upon dual ERBB2 blockade through trastuzumab and lapatinib (Blackwell et al., Although activating mutations of ERBB2 were identified in various tumor types and several potential therapeutic options are at hand, specific screening for these lesions has not been translated into clinical routine yet.Despite the plethora of ERBB2 targeted compounds, we currently lack a sound understanding why tumor shrinkage is short-lived and only a relatively small percentage of patients benefit from these therapies. Major mechanisms of primary and acquired resistance to anti-ERBB therapeutics include (reviewed in Tortora, Retrospective studies on tumors expressing truncated p95HER2 fragments revealed that these tend to be resistant to any current therapeutic antibody approach as the required epitopes are missing (Scaltriti et al., In vitro analyses identified three point mutations, L755S, L755P, and T798M to confer resistance to lapatinib (Kancha et al., in vitro and in vivo (Kobayashi et al., Analogous to a commonly observed event during TKI treatment of EGFR-driven lung adenocarcinomas, lapatinib application was shown to induce secondary mutations within the ERRB2 kinase domain consequently leading to TKI resistance. During the past decades, the ERBB2 signaling cascade gained significant importance in the oncogenesis of many tumor types. The discovery of primary activating mutations and the emergence of acquired secondary mutations represent sophisticated challenges for effective treatment approaches. Our next steps in evaluating potential ERBB2-directed therapeutics clearly rely on: adequate diagnostic properties for specific patient selection and identification of tissue-specific mechanisms of resistance to initiate well-designed clinical trials of combinational treatment strategies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hypoxia/ischemia induces the neural stem cells (NSCs) proliferation in mammalian brain; but the mechanisms remain unknown.In this study, we investigated the effects of metabotropic glutamate receptor 5 (mGluR5) on NSC proliferation under hypoxia by 3--2,5-diphenyltetrazolium bromide (MTT) assay, diameter measurement of neurospheres, bromodeoxyuridine (BrdU) incorporation assay and cell cycle analysis. The cell death of NSCs was evaluated by terminal dUTP nick-end labeling (TUNEL) assay and Hoechst staining. The expression of cyclin D1 and the activation of mitogen-activated protein kinases (MAPKs) signaling pathway were analyzed by immunoblotting assay.The results showed that hypoxia promoted the mGluR5 expression on NSCs. Under hypoxia, mGluR5 agonist DHPG and CHPG significantly increased NSC proliferation in cell activity, diameter of neurospheres, bromodeoxyuridine (BrdU) incorporation and cell division, and expression of cyclin D1 with decreasing of cell death. mGluR5 siRNA and antagonist MPEP decreased the NSC proliferation and expression of cyclin D1 with increasing of cell death. Phosphorylated JNK and ERK increased with the proliferation of NSCs after mGluR5 agonist DHPG and CHPG treatment under hypoxia, while p-p38 level decreased.These results demonstrated that the expression of mGluR5 was upregulated during the proliferation of NSCs stimulated by hypoxia in vitro. The activation of ERK and JNK signaling pathway and the expression of cyclin D1 were increased in the process. These finding suggesting the involvement of mGluR5 in NSC proliferation and providing a target molecule in neural repair after ischemia/hypoxia injury of CNS."}
+{"text": "Grid cells in the medial entorhinal cortex (MEC) encode location through firing fields that form grid-like maps of the environment. At the same time network activity in the MEC is dominated by oscillations in the theta 4-12 Hz) and gamma (30-100 Hz) bands. Our recent experimental data established that feedback inhibition between excitatory stellate cells and inhibitory fast spiking interneurons dominates the synaptic connectivity in layer II of the MEC, and that continuous attractor models derived from these properties are sufficient to explain both the network oscillations and grid firing fields [2 Hz and"}
+{"text": "To the Editor: I read with interest the article by Jones-Engel et al. (Because current evidence shows that SV40 infections are identified in some humans and that the virus is associated with selected human malignancies ( In response: Dr. Vilchez (Specificity of SV40 seroreactivity in macaques has recently been demonstrated by competitive inhibition assays ("}
+{"text": "To the Editor: Since 1987, morbillivirus  outbreaks among pinnipeds and cetaceans in the Northern Hemisphere have caused high rates of death (Phocine distemper virus (PDV) and Cetacean morbillivirus (CeMV). PDV has been isolated from pinnipeds, and 3 strains of CeMV  have been isolated from dolphins and whales (Tursiops truncatus) has been confirmed in the Southern Hemisphere (in the southwestern Pacific Ocean) (Lagenodelphis hosei) stranded off Brazil and Argentina in 1999 indicate the exposure of South Atlantic cetaceans to morbillivirus , a coastal marine and estuarine species that occurs off the Atlantic Coast of South and Central America. Serologic surveys indicate that morbilliviruses infect marine mammals worldwide  , a monoclonal antibody against the nucleoprotein antigen of canine distemper virus that cross-reacts with cetacean morbilliviruses (Morbillivirus spp.\u2013specific primers were used for PCR: 5\u2032-ATGTTTATGATCACAGCGGT-3\u2032 (forward) and 5\u2032-ATTGGGTTGCACCACTTGTC-3\u2032 (reverse) (http://megasoftware.net/) was used to construct a neighbor-joining phylogenic tree based on the sequenced amplicon from this study (GenBank accession no. KF711855) and 12 other GenBank sequences that represent the 6 morbillivirus species already described in the literature. The analysis placed the Guiana dolphin strain at the CeMV clade, but segregated it from the already described dolphin morbillivirus strains PMV, DMV, and PWMV . We extracted RNA from frozen lung samples by using TRIzol Reagent  according to the manufacturer\u2019s instructions and amplified a 374-bp conserved fragment of the phosphoprotein (P) gene by reverse transcription PCR. The following and PWMV . The samIn summary, sequence analysis of the morbillivirus from the dead Guiana dolphin suggests that the virus is a novel strain of the CeMV species; this conclusion is supported by phylogenic analysis and geographic distribution of the virus and by its distinct host. Emaciation, marked lymphoid depletion, interstitial pneumonia, and meningoencephalitis are common findings in morbillivirus-infected animals (Morbillivirus outbreaks have caused a high number of deaths among pinnipeds and cetaceans and are a major risk to previously unexposed nonimmune populations of aquatic mammals ("}
+{"text": "Atrial fibrillation (AF) is the commonest sustained arrhythmia afflicting the adult population. Identifying and ablating triggers in the left atrium (LA) or more often the pulmonary veins (PV) with radiofrequency energy to restore sinus rhythm is fast becoming the mainstay of treatment. The success of the procedure often requires a combination of imaging techniques with an electroanatomical mapping system. We describe the use of three dimensional (3D) delayed enhancement cardiovascular magnetic resonance imaging (DE-MRI) to provide a road map of the anatomy as well as regions of scar tissues in the LA and PV for AF ablation.Images were acquired with a Siemens Avanto 1.5 tesla scanner. Standard acquisition of cardiac anatomy and function were performed as well as the atrial short-tau inversion recovery (STIR) sequences in the axial plane. In addition, 3D steady-state free precession (SSFP) axial plane, 3D magnetic resonance angiography (MRA) coronal plane and 3D DE-MRI axial plane of both LA and PV were acquired.The 3D SSFP axial plane, 3D MRA coronal plane and 3D DE-MRI axial plane of both LA and PV obtained were then incorporated into an electroanatomical mapping system which generated a 3D road map of the LA and PV together with regions of scar tissues as shown by DE-MRI. The merging of this road map with the electroanatomical map enables AF ablation to be done effectively.Together with the electroanatomical mapping system, 3D DE-MRI provides an invaluable non-invasive assessment of the anatomy and scar tissues of the LA and PV for AF ablation.No external funding."}
+{"text": "Idiopathic toe walking (ITW) has been associated with ankle equinus, and while equinus has been linked with foot deformity in adults, there has been limited investigation on its impact on structural foot change in children. This study used the weight bearing lunge (WBL) test and Foot Posture Index-6 (FPI-6) to evaluate the foot and ankle measures of children with an ITW gait.Sixty children between the ages of four and eight years were grouped into an ITW (N=30) and a non-toe walking (NTW) (N=30) cohort. The ankle range of movement and FPI-6 was calculated during appropriate weight\u2013bearing test and stance.There was a highly significant difference in the WBL test measures between the ITW cohort and the NTW cohort. The FPI-6 comparison was not significant. The WBL test was also not predictive of an abnormal FPI-6 in the ITW cohort.These results demonstrate that ITW gait style impacts only on the available dorsiflexion at the ankle. The WBL measure may be utilised within the clinical setting to guide and monitor treatment interventions."}
+{"text": "Staphylococcus aureus. In an adaptive response, bacteria have evolved systems to acquire the metals in the face of this competition while effluxing excess or toxic metals to maintain a bioavailability of transition metals that is consistent with a particular inorganic \u201cfingerprint\u201d under the prevailing conditions. This review highlights recent biological, chemical and structural studies focused on manganese (Mn) acquisition and homeostasis and connects this process to oxidative stress resistance and iron (Fe) availability that operates at the human host-pathogen interface.Pathogenic bacteria acquire transition metals for cell viability and persistence of infection in competition with host nutritional defenses. The human host employs a variety of mechanisms to stress the invading pathogen with both cytotoxic metal ions and oxidative and nitrosative insults while withholding essential transition metals from the bacterium. For example, the S100 family protein calprotectin (CP) found in neutrophils is a calcium-activated chelator of extracellular Mn and Zn and is found in tissue abscesses at sites of infection by  The most abundant transition metals in humans are iron (Fe) and zinc (Zn) , Mn(IV) and Mn(V)] and is most strongly linked to oxidative stress resistance mediated by Mn superoxide dismutase (Mn-SOD) . This is generally expressed in nmol or ng of each metal per mg total protein and is readily measured by inductively coupled plasma mass spectrometry (ICP-MS) of acid-solubilized cells. A remarkable aspect of the inorganic fingerprint relevant to this discussion is the fact that the total Mn:Fe ratio varies by over seven orders of magnitude when various single-celled organisms are compared with one another  when grown in the presence of oxygen  and Fe(II), if left unregulated  metal ions to the exclusion of all others  or hydrogen peroxide (H2O2)  atoms from enzymes harboring mononuclear Fe and 4Fe-4S cluster cofactors  dissociation, essentially analogous to that which occurs in the peroxide sensor Fe-PerR  H2O2 induces the OxyR regulon which includes genes encoding a manganese import pump MntH and the DNA binding iron-scavenging protein Dps .Manganese as a micronutrient is critical to the viability and virulence of many Gram-positive and Gram-negative bacterial pathogens . First, increased Mn(II) availability allows for increased metallation of Mn-SOD which efficiently catalyzes the dismutation of the superoxide anion radical to Hi) and Mn-carbonate complexes are efficient catalysts of superoxide disproportionation and the chemical mechanism of this reaction has recently been investigated in detail  to one based on Mn(II) in order to protect key enzymes from inactivation by ROS. Another example of this type of cofactor replacement is the iron sequestration protein, Dps, in Kineococcus radiotolerans  via cofactor substitution in the oxidative stress response  functions as an antioxidant through a combination of enzymatic degradation of oxidants by Mn-SOD and other Mn(II)-containing enzymes, nonenzymatic degradation of oxidants by LMW-Mn complexes, and metalloenzyme cofactor substitution to prevent Fe-induced peroxide chemistry and subsequent enzyme inactivation Figure . The exto Figure , may repo Figure .The ability of a bacterial pathogen to obtain sufficient Mn(II) is critically important for pathogenesis and as such, Mn(II)-dependent metal sensor proteins control the expression of operons that encode additional virulence factors unrelated to the acquisition of Mn(II)  are known to modest resolution  reveal essentially closed, metal bound-like structures, with BtuF indicative of a slightly more open and conformationally dynamic structure that collapses around the Co(II)-ligand complex -specific cluster A-I SBPs have been reported including those from distant bacterial phyla such as cyanobacteria  depending on the transporter  is often too tight to measure at the protein concentrations required to make the measurement . As can be seen, determined KdMn values range from the low nM to several hundred nM, with some indication that Zn(II) may bind more weakly than Mn(II)  is robust since this value was extracted from a nonstoichiometric binding isotherm acquired in the presence of 50 mM citrate as a Mn(II) competitor chelator  from the SBP into the transport cavity  can only enter the cytoplasm efficiently through Mn(II)-specific transporters, elucidation of the affinity of each for Mn(II) vs. noncognate Zn(II) and the rates at which Mn(II) is transported across the plasma membrane takes on added significance when considered in the context of the discovery of calprotectin (see below). This is also true from the perspective of fundamental inorganic chemistry since Mn(II) complexes will tend to be far less thermodynamically stable than \u201cisostructural\u201d Zn(II) complexes Figure  Waldron. Metal tt Figure , despiteE. coli, Mycobacterium tuberculosis, or Bacillus anthracis in this case) that secretes these siderophores to capture bioavailable Fe from the host  and Zn(II) to sequester these metals from the invading bacterium. For example, the S100A7 homodimer limits growth and invasion at epithelial surfaces through chelation of Zn(II) . One simple explanation is that more resistant bacteria express Mn(II) uptake systems that possess a higher affinity than CP for Mn(II) and thus will compete more effectively with CP for extracellular Mn(II). This requires knowledge of the structure and Mn(II) and Zn(II) binding affinities of CP. Initial studies established that a single S100A8/S100A9 heterodimer is capable of binding two molar equivalents of transition metal, designated S1 and S2; however, while Zn(II) could fill both sites, Mn(II) could fill only one with high affinity (S1)  which is well-modeled in metal binding experiments as two functionally independent heterodimers  as a competitor ligand for Zn(II) revealed KdZn1 = 0.13 nM and KdZn2 = 185 nM (\u2013Ca) and KdZn1 \u2264 0.01 nM and KdZn2 \u2264 0.24 nM (+Ca)  Mn(II) site conforming to octahedral coordination geometry  site, thus likely connecting Mn(II) sequestration to the biological activity of CP. Although CP may have a lower affinity for Mn(II) than bacterially encoded SBPs  transport into the cytoplasm  with significantly higher affinity (\u2265100-fold), a finding consistent with the Irving-Williams series  and Fe(II) can influence Mn(II) acquisition and intracellular Mn(II)-dependent metalloregulation of transcription. For example, Zn(II) has been shown to inhibit Mn(II) uptake by binding irreversibly to s Figure  - or Mn(II)-specific metal-sensing repressor -MntR and two related Fur family members, the peroxide sensing, Fe(II)-binding PerR  levels to rise to a level sufficient level to fill the mutant PerR regulatory site with cognate Fe(II)  and Mn(II) homeostasis systems may well be more relevant to bacterial cell physiology and pathogenesis than is Zn(II)-Mn(II) crosstalk. These two metals lie at the same weakly competitive end of the Irving-Williams series and the Fe:Mn ratio might be considered a reporter of microbial lifestyle, capable of altering the altering the resistance of an organism to ROS -specific in vivo. Remarkably, this Fe(II)-specificity is lost in a perR mutant strain. Here, the combined impact of increasing Fur concentrations and intracellular Mn(II) levels relative to Fe(II), leads to conditions where Fur binds Mn(II), which in turn, leads to inappropriate Mn(II)-mediated repression of the fur regulon, including genes responsible for Fe(II) uptake. Thus, PerR may directly impact Fe(II) homeostasis by modulating Fur levels in response to a change in the Mn:Fe ratio, i.e., that which might occur under conditions of high Mn(II) and Fe(II)-deplete conditions :Fe(II) ratio :Fe(II) ratios under conditions of low iron is also critical to virulence in sepsis models  effluxer, MntE, that is required for virulence -Mn(II) crosstalk influences bacterial pathogenesis is not firmly established, a number of recent studies suggest that maintenance of an optimal Mn(II):Fe(II) ratio can impact the virulence of pathogenic bacteria. For example, the ability of Recent studies of bacterial transition metal physiology and crosstalk places manganese acquisition by human microbial pathogens on center stage of the host-pathogen \u201carms race\u201d  proteins attached on the cell surface known to bind zinc -specific uptake systems compete for the same metal on the basis of their respective affinities, there is much more to be learned about this process. This includes elucidation of the rates and rate-limiting steps of Mn(II) transport, and structural studies of intact bacterial ABC transporters positioned at the \u201cfront line\u201d of Mn(II) acquisition. This is particularly interesting since Mn(II) is generally handicapped relative to other divalent metal ions, notably Zn(II), in chelate stability, and as a result, other factors including formation of kinetically trapped Mn(II) metalloenzyme complexes in the cell (Whittaker, Further insights into molecular mechanisms of host nutritional immunity against bacterial pathogens will continue to rely on concerted and collaborative efforts of microbiologists, coordination chemists and structural biologists in an effort to win the \u201ctug-of-war\u201d over transition metals at the host-pathogen interface through the development of intervention strategies based on metals in biology of infectious disease.John P. Lisher and David P. Giedroc wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Acinetobacter baumannii(CRAB) is an emerging pathogen of healthcare associated infection and little is known about the effectiveness of the active surveillance culture of CRAB.Carbapenem resistant This study aims at evaluating the effect of active surveillance culture of CRAB upon intensive care unit(ICU) admission on the occurrence of new CRAB bacteremia in ICU.Since February 2011, the active surveillance culture of CRAB was performed in all patients admitted to medical ICU in Seoul national university hospital. Contact precaution was applied for the patients who had positive surveillance culture results. Respiratory specimen were obtained and the isolates were cultured overnight in blood agar plates which contain imipenem. To assess the effectiveness of active surveillance culture of CRAB and contact precaution, the rate of new CRAB bacteremia was compared between baseline period(February 2012-January 2011) and intervention period(June 2011-February 2012). The new CRAB bacteremia case was defined as the CRAB bacteremia occurred later than 48 hours of ICU admission in patients without positive CRAB clinical culture in the prior 12 months and within the 48 hours of ICU admission.P=0.019).In the baseline period there were 242 total admissions to the ICU(7355 patients-days) and in the intervention period there were 266 total admissions to the ICU(5432 patients-days). During the intervention period, 21(7.9%) patients showed positive CRAB surveillance culture results. The rate of new CRAB bacteremia is 2.72 cases per 1000 patients-days in the baseline period and 0.92 case per 1000 patients-days in the intervention period(When active surveillance culture of CRAB and contact precaution for the patients of positive results were applied in a medical ICU, the rate of new CRAB bacteremia was lowered and the time betweennew CRAB bacteremia and ICU admission was lengthened.None declared."}
+{"text": "In this work we present a large-scale three stage model of the early mammalian olfactory system, including the olfactory epithelium (OE), the olfactory bulb (OB) and the olfactory (piriform) cortex (OC). All neurons in the network are modeled with a single or few compartments using the Hodgkin-Huxley formalism and are implemented in the NEURON simulator for parallel execution ,2. We inThe OE model comprises families of olfactory receptor neurons (ORNs) with different sensitivities, each family expressing one type of olfactory receptor (OR) with a vector of affinity values for each ligand . These dResults from runs with network sizes comprising thousands of model neurons show that this biophysically plausible network model generates response patterns of cells reminding of their real counterparts (see Figure"}
+{"text": "Loss of phosphatase and tensin homologue (PTEN) function evaluated by loss of PTEN protein expression on immunohistochemistry (IHC) has been reported as both prognostic in metastatic colorectal cancer and predictive of response to anti-EGFR monoclonal antibodies although results remain uncertain. Difficulties in the methodological assessment of PTEN are likely to be a major contributor to recent conflicting results.We assessed loss of PTEN function in 51 colorectal cancer specimens using Taqman\u00ae copy number variation (CNV) and IHC. Two blinded pathologists performed independent IHC assessment on each specimen and inter-observer variability of IHC assessment and concordance of IHC versus Taqman\u00ae CNV was assessed.Concordance between pathologists (PTEN loss vs no loss) on IHC assessment was 37/51 (73%). In specimens with concordant IHC assessment, concordance between IHC and Taqman\u00ae copy number in PTEN loss assessment was 25/37 (68%).Assessment PTEN loss in colorectal cancer is limited by the inter-observer variability of IHC, and discordance of CNV with loss of protein expression. An understanding of the genetic mechanisms of PTEN loss and implementation of improved and standardized methodologies of PTEN assessment are required to clarify the role of PTEN as a biomarker in colorectal cancer. Survival for patients with metastatic colorectal cancer (mCRC) has improved significantly over the past 15 years, largely due to improved systemic treatment options-6. In adPTEN is an important negative regulator of PI3K/AKT pathway and controls cell proliferation, survival and angiogenesis. Loss of PTEN function leads to persistent activation of the PI3K pathway and has been observed in breast, prostate, glioblastoma, endometrial and colon cancers,13. LossSeveral crucial factors make testing and interpretation of PTEN difficult. Loss of PTEN function results from several genetic mechanisms including small scale PTEN gene mutations , allelic loss at chromosome 10 and epigenetic silencing via hypermethylation of the PTEN promoter region. PTEN geFurther complicating the situation, the frequency of loss of PTEN expression increases from progression from normal colonic mucosa to adenoma, primary CRC and ultimately metastasis. The resClearly the role of PTEN is more complex than KRAS gene mutation where a single identifiable mechanism (activating mutation), largely concordant between primary and secondary tumours, confers near complete resistance to anti-EGFR MoAbs. Understanding this complexity is central to interpreting the current literature relating to PTEN and its potential role as a predictive biomarker. Recently reported cohorts of mCRC patients receiving anti-EGFR MoAbs have used PTEN loss of IHC expression to report loss of PTEN function. While this represents the functional outcome of several genetic mechanisms of PTEN loss, IHC relies on subjective interpretation and has the potential for inter reporter variation. Furthermore there is variability over the definition of 'loss of PTEN\u2019 based on IHC scoring. In the largest cohort of mCRC patients, PTEN loss was defined as no staining in any cells at any intensity, while oOur group undertook an analysis of PTEN status in the AGITG MAX study of mCRC patients to identify the rate of inter-observer variability in IHC assessment and the rate of discordance between IHC and PCR assessment of PTEN status.The MAX study design and eligibility criteria have been reported previously.The primary objective of this Phase III randomized trial was to evaluate the effect of adding bevacizumab to capecitabine (with or without mitomycin C) on progression free survival (PFS) among patients receiving first line chemotherapy for mCRC. Four hundred and seventy-one patients were enrolled between July 2005 and June 2007. We have used the TaqMan\u00ae Copy Number Assay  to assess for PTEN allelic loss and have previously reported that loss of PTEN copy number was not prognostic nor predictive of outcome in the MAX trial cohort. In thisFormalin-fixed, paraffin-embedded (FFPE) samples of tumor tissue from archival specimens collected at the time of diagnosis were retrieved from storage at hospital pathology departments. For Copy Number PCR, genomic DNA was extracted from FFPE tissue sections with the use of the QIAamp DNA FFPE tissue kit . Manual micro-dissection was performed on samples with less than 80% malignant cells when visualized by microscopy. The same tissue blocks were used to make tissue microarrays (TMAs) and were assessed for PTEN expression by IHC. Researchers who assessed PTEN IHC expression were blinded to the PCR results.Immunohistochemical staining was carried out on TMAs using the PTEN monoclonal antibody 6H2.1  that has been used previously-36. EssePTEN, at cytoband 10q23.31a, location Chr.10:89727445 on NCBI build 37 (Life Technologies). The assay is a duplex PCR for the PTEN gene and the reference gene, RNaseP , set up according to the supplier\u2019s protocol and run on the Rotorgene 6000 real time PCR instrument . The results are calculated as a ratio relative to a 2-copy control using the 2-\u2206\u2206Ct method (Rotorgene software), and multiplied by 2 to give the copy number. We tested DNA from colon cancer cell lines to determine the reproducibility of the assay and to select cell lines to use as copy number controls. HT29 (ATCC) is known to have 3 copies of chromosome 10 as determined by spectral karyotyping and comparative genomic hybridization[The PTEN TaqMan\u00ae copy number assay  was performed using 10 ng DNA in quadruplicate PCR. The primers provided in the assay were entirely within exon 9 of dization. For theFifty-nine tumor specimens were analysed for loss of copy number by Taqman\u00ae and for loss of protein expression by IHC. Eight samples were found to contain no tumor tissue and were excluded from further analysis..Two blinded pathologists assessed 51 specimens independently for PTEN protein expression with IHC. Pathologist JC assessed 29/51 (57%) as having PTEN expression loss, while pathologist AR assessed 17/51 (33%) as having loss of PTEN expression. Concordance between pathologists on final IHC assessment (PTEN loss/no loss) was 37/51 (73%), indicating in 14/51 (27%) of specimens there was discordance in the final assessment of IHC PTEN loss  had \u22641.5 copy number and were thus classified as PTEN loss.\u00ae PCR concordance analysis. Fifteen specimens had PTEN loss on IHC of which 10 (67%) also had PTEN allelic loss on Taqman\u00ae PCR. Seventeen specimens had PTEN allelic loss on Taqman\u00ae PCR of which 10 (58%) had PTEN loss on IHC. Fifteen specimens had preserved PTEN on both IHC and Taqman\u00ae PCR analysis. Overall concordance between IHC and Taqman\u00ae copy number in PTEN loss assessment was 25/37 (68%)  whether protein expression is reduced and whether such reduction confers a growth advantage is unknown. Sood et al. also demonstrated monoallelic PTEN dysfunction (by mutation or promoter methylation) resulted in loss of protein expression in only 38% of samples, while biallelic inactivation resulted in loss of PTEN expression in 80% of cases. Ali et In our cohort 25% of cases without PTEN allelic loss demonstrated complete absence of PTEN expression on IHC. These findings confirm alternative genetic mechanisms, beyond allelic loss, are responsible for loss of PTEN protein expression. Several authors have undertaken more comprehensive analysis of PTEN status on CRC specimens and provide an important insight into the often coexisting genetic mechanisms of PTEN dysfunction. Goal et al. demonstrated hypermethylation of the PTEN promoter region occurred in 10/132 (7.6%) sporadic CRC specimens, with a higher rate (19.1%) in microsatellite unstable CRCs. PTEN mutations coexisted in 4/10 (40%) of hypermethylated PTEN specimens. Eighty percent of patients with promoter hypermethylation had reduced (+1) or loss of PTEN protein expression and in the 3 cases of complete loss of PTEN staining, promoter hypermethylation coexisted with PTEN mutation or allelic loss. PerroneAlternatively, focusing on loss of protein expression at least represents the functional outcome of any such genetic insult. We have demonstrated the current limitations of IHC for this purpose. In our cohort, IHC assessment of PTEN loss by two pathologists was 33% and 57%, with overall concordance of 73%. As this was designed as a validation subset we did not ask the two pathologists to discuss the results that were not concordant, nor seek a further opinion, methods commonly described in papers reporting PTEN IHC aimed at reducing the apparent discordance rate. In all Overall the current literature highlight the difficulty in accurately measuring PTEN function to date; measurement of a single genetic insult, while minimizing inter-observer variability, does not capture the often coexisting mechanisms required for biallelic inactivation. The use of IHC, while potentially a better measure of PTEN function, is observer dependent and there remains a lack of consensus on optimal methodology and scoring.Given the limitations of PTEN assessment discussed here, it is not surprising reports of the predictive value of PTEN as a biomarker in CRC remain conflicting,17,27,31The lack of standardization in assessing loss of PTEN function appears to have contributed significantly to the conflicting results from retrospective cohort studies. Further elucidation of PTEN as a potential biomarker for colorectal cancer relies on defining PTEN loss of function and standardizing analytical methods and scoring systems. Future studies assessing PTEN function may be better served by obtaining a more comprehensive analysis of PTEN function by assessing PTEN mutation, hypermethylation of PTEN promoter, PTEN allelic loss and protein expression on each specimen. An alternative approach may be to explore improved methods of measuring reduced protein expression beyond IHC, given reduced or absent protein expression should reflect the functional outcome of PTEN loss irrespective of the genetic mechanism. Immuno-PCR may provide an option of combining the protein-specific capability of antibodies with the objective quantification of real-time PCR. This wiCNV: Copy number variation; CV: Coefficient of variability; EGFR: Epidermal growth factor receptor; FFPE: Formalin-fixed, paraffin-embedded; FISH: Fluorescent in situ hybridization; IHC: Immunohistochemistry; mCRC: Metastatic colorectal cancer; MoAbs: Monocloncal antibodies; PTEN: Phosphatase and tensin homologue; TMAs: Tissue microarrays; VEGF: Vascular endothelial growth factor.The authors declare that they have no competing interest.CH drafted the manuscript. JH conceived the study and coordinated all laboratory aspect of the study. VB participated in the design of the study and assisted with writing of manuscript. JW was involved in performing the DNA isolation and copy number PCR. NT contributed to trial conception and design as well as assisting with manuscript preparation. JC undertook the immunohistochemistry of the specimens and contributed to study design. AR undertook the immunohistochemistry of the specimens and contributed to study design. CL undertook data analysis and statistical analysis. TP conceived the study and participated in its design and coordination of all aspects of the study including drafting of the manuscript. ART designed study and assisted with manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/128/prepub"}
+{"text": "The study is aimed at i) optimization of techniques for preparing microcapsules; ii) generation of multicellular tumor spheroids (MTS) by culturing tumor cells in the microcapsules; iii) study of anticancer treatment effects for both photodynamic therapy (PDT) and anti-cancer drug screening. The model allows to estimate drug doses or parameters for PDT To form MTS, tumor cell lines  were encapsulated in polyelectrolyte microcapsules (200-600 \u03bcm), and cultivated for 3-4 weeks . MicrocaMTS based MCF-7 cells were prepared and used to study effects of PDT. To study the effect of irradiation parameters on cell viability, 2 photosensitizers (PS), namely photosense and chlorine e6 were used. Phototoxicity of PS depended on PS concentration and light energy density in both monolayer culture (MLC) and MTS. Study of cell morphology in MLC and MTS before and after PDT revealed that light energy density increase within the range of 30-70 J/cm2 resulted in cell apoptosis. However, cell survival in MTS was much higher than this in the MLC. MTS were also used to test some antitumor therapeutics . An enhanced cell resistance in MTS compared to MLC both for normal and Dox-resistant cells  were observed. MTS were also proposed to evaluate cytotoxicity not only of novel therapeutics but also nanosized drug delivery systems ."}
+{"text": "NCC is considered as potential therapeutic target for several pathological disorders like neuropathic pain and stroke disease. For understanding mechanism of action at the atomic level crystal structure provide valuable inside but lack of crystal structure of ion channel lead sequence analysis of different types of voltage dependent Ca2+ channel (VDCC) and we found identical/similar active site residues, which was confirmed by site-directed mutagenesis analysis of L-type Ca2+ channel (LCC). Based on these observations, we have developed for the first time the homology model of the closed state of NCC receptor at the ligand-sensing region by using bacterial K+ channel receptor. Further, molecular docking using different dihydropyridine (DHP) blockers identified NCC receptor hot spot binding residues, which is in consonance with that of the LCC. These residues are potential for further biochemical investigations. To understand binding and stability behavior of NCC with the DHP (amlodipine) in closed state, 50 nano second molecular dynamics simulation in lipid bilayer membrane environment were carried out. This analysis revealed the closed state stabilizing by binding of ligand into inner part of S6 region.The voltage dependent N-type Ca"}
+{"text": "Post-zygotic aneuploidy is the prominent genetic feature of the human brain (1). Genomically mosaic brain results from that the excess of aneuploid neurons due to early developmental disturbances (somatic genome variations), abnormal cell cycle regulation and altered programmed cell death. As the result, aneuploidization of the brain is a likely susceptibility factor (mechanism) for brain disorders including Alzheimer\u2019s disease.The proportion of aneuploid cells was determined in brain areas differentially affected by neurodegeneration  by molecular-cytogenetic and immunohistochemical techniques  in brain tissues of individuals with AD and controls as described ealier (2).Increased levels of aneuploidy (monosomy and trisomy) involving chromosome 21 and chromosome X was observed in AD brain. The high level of aneuploidy involving chromosome 21 was observed in the AD cerebrum and hippocampus. In total, the incidence of abnormal (aneuploid) neural cells was significantly higher in degenerating brain areas  comparing to the less degenerating area (cerebellum).Our data indicates that AD brain areas subjected to neurodegeneration are more significantly affected by aneuploidy . We propose that widespread postzygotic aneuploidization of selected brain areas is a mechanism for AD neurodegeneration. Such area-specific distribution of aneuploidy can be explained by the accumulation of aneuploid cells during postnatal life or abnormal selective pressure against non-aneuploid cells (3). Finally, these data provide for the speculation that acquired neural aneuploidy could be generated during both developing and adult neurogenesis/gliogenesis."}
+{"text": "To the Editor: Diversity of genotypes among Pneumocystis jirovecii (human-specific Pneumocystis species) isolates mainly involves internal transcribed spacer (ITS) loci (Pneumocystis pneumonia (PCP). Studies of the DHPS locus have found mutations at positions 165 and 171, which confer potentially lower sensitivity to sulfonamides to mutant P. jirovecii organisms  from 15 PCP patients and in 15 air samples collected 1 meter from each patient\u2019s head  of the 15 pulmonary samples; none of the15 patients had received sulfonamide treatment at the time of PCP diagnosis. These results were not unexpected because frequency of finding DHPS mutants in PCP patients in Paris who had no prior sulfonamide treatment is high (Several lines of evidence suggest that P. jirovecii genotypes in pairs of pulmonary and room air samples argue in favor of P. jirovecii exhalation by infected patients. The exhalation of P. jirovecii organisms emphasizes the risk for their nosocomial transmission. Our data provide additional arguments in favor of the application of measures to prevent the airborne transmission of P. jirovecii in hospitals.Matches of"}
+{"text": "Results of a recent National Insitute of Drug Abuse-funded pilot randomized controlled trial of Mindful Awareness in Body-oriented Therapy (MABT) for women in substance use disorder treatment showed improved substance use outcomes for MABT compared to treatment as usual. In addition 80% of the MABT participants maintained a daily mindful body awareness practice at nine month follow-up. The purpose of this subsequent study was to explore the perceived role of MABT and mindful body awareness practice in the recovery process.A qualitative design utilizing a focus group method was employed. Participants from the larger RCT that had completed the MABT intervention (n =18) were recruited for the focus group, and five attended. Semi-structured questions were used to explore participants\u2019 utilization of mindful body awareness practice in substance use disorder recovery, and the usefulness of various aspects of MABT delivery. Content analysis was used. Two researchers individually coded for themes across participant responses and together verified the coded themes.The primary themes were: (1) motivation to maintain body awareness practices one year post-intervention was due to improved ability to access and process emotions when using these practices; (2) exploration of uncomfortable feelings was perceived as critical for relapse prevention, as substance use was associated with escalated emotions and an inability to attend to feelings; (3) MABT facilitated awareness of inner experience and the connection between emotions and the body; they had not been able to achieve this awareness with prior therapeutic approaches. Also, three aspects of MABT were considered critical for learning mindful body awareness practice: (1) individual delivery to allow for safe exploration of emotional experiences, (2) manual/touch-based processes to learn interoceptive skills, and (3) homework to integrate body awareness practice into daily life.These findings point to the importance of studying emotional awareness in mind-body interventions, and in women\u2019s substance use disorder prevention and treatment specifically."}
+{"text": "Treatment of chronic urticaria consists of antihistamines as the first-line treatment. For more severe symptoms, combinations can be necessary as well as dose augmentations. The recent guidelines suggest the possibility of using omalizumab in resistant cases. We treated 2 patients with cold-urticaria (CO), 1 with cholinergic urticaria(CH) and 11 with chronic spontaneous urticaria (CSU) with omalizumab, who had not benefited from the recommended first-line, second-line and third-line treatments.Patients were required to document their CU symptoms once daily with urticaria activity scores for 7 days (7UAS). Briefly, the symptoms were monitored in terms of numbers of wheals , and the intensity of their pruritus , for a total of 42 points. To evaluate the efficacy of the omalizumab treatment, 7UAS obtained at baseline was compared to that at the third and sixth month of the therapy. Omalizumab was given at 150 \u03bcg/month irrespective of IgE levels and increased to 300 mg if needed (no response). The concomitant medication was slowly reduced according to clinical response.The 7UAS improved significantly in all severe urticaria patients with omalizumab as early as one month (not shown) after initiation of therapy and was sustained for the 6 month observation Figure . 7UAS inOur results show that omalizumab improves significantly recommended treatment-resistant urticaria patients (13/14) in terms of clinical symptomatology (7UAS) and drug reduction in a real life setting. None of the patients reported any adverse effect."}
+{"text": "A proper infection control program in the Ministry of Health's hospitals-Jeddah, Saudi Arabia has never been applied based on focused and aimed scientific plans. The objective of this study was to monitor the enforcement of a scientifically based infection prevention and control program via continuous auditing.A standardization and continuous auditing program was implemented in the year 2009 in twelve hospitals. Three auditing visits were conducted throughout this year to estimate hospital-wide compliance of the required procedures and strategies using auditing sheets based on that year's target aims.The first compliance rate for the first visit in the first year was 42% which increased to 66% during the second visit and to 78% during the third visit. During the first audit there were deficiencies in: general measures in infection control (43%), surveillance (31%), monitoring of infection control guidelines (81%), isolation practice (64%), infection control committee performance (66%) and education (46%). These deficiencies improved during the second audit as follows: (37%), (24%), (39%), (21%), (49%) and (25%) respectfully. During the third audit, deficiencies were as follows: (32%), (22%), (22%), (14%), (34%) and (9%) respectfully.A standardized infection control program for ongoing monitoring led to a significant improvement in infection control practices in all twelve hospitals in Jeddah. Consequently, these results might suggest that such a program can be applied to other Ministry of Health hospitals in the Kingdom.None declared."}
+{"text": "The inherited periodic fever syndromes are single gene disorders of innate immunity which have provided invaluable insights into the regulation of inflammation. They are all extremely rare but are clinically important as they cause very significant day to day symptoms and carry a high risk of early death due to AA amyloidosis. With the exception of familial Mediterranean fever treatment was essentially ineffective until this century.The discovery in 2002 that specific IL-1 blockade completely prevented all symptoms in cryopyrin associated periodic syndrome (CAPS) transformed treatment of this rare genetic disease. Isolation of the responsible gene, NLRP3, followed by rapid advances in molecular biology and identification of the inflammasome has made it clear that CAPS is purely a disease of IL-1 dysregulation. These discoveries combined with the availability of specific anti IL-1 agents have resulted in new insights into the regulation of IL-1 beta production in humans and its long term consequences.IL-1 is now recognised to be an important mediator of inflammation in other inherited autoinflammatory diseases such as Familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), deficiency of IL-1 receptor antagonist (DIRA) and mevalonate kinase deficiency and has transformed patient prognosis and quality of life. In addition the recognition that IL-1 blockade provides complete disease control in acquired diseases of uncertain aetiology particularly Schnitzler\u2019s syndrome and systemic onset juvenile chronic arthritis (SoJIA), adult onset Stills disease and recurrent idiopathic pericarditis has made it clear that these too are autoinflammatory disorders. One of the most striking features of these diseases is that IL-1 blocking agents have been used for prolonged periods as monotherapy without serious side effects or breakthrough of inflammatory activity thus differentiating them from the commoner autoimmune disorders such as rheumatoid arthritis and vasculitis."}
+{"text": "Occult hepatitis B (OHB) is not a new entity and there are many reports of patients with hepatitis B virus (HBV) evidence replication in the absence of detectable hepatitis B surface antigen (HBsAg) and occasionally other HBV serologic markers . After iEgypt has the highest prevalence of HCV infection in the world . HoweverEnd-stage renal disease (ESRD) is a significant problem in almost all countries and the prevalence has increased considerably in developing countries especially in Middle East countries. The prevalence of HCV infection among hemodialysis patients differs in different parts of Middle East countries which is 48% in Egypt . The pre"}
+{"text": "Agnotecous, a cricket genus endemic to New Caledonia showing a generalized pattern of sympatry between species making sympatric speciation plausible. We obtained five mitochondrial and five nuclear markers (6.8 kb) from 37 taxa corresponding to 17 of the 21 known extant species of Agnotecous, and including several localities per species, and we conducted phylogenetic and dating analyses. Our results suggest that the diversification of Agnotecous occurred mostly through allopatric speciation in the last 10 Myr. Highly microendemic species are the most recent ones (<2 Myr) and current sympatry is due to secondary range expansion after allopatric speciation. Species distribution should then be viewed as a highly dynamic process and extreme microendemism only as a temporary situation. We discuss these results considering the influence of climatic changes combined with intricate soil diversity and mountain topography. A complex interplay between these factors could have permitted repeated speciation events and range expansion.Islands are bounded areas where high endemism is explained either by allopatric speciation through the fragmentation of the limited amount of space available, or by sympatric speciation and accumulation of daughter species. Most empirical evidence point out the dominant action of allopatric speciation. We evaluate this general view by looking at a case study where sympatric speciation is suspected. We analyse the mode, tempo and geography of speciation in  Diversity hotspots in islands are characterized by very high specific richness and endemism resulting from local diversification of groups which are \u201ctrapped\u201d in very limited spatial areas Empirical case studies showed or suggested that diversifications in islands most often result from repeated events of local allopatric speciation and subsequent establishment of microendemism New Caledonia, one of most diverse island biodiversity hotspots AgnotecousHere we analyse the mode, tempo and geography of speciation in the microendemic species of the cricket genus We use a dated species-level phylogeny, analyses of diversification time-course, and age-range correlation methods to investigate the mode of speciation and causes of microendemism. We aim at discriminating between two alternative scenarios:Under a scenario of dominant allopatric speciation, the observed pattern of sympatry is caused by secondary sympatry with post-speciational movements.Under a scenario of dominant sympatric speciation, the observed pattern of sympatry results directly from recent sympatric speciation, with little or no post-speciational movements.According to the dominant mode of speciation, we will compare and discuss the pattern of microendemism and tempo of species diversification in New Caledonia with respect to the influence of climatic changes combined with intricate soil distribution and mountain topography. This study will allow us understanding the origin of microendemic distributions in an evolutionary and biogeographical perspective.Agnotecous. Each species is represented by specimens known from 1\u20137 localities (mean\u200a=\u200a1.8). Three species from different eneopterine tribes  and one species belonging to another cricket subfamily  were used as outgroups The molecular sampling consists of 37 individuals corresponding to 17 out of the 21 known extant species of Agnotecous, we generated a consensus sequence per Agnotecous species using IUPAC ambiguity codes under BIOEDIT v 7.0.9.0 DNA sequences were aligned under Muscle with default parameters Agnotecous at 10.5 Myr ago, and its divergence with L. santoensis at 15 Myr ago, with standard deviations of 1 Myr for each calibration point Likelihood-ratio test Agnotecous phylogeny using the software SymmeTREE , which implements a whole-tree topological approach to the study of diversification rates. Diversification rate variation within the phylogeny is reported by a range of test statistics that vary in their sensitivity to nodal depth scales Lineage Through Time (LTT) plot derived from the BEAST MCC tree was used to visualise the time-course of diversification. We tested the null hypothesis of equal diversification rates across the Agnotecous data set and using the estimated pure speciation value.We also compare the fit of rate-variable models to the null hypothesis of constant diversification by using likelihood methods based on birth-death models and model-fitting approach (BDL) implemented in the R package LASER A. petchekara is close to A. azurensis, A. humboldti and A. nekando are close to A. chopardi, and A. novaecaledoniae is close to A. sarramea (within clade B2).To compare diversification rates, we used APE Data on geographic distribution of the species were obtained from the collections of the following institutions: Mus\u00e9um national d\u2019Histoire naturelle (Paris), Natural History Museum (London), Queensland Museum (Brisbane), Osaka Museum of Natural History (Osaka), Naturhistorisches Museum (Vienna) and National Museum of Natural History (Leiden). The material examined in previous taxonomic studies of the genus was taken into account Agnotecous azurensis, aimed at generating a continuous distribution area for this species. Considering these range sizes, our sampling covers 70% of Agnotecous main potential habitat (rainforest)  method test Agnotecous is not characterised by high mobility (short-winged species unable to fly), we also computed two modified indicators following Although Finally, we computed the relationship between areas and ages of species to investigate post-speciational range expansion, and test whether microendemism is mostly found in younger clades.Distribution areas and ages of clades were compared with the map of soil diversity using the GIS layers provided by Direction des Infrastructures, de la Topographie et des Transports Terrestres of the Gouvernement de la Nouvelle-Cal\u00e9donie, and past climatic events with data in Chevillotte et al. Agnotecous (Agnotecous are found around three major recent climatic events (Two main lineages (A and B) of similar age  are recovered within the genus notecous . Each clc events : The genThe species-level LTT plots suggested two minor increases in diversification rates around 3.5 and 2 Myr ago , and a sThese results are not confirmed by BDL analyses: the best rate-constant model (pure birth) had an AIC of 13.16 versus 15.97 for the rate-variable model (yule-2-rate) (\u0394AICrc\u200a=\u200a3.19) see . AlthougAgnotecous. Only three species belonging to clade B2 are not sympatric with any other  and slope (0.01244>0), thus rejecting a scenario of fully sympatric speciation . Values  species , indicatAgnotecous, a cricket genus characterized by restricted areas of distribution . However, this case of partial sympatry is mostly a consequence of our definition of estimated range sizes, and these species are indeed not syntopic, but were found at different altitudes on the same mountain (Mont Mou: 375 m for A. minoris versus 1010\u20131140 m for Agnotecous sp.).In se study  and 4, dAgnotecous?All the studies analysing the mode of speciation in New Caledonia have concluded that both the faunal and floral diversity originated from dominant allopatric speciation Recent events may have affected the post-speciational distributions of the species, resulting in secondary contacts between them. This kind of pattern was already found in other microendemic taxa showing lower levels of sympatry. For example, sympatric species occupy different microhabitats as a consequence of character displacement in Australian freshwater snails 2), and younger species show more restricted distributions. This is especially true in the clade B2 (2 (mean\u200a=\u200a100 km2), compared to the 122\u2013500 km2 for other species (mean\u200a=\u200a253 km2). Highly microendemic species are thus clearly the most recent ones  show a larger distribution Click here for additional data file.Figure S2Topologies obtained in parsimony (a) and Bayesian inference (b) for mitochondrial dataset only.(PDF)Click here for additional data file.Figure S3Comparison between the phylogeny obtained from the 37 specimens  and the phylogeny from the 16 consensus sequences .(PDF)Click here for additional data file.Figure S4Repartition of p-values obtained by the analyses under apTreeshape.(PDF)Click here for additional data file.Table S1Additional information on taxonomic sampling, voucher references (specimen numbers in MNHN collections) and GenBank accession numbers of the specimens included in this study.(PDF)Click here for additional data file.Table S2Primers used in this study.(PDF)Click here for additional data file.Table S3Agnotecous species.Results of the Bayesian test of monophyly for (PDF)Click here for additional data file.Table S4Details of the geographic distribution of species used in the analysis of geographical pattern of speciation.(PDF)Click here for additional data file.Table S5Results of the asymmetry tests conducted under SymmeTREE for seven test statistics.(PDF)Click here for additional data file.Table S6Results of the diversification rate change test conducted under the R package apTreeshape.(PDF)Click here for additional data file.Table S7Results of the BDL analyses and comparison of AIC values from different diversification models.(PDF)Click here for additional data file.Text S1Additional information on sequencing protocols.(PDF)Click here for additional data file.Text S2Characteristics of mitochondrial (a) and nuclear (b) datasets used in this study.(PDF)Click here for additional data file.Text S3Congruence tests between nuclear and mitochondrial data sets.(PDF)Click here for additional data file.Text S4Details about phylogenetic analyses.(PDF)Click here for additional data file.Text S5Additional BEAST parameters and details of calibrations.(PDF)Click here for additional data file.Text S6Details of the rate.estimate function used in GEIGER.(PDF)Click here for additional data file."}
+{"text": "Traumatic Brain Injury (TBI) is a contributing factor to approximately one third of all injury-related deaths in USA annually. Updated statistical records for TBI in Egypt are lacking. The current research is aiming for estimating the prevalence of TBI in Egypt in order to develop a comprehensive TBI prevention program.One year period  descriptive epidemiological study of moderate and severe TBI cases admitted to the emergency department, Cairo main university hospital. The Data collection sheet included personal data , incident related data  and both; clinical and radiological findings.Moderate and severe injuries account for 17.2% (844) of all TBI presented cases in the 4 months for the study. Male sex was predominantly affected 79% of cases. 63% of the cases were between 19 and 55 years old and the 2 main causes were fall from height (FFH) and motor vehicle collision (MVC) which account for about 64% of cases. 17% of cases were among pediatric group (1-18 years) and FFH was the leading cause with 34% followed by MVC and stuck by or against events with the same percentages (21%). Causes of moderate and severe TBI among seniors (above 60 years) were FFH (28%), MVC (24%), and Stuck by or against events (15%).Traumatic brain injury is a serious public health problem in Egypt. Further data interpretation over wider periods of time should be conducted for better understanding of TBI prevalence is highly recommended to develop effective injury prevention program. Inefficient recording should raise the concern to establish an optimal system for data recording and interpreting."}
+{"text": "Contact electrochemical transfer of silver from a metal-film stamp  or a metal-coated scanning probe  is demonstrated to allow site-selective metallization of monolayer template patterns of any desired shape and size created by constructive nanolithography. The precise nanoscale control of metal delivery to predefined surface sites, achieved as a result of the selective affinity of the monolayer template for electrochemically generated metal ions, provides a versatile synthetic tool en route to the bottom-up assembly of electric nanocircuits. These findings offer direct experimental support to the view that, in electrochemical metal deposition, charge is carried across the electrode\u2013solution interface by ion migration to the electrode rather than by electron transfer to hydrated ions in solution. The quest for a chemical methodology applicable to the bottom-up fabrication of planned electric nanocircuits that can be effectively addressed from the external macroscopic world continues to pose major synthetic challenges. Metal growth or deposition on or within a preformed template structure has been successfully used in the fabrication of various metallic nanoscale objects and periodic nanostructures \u201312; howe3 groups of a self-assembled OTS/Si monolayer  to \u2013olecules ,16. The olecules \u20131518,27 ecules 15.contact electrochemical patterning and transfer (CEP\u2013CET), whereby OTSeo features are first printed or inscribed on a target OTS monolayer by using a stamp electrode consisting of a patterned silver film on OTS (Ag/OTS@OTS/Si) or a silver-coated SFM tip electrode, and then in-situ metallized by direct electrochemical transfer of the metal from the patterning electrode itself 30], respAll monolayer nanopatterning (CNL) and serial metallization (CET) operations were carried out in the contact mode , under controlled humidity at 55\u201365% RH. A SOLVER P47 SFM system (NT-MDT) was used in the fabrication of the OTSeo@OTS nanopatterns in 2C-coated HSC20 contact probes (Team Nanotec) were used in the inscription of the OTSeo lines, (under conditions similar to those mentioned above in relation to The serial CET experiments  were perFile 1Serial CET trial experiments and comparison of imaging results obtained under different SFM imaging conditions."}
+{"text": "Occluded Artery Trial (OAT) demonstrated that percutaneous coronary intervention (PCI) with optimal medical therapy does not reduce the frequency of major adverse events compared to optimal medical therapy alone when performed on days 3-28 post ST-elevation myocardial infarction (STEMI) in stable patients. However the assessment of infarct zone (IZ) viability was not used as an inclusion criterion in the this trial. Several studies in patients with stable coronary artery disease have shown that only patients with preserved myocardial viability benefit from revascularization.Therefore we decided to assess the frequency of IZ viability in patients fulfilling the criteria for randomization in the OAT trial.Until now the registry included 16 patients  screened for participation in the Cardiac magnetic resonance for the Occluded infarct-related Artery Treatment (COAT) trial  which is a single center randomized study conducted in the Institute of Cardiology in Warsaw to compare late revascularization with optimal medical therapy alone on days 3-28 post MI in stable patients with preserved IZ viability. Estimated enrollment into the randomized phase is 40 patients. Viability is defined as necrosis transmurality <50% in at least 4 segments of IZ on cardiac magnetic resonance. The primary end-point of the study is a change in systolic wall thickening (SWT) at 6 months. Secondary end-points include change in left ventricular ejection fraction (LVEF), wall motion score index (WMSI), end-diastolic and end-systolic left ventricular volumes .In the studied group 8 patients (50%) did not have preserved viability of the infarct zone. Patients with preserved IZ viability were randomized to late revascularization (4 patients) or optimal therapy alone (4 patients).Lack of preserved IZ viability in 50% of patients fulfilling the criteria for randomization in the OAT trial might have influenced the negative results of this trial regarding late revascularization in STEMI. Hypothesis tested in the ongoing COAT trial assumes that late opening of the occluded infarct-related artery only in patients with preserved myocardial tissue viability may lead to improvement of left ventricular function and/or volumes."}
+{"text": "Arabidopsis thaliana ovules initiate within the developing gynoecium from meristematic tissue located along the margins of the floral carpels. When fertilized the ovules will develop into seeds. SEUSS (SEU) and AINTEGUMENTA (ANT) encode transcriptional regulators that are critical for the proper formation of ovules from the carpel margin meristem (CMM). The synergistic loss of ovule initiation observed in the seu ant double mutant suggests that SEU and ANT share overlapping functions during CMM development. However the molecular mechanism underlying this synergistic interaction is unknown. Using the ATH1 transcriptomics platform we identified transcripts that were differentially expressed in seu ant double mutant relative to wild type and single mutant gynoecia. In particular we sought to identify transcripts whose expression was dependent on the coordinated activities of the SEU and ANT gene products. Our analysis identifies a diverse set of transcripts that display altered expression in the seu ant double mutant tissues. The analysis of overrepresented Gene Ontology classifications suggests a preponderance of transcriptional regulators including multiple members of the REPRODUCTIVE MERISTEMS (REM) and GROWTH-REGULATING FACTOR (GRF) families are mis-regulated in the seu ant gynoecia. Our in situ hybridization analyses indicate that many of these genes are preferentially expressed within the developing CMM. This study is the first step toward a detailed description of the transcriptional regulatory hierarchies that control the development of the CMM and ovule initiation. Understanding the regulatory hierarchy controlled by SEU and ANT will clarify the molecular mechanism of the functional redundancy of these two genes and illuminate the developmental and molecular events required for CMM development and ovule initiation.In flowering plants the gynoecium is the female reproductive structure. In  Arabidopsis thaliana, two rows of ovules develop from a ridge of meristematic tissue on the inner surface of the seed pod or gynoecium. Within the developing ovule primordia, much is known about molecular patterning events along the proximal to distal axis and the mechanisms of integument development In both gymnosperms and angiosperms, ovules are critical for reproductive competence. Ovules contain the female gametophyte and thus the egg cell. Additionally, upon fertilization the ovules develop into the seeds that nurture and protect the developing embryos. In Gynoecial development in Arabidopsis initiates at stage 6 of floral development  single mutant is nearly wild type while the aintegumenta (ant) mutant conditions the loss of about 50% of the ovule primordia. Together the loss of both the SEU and ANT activities in the seu ant double results in the complete loss of ovule initiation, indicating a synergistic genetic interaction and suggesting a degree of overlapping function for SEU and ANT during CMM development.A number of genes have been suggested to play a role in the maintenance of meristematic potential in the CMM and for the subsequent initiation of ovule primordia from the flanks of the CMM. While no single mutant has been reported to strongly disrupt ovule initiation, several higher order mutant combinations have been reported to disrupt the initiation of ovule primordia from the CMM SEU and ANT both encode transcriptional regulators ANT encodes an AP2-type DNA binding transcription factor that is expressed in all lateral organ primordia  ANT is expressed throughout the stage 6 gynoecial mound with a higher level of expression within the adaxial core  ANT is strong in the ovule anlagen and early ovule primordia as they arise. ANT activity during primordium development supports organ growth by maintaining the developmental period during which cell growth and cell divisions occur ANT has also been shown to contribute to proper specification of floral organ identity and polarity specification ANT regulation have not yet been published, PHB and cyclinD3 have been shown genetically to be downstream of ANT regulation ANT in organ polarity specification and regulation of cellular proliferation and/or organ growth.SEU encodes a transcriptional adaptor protein that is expressed widely throughout the plant SEU does not have a specific DNA binding activity but rather complexes with sequence specific DNA binding proteins in order to exert its effects on transcriptional regulation AGAMOUS (AG) expression during floral organ identity specification AG transcription through the recruitment of histone deacetylase proteins seu ant mutant is not conditioned simply by a de-repression of AG, but rather that SEU and ANT function to maintain or specify adaxial fate in the gynoecium and that this fate specification is critical for proper CMM development PHABULOSA (PHB) and REVOLUTA (REV) are reduced in the adaxial core of the stage 6 gynoecium in seu ant mutant plants. PHB and REV encode transcriptional regulators of the Homeodomain Leucine Zipper Class III type (HDZip-III) that are known to play a key role in the specification of adaxial identity in lateral organs SEU and ANT activity on HDZip-III expression was due to a direct or indirect regulation of their expression or accumulation. Additionally the defects in ovule and CMM development observed in the seu ant double mutant were not rescued when PHB activity was replaced, suggesting that either that PHB could not substitute for the other HDZip-III family members or that gene functions in addition to HDZip-IIIs are required downstream of SEU and ANT for CMM development ant rev double mutant, but not in ant phb double mutant support the idea of a functional differentiation between the PHB and REV activities within the CMM SEU and ANT that remain to be elucidated.A variety of experimental data suggest that the disruption of CMM development observed in the SEU and ANT are members of gene families whose members have been shown to share redundant function SEUSS-LIKE genes, SLK1, and SLK2 genetically enhance the ant mutant phenotype with respect to ovule initiation defects ANT-LIKE family member, AIL6, shares a critical redundant function with ANT as the ant ail6 double mutants flowers display reduced medial domain development and initiate very few ovule primordia ANT and the YABBY family members YAB1 and YAB3 is suggested by the synergistic disruption of ovule initiation observed in the ant yab1 and ant yab1yab3 mutants ant shatterproof1 (shp1) shatterproof2 (shp2) crabs claw (crc) mutants implicates the SHP MADS domain transcription factors in CMM development. These studies together highlight an important role for ANT function during CMM development and ovule initiation as well as reveal a high degree of functional redundancy within this tissue.Although no single mutant has been identified that eliminates CMM development or ovule initiation, a number of double mutant or higher order mutant combinations condition a severe disruption of the CMM and CMM-derived tissues (e.g. ovules) seu ant double mutant. In particular we sought to identify transcripts whose expression was dependent on the coordinated activities of SEU and ANT gene products. We hoped to both identify novel regulators of CMM development and to examine the molecular mechanism of the functional redundancy of SEU and ANT during CMM development. Our analysis identified a diverse set of transcripts that display altered expression in the seu ant double mutant tissues. Our in situ hybridization analyses indicate that many of these genes are preferentially expressed within the developing CMM. The analysis of overrepresented Gene Ontology classifications suggests a preponderance of transcriptional regulators including multiple members of the REPRODUCTIVE MERISTEMS (REM) and GROWTH-REGULATING FACTOR (GRF) families of transcriptional regulators are mis-regulated in the seu ant gynoecia. This study is the first step toward a detailed description of the transcriptional regulatory hierarchies that control the development of the CMM and ovule initiation.A number of key regulators of CMM development may be difficult to recover with standard forward genetic approaches due to a high degree of redundancy. Identifying genes that have specific patterns of spatial and temporal expression in the CMM would generate a set of candidate genes that could then be analyzed by reverse genetic approaches. In this paper we employ a transcriptomic profiling approach to identify sets of genes that are differentially expressed in the developing carpels of the seu ant double mutant relative to either single mutant. We isolated RNA from staged  and hand-dissected gynoecia to limit the developmental window of the sample to the period just before and then during ovule primordia initiation, the earliest steps of ovule development. This differentiates our work from that of the Gasser and Colombo groups that have focused on later ovule developmental stages when identifying ovule-specific transcripts In an effort to identify novel regulators of CMM development and ovule initiation we identified genes that are preferentially expressed within the CMM within the context of the gynoecium. Additionally we endeavored to prioritize genes whose expression is synergistically disrupted in the seu-3, ant-1, and seu-3 ant-1 double mutant). We first analyzed mRNA accumulation in each single mutant relative to the Col-0 wild type gynoecial samples. To identify transcripts whose steady-state levels were altered in the single mutants relative to wild type, we utilized a 1-way ANOVA and identified probe sets (transcripts) that displayed a statistically significant difference in accumulation by the genotype term. This analysis identified 120 under-expressed and 200 over-expressed transcripts in the seu single mutant and 219 under-expressed and 241 over-expressed transcripts in the ant single mutant (We utilized the Arabidopsis ATH1 Gene Chip (Affymetrix) to compare transcript levels between four different genotypes  over-represented GO terms suggest a role for this gene set in transcriptional regulation and relevant developmental processes, and 2) the reduced accumulation of these transcripts in the seu ant double mutant suggests that they may be preferentially expressed in the CMM in the wild-type gynoecium and, thus, are candidates for novel regulators of CMM development.We focused our attention on the genes that displayed seu ant double mutant we used a second analytical approach (Approach II) comprised of two steps. We first selected probe sets for which the mean expression was significantly lower in the seu or ant single mutant relative to wild type . These include AT1G02800 (ATCEL2), AT3G55560 (AGF2), AT5g57720 (REM15) AT2g46870 (NGA1), AT1G68640 (PAN), AT2G34710 (PHB), AT4G37750 (ANT), AT1G70560 (TAA1), AT5G18000 (VDD), AT3G17010 (REM22), and AT4G31610 (REM34 - previously AtREM1) PHB and TAA1) has been previously shown to be reduced in seu, ant or seu ant mutant gynoecia SEU and ANT have been implicated in the repression of AG in perianth organs, the levels of AG expression were not significantly different from wild type in the seu or ant single mutant gynoecial RNA samples . The Arabidopsis B3 superfamily consists of 118 genes all of which encode proteins containing one or more B3-type DNA binding domains. The B3 superfamily is comprised of four sub-families: REPRODUCTIVE MERISTEM); LAV (LEAFY COTYLEDON2[LEC2]-ABSCISIC ACID INSENSITIVE3 [ABI3]-VAL); ARF(AUXIN RESPONSE FACTOR);REM ( and RELATED TO ABI3RAV( and VP1). Six of the seven B3 regulators that were identified in our transcriptomics approach are from the REM subfamily for which there is little functional data. Four of these genes, AT4G31610 (REM34/AtREM1), AT5G18000 (VDD), At5G57720 (REM15) and AT3G17010 (REM22), have been previously reported to display CMM-enriched expression Surprisingly, seven out of the 31 Approach II candidate genes were members of the  factors  [49],  with experiment number (E-MEXP-3293).Two analyses were run on our data. The first was a simple 1-way ANOVA by genotype. This method identified genes with expression levels that were statically different from that of the mean of the expression values. Class variables were specified as the genotype and the genotype was modeled as a fixed effect. The data was not compared to any baseline, but the LSMeans were run for simple differences of genotype using pFDR for the multiple testing method with an alpha of 0.05. Additionally we required that log2 of the magnitude of the expression level difference between the compared genotype means was greater than 0.35. The fixation method for the data points with large residuals was set as the False Positive Rate and the LSMeans standardization rate was set for Standard Deviation. The second analysis method (Approach II) was directed at detecting genes whose expression was synergistically affected in the enes See . Gene liseu, ant, and seu ant genotypes. Each biological replicate was assayed in triplicate. Results in ADENOSINE PHOSPHORIBOSYL TRANSFERASE1 . Results shown are the average expression normalized to APT1 and the standard error of the mean for four biological replicates. APT1 was shown to be unaffected by genotype in our gynoecial RNA samples by comparison of APT1 expression levels with two other standards  across the four genotypes. Statistical analysis of one way ANOVA was conducted in JMP8  using a Tukey-Kramer HSD test and a p value cutoff of 0.05. Sequences of the oligonucleotides used for qRT-PCR analysis are described in in situ hybridizations were carried out as reported previously http://www4.ncsu.edu/~rgfranks/research/protocols.html.For analysis of transcript abundances, RNA from stage 8\u201310 gynoecia isolated for microarray analysis (pre-amplification) was used. cDNA synthesis and qRT-PCR were performed as previously described Table S1seu single mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S2Genes over-expressed (increased accumulation) in the seu single mutant via one way ANOVA.(XLS)Click here for additional data file.Table S3ant single mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S4ant single mutant via one way ANOVA.Genes over-expressed (increased accumulation) in the (XLS)Click here for additional data file.Table S5seu single mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S6seu single mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S7ant single mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S8ant single mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S9seu ant double mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S10seu ant double mutant via one way ANOVA.Genes over-expressed in the (XLS)Click here for additional data file.Table S11seu ant double mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S12seu ant double mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S13Sequences of oligonucleotides used for qRT PCR analysis of candidate gene expression.(XLS)Click here for additional data file.Table S14Output from JMP Genomics (SAS) ANOVA analysis with values for estimate builder (non-additivity) model for double mutant.(XLS)Click here for additional data file."}
+{"text": "To identify the origin of synchronous and metachronous urothelial carcinoma (UC) of the bladder and upper urinary tract to get a better understanding of the basic mechanism behind the multifocality of UC, which may provide a sound bases for the future development of new strategies for detection, prevention and therapy.Six patients with UC of the bladder and synchronous or metachronous UC of the upper urinary tract were studied. Genetic analysis involving the study of loss of heterozygosity (LOH) has been evaluated on their tumours using well characterised and new markers of UC .Five of the six patients demonstrated informative results. Four of five (80%) of patients had synchronous or metacharonous UC tumour and showed patterns of LOH consistent with tumorigenesis from monoclonal tumour origin. One of five (20%) patients exhibited a LOH consistent with oligoclonal tumorigenesis.These findings suggest that both the monoclonal and field cancerization theory of tumorigenesis may play a role in tumors of the urothelial tract. However, more data is needed. Urothelial carcinoma (UC) of the bladder is the fifth most common solid cancer in the industrialized world  as a measure of clonality   model exposed to known carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine has shown oligoclonal tumour development in 30% of mice, suggesting that the field defect means of tumorigenesis plays a significant role in cancer of urothelial tract  with UC of the UUT and synchronous or metachronous bladder UC that underwent surgical excision of their tumours were identified. These patients underwent nephroureterectomy for their UUT tumour(s) and transurethral resection of their bladder tumour(s). All tumours excised were high grade UC. The patients were not treated with any radiotherapy or chemotherapy prior to their surgical resection. Patients had not received any intravesical chemotherapy or immunotherapy for the bladder tumours. Tissue sample and microdissection: Formalin fixed paraffin embedded archival tissue was cut to 5um sections, and stained with haematoxylin and eosin for microscopic evaluation. Pathological identification of tumours was done with guidance of pathologist. Laser assisted microdissection of neoplastic tissue was performed using the PixCell II Laser-Capture Microdissection\u00ae apparatus  was used to amplify genomic DNA at four specific loci on two different chromosomes: 9p21 (D9S171), 9q32 (D9S177), 9q22 (D9S303) and 17p13 (TP53). D9S171 is associated with tumour suppressor gene p16, a well characterized marker of early bladder tumorigenesis  was examined in 6 patients. Of the six patients, five patients showed informative results (83%) in one of the four loci studied. However, no patient showed informative results through all four loci  with informative loci showed a monoclonal pattern of LOH, while only one of five patients (. (20%) showed an oligoclonal pattern of LOH. Unfortunately, the patient with the oligoclonal pattern of LOH was male, and a confirmatory x-inactivation study could not be conducted. These findings are consistent with results seen by Sidranksy et al.  Habuchi   while the overgrowth of one clone in late stages tumorigenesis (high-grade tumours) may result in pseudomonoclonality  or intraepithelial spread. In one of case however, there was evidence for tumour that may arise independently, consistent with the field cancerization model. This suggest that although the single cell theory of tumorigenesis may be the predominate means of UC progression, the field cancerization model may also play a small albeit significant role, which must not be overlooked when considering appropriate treatments modalities, and when using molecular diagnostic techniques to diagnosis and monitor for disease recurrence."}
+{"text": "Right heart catheterization (RHC) is required for definitive diagnosis of pulmonary hypertension (PH) and serial echocardiograms or RHC are necessary for long term disease management. However, RHC is invasive, costly and risky for the patient. EchocarTo evaluate the use of Cardiac MR for measuring right ventricular parameters in order to assess Pulmonary Hypertension.23 patients with PH and 12 controls underwent CMR on a 1.5T Siemens Avanto scanner. All patients underwent RHC to diagnose PH within 1 month of CMR study. The CMR protocol included cine SSFP of the whole heart and phase contrast MRI of the pulmonary valve (PV). The following conventional right ventricular (RV) functional parameters were calculated: ejection fraction (EF), end diastolic volume (EDV) and end systolic volume (ESV). Time to peak systole (TPS), an indirect measure of RV strain, was derived from the volume-time curves of the RV. PV flow analysis was performed and the following parameters were calculated: peak velocity, full-width at half maximum (FWHM), acceleration time (AT) and ejection time (ET).The results of RV functional parameters and PV flow values are shown in Tables TPS, calculated by CMR, may be a useful additional quantitative measure for diagnosis of PH and may be of value in long-term non-invasive assessment of treatment efficacy."}
+{"text": "Microthrombosis has been demonstrated in early and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Markers of coagulation activation as microparticles (MPs) are an established risk factor for thrombosis. Our hypothesis was that levels of microparticles might correlate with aSAH severity, early cerebral ischemia (ECI) and delayed cerebral ischemia (DCI).Consecutive aSAH patients (age 18 to 80) admitted to our department between November 2011 and September 2012 were enrolled in the study. Total MPs (anxV+), platelet MPs , tissue factor MPs , and endothelial MPs  were assessed in venous blood samples. Measurement of MPs levels were obtained at early (<3 days) and delayed phase (7 to 10 days). Multiparameter MRI  was performed to evaluate ischemic damage and vasospasm at the same time points. Qualitative evaluation of severity of ischemic damage was performed on DWI sequences. Levels of MPs were evaluated comparing different groups in terms of SAH severity , ECI severity and occurrence of delayed complications (vasospasm and DCI).n = 9) when compared with WFNS 1 to 2 (n = 16) patients. Interestingly, patients with most severe ECI and DCI showed the highest values of MPs, but this trend did not reach statistical significance, probably because of the small number of patients included in the study.Twenty-five patients  were included in the analysis. Overall increased levels of MPs were observed at early phase after aSAH when compared with controls. Contrarily to our hypothesis, in the early phase no significant differences of MP level were observed in WFNS 4 to 5 (Microparticles and microthrombosis may increase the severity of early and delayed ischemic damage after aSAH."}
+{"text": "Studies report that women with Rheumatoid Arthritis (RA) are not wearing therapeutic footwear. It is likely they are wearing normal retail footwear. Previous research gives limited information on people\u2019s perceptions on the relationships that exist between retail footwear, well-being and quality of life (QOL). This study aimed to explore these perceptions and to identify the factors influencing footwear selection.Eleven women with RA wearing retail footwear were recruited from an out-patient podiatry clinic in the south east of England. Semi-structured interviews were carried out and a hermeneutical approach; interpretative phenomenological analysis of transcripts occurred to identify recurring themes.Six main themes were revealed from the analysis. These included: (1) the nature of foot complaints and deformities, (2) aesthetic appearance and design of footwear, (3) body image, (4) psychosocial aspects, (5) Perceptions of footwear and (6) the therapeutic value of retail shoes.Retail footwear for these women with RA has impacted on their individuality which has been shown to link significantly with their body images. Whilst footwear itself has not impacted solely on the well-being of these women; the disease process has. These consequences have been identified in their quality of life."}
+{"text": "Tau pathology is characteristic of Alzheimer\u2019s disease (AD) and related tauopathies including Parkinson\u2019s disease (PD) wherein a significant percentage of PD patients who develop dementia harbor AD-like tau pathology. Tau pathology is characterized by insoluble filamentous aggregates of hyperphosphorylated tau in CNS neurons known as neurofibrillary tangles (NFTs) and neuropil threads (NTs). NFTs and NTs are implicated in mechanisms of neurodegeneration through gains of toxic functions or losses of normal tau functions. Hyperphosphorylation and decreased solubility of tau leads to a loss of the ability of tau to bind to and stabilize microtubules (MTs) which impairs axonal transport and results in neuronal dysfunction and degeneration. This presentation describes the use of MT stabilizing drugs to counteract the loss of tau function and prevent/ameliorate tau mediated neurodegeneration in a transgenic (Tg) mouse model of an AD-like neurodegenerative tauopathy. Briefly, proof of concept prevention and intervention studies of the brain-penetrant MT-stabilizing agent epothilone D (EpoD) are described in young (prevention) and aged (intervention) P301S mutant tau Tg mice (PS 19 mice) with little (young PS 19 mice) or abundant tau pathology and behavioral impairments (aged PS19 mice). In the prevention and intervention studies, EpoD treatment reduced axonal dystrophy and increased axonal MT density which led to improved neuronal integrity and cognitive performance. EpoD treatment also improved fast axonal transport in the aged PS19 Tg mice. Unexpectedly, aged PS19 mice treated with EpoD showed a marked reduction in forebrain tau pathology and increased hippocampal neuronal integrity. There were no dose-limiting side effects in the EpoD treated young and aged PS19 mice. These studies support the view that EpoD and other brain-penetrant MT-stabilizing drugs offset the loss of tau function in neurodegenerative tauopathies and therefore are potential therapeutics for the treatment of AD and related tauopathies. Finally, a new seeded transmission model of tauopathy is presented using injections of preformed tau fibrils into the brains of PS19 mice which presents new opportunities to assess the efficacy of MT stabilizers and other potential passive immunization therapies for AD and related tauopathies.Supported by grants from the NINDS/NIA."}
+{"text": "The overall outcome of HIV disease may depend on the host's capacity to maintain dendritic cell (DC) homeostasis at mucosal sites, where DC populations, one of the earliest cell types to be exposed to the virus, present an inherent capacity to modulate the balance between tolerance and protection. DCs may influence mucosal B cell responses against HIV through contact and/or production of B cell growth factors such as B lymphocyte stimulator (BLyS/BAFF), which in turn modulate the outcome of CD4[superscript]+[/superscript] T cell HIV effectors/targets. Recent observations of HIV/SIV infections in non-pathogenic animal models and from mucosal vaccination of nonhuman primates suggest that maintenance of systemic integrity may be achieved through constraining highly efficient immune responses to mucosal sites.B lymphocyte disorders are important consequences of HIV infection  mice Indeed, there is an increasing body of experimental evidence demonstrating the role of B cells in regulating the development, proliferation, and maintenance of CD4+ T cell HIV effectors/targets. Recent observations of HIV/SIV infections in non-pathogenic animal models and from mucosal vaccination of nonhuman primates suggest that maintenance of systemic integrity may be achieved through constraining highly efficient immune responses to mucosal sites.The overall outcome of HIV disease may depend on the host's capacity to maintain dendritic cell (DC) homeostasis at mucosalsites, where DC populations, one of the earliest cell types to be exposed to the virus, present an inherent capacity to modulate the balance between tolerance and protection. DCs may influence mucosal B cell responses against HIV through contact and/or production of B cell growth factors such as B lymphocyte stimulator (BLyS/BAFF), which in turn modulate the outcome of CD4BLyS expression levels correlate with both the extent to which the B cell compartment is compromised and HIV disease progression status. The fact that HIV elite controllers expressed relatively low levels of BLyS suggest that therapeutic blockage of BLyS in HIV progressors may restore balanced effector to regulatory cell ratios to reduce both HIV target cells and systemic immune activation that are the hallmarks of HIV disease progression."}
+{"text": "We show that intracerebral injection of such isolates into C57BL/6 mice produces a disease with preservation of PrPres molecular features distinct from BSE.We previously reported that cattle were affected by a prion disorder that differed from bovine spongiform encephalopathy (BSE) by showing distinct molecular features of disease-associated protease-resistant prion protein (PrP Characterization of the infectious agent associated with BSE showed unique features. These include defined incubation periods and distribution of brain lesions after transmission to wild-type mice, not only directly from cattle, but also after natural or experimentally induced cross-species transmission (res) accumulating in the brains of animals and humans with BSE have demonstrated specific molecular features. These include a low molecular mass of unglycosylated PrPres with high proportions of diglycosylated PrPres  and decreased levels of diglycosylated PrPres when compared with BSE isolates  and labeling with P4 monoclonal antibody  C57BL/6 female mice  were injected intracerebrally with 20 \u03bcL of 10% (weight/volume) homogenates per mouse prepared from brain stem samples of 3 cattle TSE isolates. Two of the isolates were characterized, as previously described   or Supersignal  and visualized either on film  or directly in an image analysis system . Molecular masses of PrPres glycoforms were determined as the average of the center positions of the bands from at least 3 repeated electrophoretic procedures, as measured by comparison with a biotinylated marker  included on each gel. Immunologic reactivities of antibodies 12B2 and Sha31 were compared in Western blots run in parallel with the same samples with both antibodies.Frozen mouse brain tissues and fixed brain tissues were examined by Western blot analysis and immunohistochemical tests as previously described (res detection among mice analyzed by Western blot are shown in the Table.After intracerebral injection of cattle brain samples into C57BL/6 mice, disease was observed in mice with the 2 H-type isolates, as well as with the BSE sample. Survival periods of mice and results of PrPres from H-type\u2013infected mouse brains in comparison with BSE-infected mice is shown in res glycoforms in mice infected with H-type isolates than in mice infected with a typical BSE agent (1.1- to 1.5-Da difference in the unglycosylated PrPres (res protease cleavage showed that only the PrPres of mice infected with H-type isolates was recognized by antibody 12B2 (Western blot analysis of PrPd PrPres A. Studieody 12B2 B. This fHistopathologic analysis showed vacuolar lesions in the thalamus A that weres molecular signature. This evidence in favor of a new bovine prion strain in cattle suggests that BSE is not the only transmissible prion disease in cattle. The origin of such cases has not been determined (res after infection with the BSE agent. However, based on analysis of molecular features of prion diseases in cattle, this situation is similar to that in humans (Our data show that the recently identified bovine H-type isolates involve an infectious agent that can induce development of a disease across a species barrier, while maintaining the specific associated PrP"}
+{"text": "Objectives: To investigate cognitive components and mechanisms of learning and memory in primary progressive aphasia (PPA) using a simple clinical measure, the Three Words Three Shapes Test (3W3S).Background: PPA patients can complain of memory loss and may perform poorly in standard tests of memory. The extent to which these signs and symptoms reflect dysfunction of the left hemisphere language versus limbic memory network remains unknown.Methods: 3W3S data from 26 patients with a clinical diagnosis of PPA were compared with previously published data from patients with typical dementia of the Alzheimer type (DAT) and cognitively healthy elders.Results: PPA patients showed two bottlenecks in new learning. First, they were impaired in the effortless (but not effortful) on-line encoding of verbal  items. Second, they were impaired in the retrieval (but not retention) of verbal  items. In contrast, DAT patients had impairments also in effortful on-line encoding and retention of verbal and nonverbal items.Conclusions: PPA selectively interferes with spontaneous on-line encoding and subsequent retrieval of verbal information. This combination may underlie poor memory test performance and is likely to reflect the dysfunction of the left hemisphere language rather than medial temporal memory network."}
+{"text": "Research indicates a clear need for easily accessible interventions of different lengths and intensity for individuals with problematic substance use. Internet interventions with therapist support for problematic alcohol use have yielded positive results in prior studies, but have never been investigated in Sweden. This pilot study tested an online structured relapse prevention program with and without therapist support. 80 internet help-seekers from the general population were recruited through a national self-help site and randomized into three groups: 1) therapist support via secure messages (n=20); 2) a choice between therapist support via messages or live chats (n=20); 3) self-help (n=40). Baseline data showed no significant differences between the three groups concerning age, gender, Time Line Follow Back (TLFB), Alcohol Use Disorders Identification Test (AUDIT), Readiness to Change Questionnaire (RTCQ) and Quality of Life (WHOQOL). In the group with a choice between messages and chat, 35% chose chat. All follow-up data for the study have recently been collected, and results will be analyzed for presentation at the conference. This study has the potential to further broaden knowledge about internet-based interventions for problematic alcohol use, and provide information about the significance of therapist support."}
+{"text": "Neurons of the striatum receive important glutaminergic input from the cortex and thalamus and massive dopaminergic innervation from midbrain dopamine neurons. The majority (95%) of striatal neurons are medium spiny projection neurons and 5% are aspiny interneurons. The projection neurons are GABAergic and form the direct and indirect striatal output pathways that have been shown to be crucial for normal motor function and appetitively motivated learning. The importance of the medium spiny projection neurons is highlighted by the severe debilitation associated with the loss of their dopaminergic input in Parkinson\u2019s disease or degeneration of these cells in Huntington\u2019s disease . Approximately half of all medium spiny striatal neurons express the dopamine D1A receptor (Drd1a) and these neurons comprise the direct output pathway to the medial globus pallidus and substantia nigra pars reticulata . Early deletion of the Drd1-expressing striatal neurons in mice results in severe motor impairment, eating deficits and reduced striatal volume . In order to separate potential developmental effects from the normal role of the Drd1a-expressing striatal cells in adult mice, we have made a mouse model that allows for the inducible deletion or expression of targeted genes specifically within the Drd1a-expressing striatal neurons using BAC transgenesis.A bacterial artificial chromosome (BAC) designated RP23-47M2 was obtained from BACPAC resources of the Children\u2019s Hospital Oakland Research Institute (CHORI). This BAC contains the Drd1a locus. Using the techniques of bacterial homologous recombination , a cassette containing the reverse tetracycline-controlled transactivator (rtTA) fused to the herpes simplex virus VP16 transactivator was inserted at the ATG start site of the Drd1a locus. Transgenic mice with the modified BAC randomly integrated into their genomes were produced by microinjection of the modified BAC into mouse zygotes at the University of Michigan Transgenic Core. Transgenic mouse lines carrying the rtTA allele were crossed with reporter transgenic mice carrying the allele for tetO-lacZ. In bi-transgenic mice this approach (TET-ON) allows for the activation of the tet operator by rtTA in the presence of doxycycline (DOX). Therefore, during DOX administration, the lacZ gene produces \u03b2-galactosidase which can be detected through X-gal staining.Drd1a-rtTA/tetO-lacZ lines were screened and at least one line to date has shown strong expression specifically within the mouse striatum. X-gal staining is present throughout the striatum, with somewhat higher levels in the medial aspects of the structure. We are continuing to screen additional lines and are determining the minimal parameters of DOX administration (dose and duration) necessary for the inducible expression of rtTA/VP16.We have made the first inducible Drd1a TET-ON mouse. This mouse, in conjunction with other transgenic models, will allow for the inducible expression or deletion of target genes specifically within Drd1a-expressing cells and will be highly useful in the study of Parkinson\u2019s and Huntington\u2019s diseases, addiction and the normal role of Drd1a-expressing cells."}
+{"text": "Adverse drug reactions (ADR) appear more frequently then what is actually reported and registered. The aim was to establish an intensive monitoring system and to analyze ADR in hospitalized patients.The prospective study covered 200 patients hospitalized in the Cardiology Center, Clinical Center of Montenegro. ADR were recorded in the following way: patients were interviewed on the basis of a symptoms list and any signs which could point to eventual ADR. Secondly, lab tests and other available parameters were monitored.At the time when interviews took place, patients received on average 8.0 \u00b1 2.6 medicines (2\u201317). In total, 67 patients (33%) had 75 ADR. Twenty one ADR (28%) are classified as serious. Fifty four ADR resulted in the recovery of the patient (72%), eight had as an outcome prolonged hospitalization (11%), another eight were life threatening (11%), while five ADR (6%) were the cause of the hospitalization. The most frequent ADR which had as an outcome admission to hospital were caused by digoxin (40%), prolonged hospital stay by furosemide (38%), while the most frequent registered ADR which were life threatening were caused by streptokinase (50%).Monitoring ADR in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and accompanying diseases. Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions induced by this class of medicinal products seems necessary. Additional educational efforts could affirm the rationalization of the pharmacotherapy."}
+{"text": "Background: Recent findings strongly promoted the hypothesis that common pelvic gynecological diseases including endometriosis and ovarian neoplasia may develop de novo from ectopic endometrial-like glands and/or embryonic epithelial remnants. To verify the frequency, the anatomical localization and the phenotype of misplaced endometrial tissue along the fetal female reproductive tract, histological and immunohistochemical analyses of uteri, fallopian tubes, and uterosacral ligaments were performed. Methods: Reproductive organs were collected from seven female fetuses at autopsy, five of them from gestational ages between 18 and 26\u2009weeks and two fetuses with gestational ages of 33 and 36\u2009weeks deceased of placental anomalies. Serial sections from areas containing ectopic glands and embryonic duct residues were analyzed by histological and immunohistochemical procedures. Results: Numerous ectopic endometrial glands and stroma were detected in the myometrium in two fetuses with low levels of expression of estrogen receptor-alpha (ER-\u03b1) and progesterone receptors (PR). The embryonic ducts were localized in the uterine broad and ovarian ligaments and under the fallopian tube serosa in six fetuses. Low levels of steroid receptors expression were found in the embryonic residues, whereas the carcino-embryonic antigen (CEA) and the tumor marker Ca 125 were not detected. The embryonic residues stromal component strongly expressed the CD 10 and vimentin proteins. Conclusion: The anatomical and the immunohistochemical features of the ectopic organoid structures identified in fetal female reproductive tract suggest that endometriotic as well as neoplastic disease in adult women may develop on the basis of misplaced endometrial glands and/or embryonic cell remnants. Endometriosis is a heterogeneous gynecological disease clinically characterized by the presence of different anatomo-clinical subtypes Giudice, . The mosIn the present study, we evaluated the incidence and the anatomical location of displaced endometrial tissue in the reproductive tract in seven female fetuses. Serial sectioning of the reproductive organs was realized followed by immunohistochemical analysis of tissue areas containing ectopic glands and embryonic cell rests. It was observed that the anatomical and the phenotypic features of the mislocated tissue components recall some pathological characteristics of both benign and malignant gynecological conditions.Reproductive organs from a series of seven human female fetuses at different gestational ages ranging from 18 to 36\u2009weeks were obtained at autopsy. All together, the causes of fetal death were placental pathology in two samples, cardiac malformations in two cases and voluntary abortions in three. The reproductive organs were carefully dissected, fixed in buffered formaldehyde, and included in paraffin.Between 200 and 400 serial sections with thickness of 5\u20137\u2009mm from each paraffin block containing uteri, fallopian tubes, ovaries, and uterosacral ligaments were prepared and stained by hematoxylin and eosin (H&E). To ascertain tissue sections containing ectopic endometrial glands and/or embryonic duct remnants, every sixth slide was separately stained and microscopically analyzed.The following antibodies were employed; rabbit anti estrogen receptor-alpha (ER-\u03b1), ; monoclonal mouse anti human progesterone receptor, clone PR 636 ; monoclonal anti human CA125, clone M11 CA125 (Dako); monoclonal anti human CD10 clone 56C6 (Dako); monoclonal anti human carcino-embryonic antigen (CEA) clone II-7 (Dako); rabbit anti human alpha-1-foetoprotein (Dako); monoclonal anti human epithelial membrane antigen (EMA) clone E29 (Dako); mouse anti human Cytokeratin 7  and monoclonal mouse anti-vimentin clone VIM 3B (Dako).Five micrometres thick sections were deparaffinized in xylene, rehydrated through graded alcohol series, and washed in PBS. For antigen retrieval, the slides were immerged in citrate buffer (pH\u2009=\u20096.0) during 25\u2009min at 96\u00b0C essentially as described , PR (14%), and ER-\u03b1 (6%) was revealed in the ectopic glandular structures localized in the uterine wall. A strong expression of CD10 (41.3%) but lower level of vimentin specific immunolabeling (20%) was observed in the stromal component surrounding the displaced glands. Representative illustrations of PR expression in orthotopic endometrial cells as well as the expression of PR, ER-\u03b1, and CD10 in the uterine ectopic glands and stroma are shown in Figures Concerning the embryonic remnants, consistent EMA immunostaining ranging between 32 and 53% was detected in the duct lining cells, while lower level of expression in duct cells of both ER-\u03b1 10\u201323%) and PR (13\u201344%) molecules was found in all samples. The stromal-like component surrounding the duct residues contained between 1 and 3% of immunoreactive cells for ER-\u03b1 and between 4 and 13% of immunoreactive cells for PR. Approximately 2\u201311% of the ductal cells and 1\u20133% of the stormal cells expressed cytokeratin 7, while CEA and CA125 molecules were not detected. Using anti alpha-1-fetoprotein antibody, close to 42% of the epithelial and duct surrounding mesenchymal cells were intensely immunoreactive on sections from two fetuses. Representative illustrations of the embryonic duct residues labeled with anti ER-\u03b1, anti PR, anti alpha-1-fetoprotein and anti CD10 antibodies are shown in Figures 0\u201323% andIn this study we show presence of misplaced endometrial glands and embryonic duct-like remnants in the reproductive organs in six of seven examined female fetuses. The phenotypic features of the ectopic glands in the myometrium of two fetuses indicate particularly weak expression of PR and ER-\u03b1 steroid hormone receptors in comparison to their high level of expression in cells lining the endometrial cavity. In these two cases, moderate level of PR expression was also revealed in the cell nuclei of the stromal component, while ER-\u03b1 receptors were not found. Overall, the presented findings are in accordance with other studies describing the levels of ER-\u03b1 and PR in misplaced glands in patients with both endometriosis and adenomyosis (Van der Walt et al., Concerning the foci of embryonic duct remnants observed, moderate expression of PR and low levels of ER-\u03b1 were uniformly revealed in the epithelial cells in all cases. Histologically, some ducts appeared dysplastic and surrounded by a dense cellular stromal layer consistently expressing vimentin and CD10 molecules. Of interest, these tubular structures in most of the samples did not clearly express cytokeratin 7, and Ca 125 protein molecules. This might be related to particular phenotypic features of coelomic metaplastic cell rests at given gestational age (Batt and Smith, de novo expression of this protein in ovarian malignancy arising from endometriosis (Horiuchi et al., In spite of the limited number of studied cases, the findings of ectopic glands and/or embryonic ducts in the reproductive tract of female fetuses is a remarkable phenomenon that could be referred to the theory of involvement of M\u00fcllerian or Wolfian cell rests in the pathogenesis of both endometriosis and particular pelvic malignancies Fujii, . At presIn conclusion, the presented data support the theory that at least some subtypes of endometriotic and gynecological neoplastic lesions may be related to anomalies occurring during the embryogenesis. These data stand in relationship with the embryological origin of certain pelvic malignancies based on the metaplastic potentiality of the secondary M\u00fcllerian system. The observed frequency of displaced embryonic structures, also suggests a complex pathogenetic mechanism in the development of endometriosis-associated neoplasms including genetic, hormonal, and/or environmental events. Consequently, further studies of endometriotic and neoplastic lesions should include novel embryonic cellular phenotypic markers, that could provide important diagnostic and predictive information to guide clinical decision making.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Our objective was to investigate the molecular mechanism underlying the processing of proBNP, levels of which are increased in heart failure ,2.Rat neonatal atrial and ventricular myocytes were cultured separately. We examined: (1) the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; (2) levels of corin and furin mRNA in atrial and ventricular myocytes and the effect their knockdown on proBNP processing; (3) molecular forms of BNP in plasma from rats and humans with and without heart failure; (4) the structure of proBNP in humans and rats; (5) the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP expressed in rat myocytes transfected with lentiviral vectors.BNP was the major molecular form secreted by atrial (75\u00b19%) and ventricular (85\u00b19%) myocytes, and was the major intracellular form in atrial myocytes (60\u00b15%). ProBNP was the major intracellular form in ventricular myocytes (58\u00b14%). The relative levels of furin mRNA correlated with those of BNP in atrial and ventricular myocytes, and transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes. BNP was the major molecular form in rat plasma 90\u00b110%), whereas proBNP was the major form in human plasma (72\u00b18%). The relative fraction of human BNP in rat myocytes expressing human proBNP was 60\u00b15%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly (Figure 0%, whereO-glycosylation and cleavage sites in humans.These results suggest that proBNP is processed into BNP and N-terminal proBNP intracellularly, most likely by furin in rat. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the"}
+{"text": "From a methodological point of view, these results demonstrate the suitability of computing bilateral CoP trajectories regularity for the assessment of lateralized postural control under pathological conditions.The present study was designed to assess the relative contribution of each leg to unperturbed bipedal posture in lower limb amputees. To achieve this goal, eight unilateral traumatic trans-femoral amputees (TFA) were asked to stand as still as possible on a plantar pressure data acquisition system with their eyes closed. Four dependent variables were computed to describe the subject's postural behavior: (1) body weight distribution, (2) amplitude, (3) velocity and (4) regularity of centre of foot pressure (CoP) trajectories under the amputated (A) leg and the non-amputated (NA) leg. Results showed a larger body weight distribution applied to the NA leg than to the A leg and a more regular CoP profiles  with greater amplitude and velocity under the NA leg than under the A leg. Taken together, these findings suggest that the NA leg and the A leg do not equally contribute to the control of unperturbed bipedal posture in TFA. The observation that TFA do  In recent years, a growing number of studies have been designed to explore the dynamical structure of the centre of foot pressure (CoP) trajectories in terms of entropy (regularity/predictability) to provide more insight into mechanisms involved in the control of bipedal unperturbed stance  , with feet parallel separated by 10 cm, and their arms hanging loosely by their sides. This system includes capacitive force sensors arranged in matrix form  body weight (BW) distribution, (2) amplitude (On the one hand, to quantify the amount of postural sway under each leg, the root mean square of the CoP displacements (The means of the three postural measurements recorded were used for statistical analyses. BW distribution,"}
+{"text": "This review aimed to ascertain the extent to which the issue of departure from treatment protocol (DTP) is reported and addressed in published analyses of RCTs.One hundred publications of RCTs were randomly selected from those published in the BMJ, NEJM, JAMA and Lancet during 2008. Each trial report was reviewed to determine the extent and nature of reporting on DTP and whether statistical methods were used to deal with DTP for both benefit and harms analyses.Even the most basic adherence information was not presented in some trials. Forty-two publications did not state how many patients actually initiated their randomised treatment. Information about treatment discontinuation can be vague and may not allow assessment of the number of patients who completed the treatment protocol.Ninety-eight publications reported at least one form of DTP, including non-receipt of allocated treatment , incomplete treatment in those who initiated allocated treatment (78), switching trial treatments (12), starting disallowed/non-trial treatment (4), starting open label treatment out of trial (7), contamination across groups (3) and other nonadherence to treatment dose or schedule (23). Treatment providers were reported to be nonadherent when delivering treatment in 12 trials.More than half (50 (51%)) of the publications that reported DTP used some method to deal with it, but none were based on randomisation-preserving techniques. The most common method was based on per protocol (PP) analysis (46) (including one instance of using inverse probability of censoring weighting) often labelled as intention to treat (ITT) (18) or modified ITT (5), but missing data techniques (2) and as treated analyses (3) were also implemented. Less than 40% (26) of the 69 trials which presented harms analyses specifically defined harms analysis populations, and the majority of these definitions were based on actual treatment received (18). The majority (31) of the 43 trials that did not explicitly specify harms analysis population appeared to analysed harms outcomes using ITT. Twelve reports explicitly commented on the fact that DTP was likely to have influenced the observed treatment effect.DTP data presented in RCT publications, particularly related to treatment initiation and discontinuation, may be ambiguous or scant. Trialists often attempt to deal with DTP using variations of PP analysis, although they may be labelled as ITT; randomisation-preserving methods are not typically used. There appears to be confusion among trialists over the appropriate analysis population for harms outcomes in the presence of DTP."}
+{"text": "Self-transcendence (ST) is one of specific human experiences often related to harmony with nature or feeling oneness with others or the self as an integral part of the whole universe. The Temperament and Character Inventory (TCI) is a widely used personality measure, and ST is one of personality dimensions  and body cooperation indexed by central (CNS) and autonomic (ANS) nervous system interaction (Cahn and Polich, In summary, growing empirical evidences indicate meditation has potential to develop ST\u2014a positive relationship between self and other that transcends self-focused needs and increases prosocial characteristics (H\u00f6lzel et al.,"}
+{"text": "Haemodynamic monitoring is essential for the management of critically ill patients. Currently there are various techniques available in clinical practice to measure cardiac output (CO) in ICUs including pulmonary artery catheter (PAC), oesophageal Doppler, lithium dilution cardiac output (LiDCO) and pulse-induced contour cardiac output (PiCCO) studies. In recent times PAC has been used less with less invasive methods becoming more popular. We conducted a telephone survey of the current CO monitoring practices in adult ICUs in the United Kingdom.All general adult ICUs in the United Kingdom were surveyed via telephone. The nurse-in-charge or the senior physician for the shift was consulted to ascertain which cardiac output monitors (COMs) were available for use, which was their first choice and if they used PAC in the past 12 months.A total of 225 adult ICUs were surveyed and all the replies were recorded on paper (98% response). Two hundred and eleven (96%) units used at least one form of COM while the rest of the 14 units did not use any COM tool. One hundred and two (48%) use more than one form of cardiac output monitoring. Oesphageal Doppler was most popular , followed by LiDCO and PICCO both used in 73/211 (35%) of the units, and pulse contour analysis . Seven out of 211 (3%) units still use PAC as the preferred method of COM, of these two had other COM devices available and five used PAC only. Forty-six out of 211 (22%) units were using PAC at least occasionally. In contrast, a similar survey performed in 2005 [The results show the changes in COM over the past 5 years in comparison with a previous survey in 2005 . There a"}
+{"text": "National and international guidelines on antiretroviral therapy for HIV infection recently changed to recommend earlier treatment, following the publication during 2009 of two collaborative analyses of HIV cohort studies ,2. These"}
+{"text": "However, the detection of other genomic variants remains a challenge due to the lack of appropriate tools for heterozygous base-calling fluorescence chromatogram data analysis. In this study, we developed a free web-based program, Mixed Sequence Reader (MSR), which can directly analyze heterozygous base-calling fluorescence chromatogram data in .abi file format using comparisons with reference sequences. The heterozygous sequences are identified as two distinct sequences and aligned with reference sequences. Our results showed that MSR may be used to (i) physically locate indel and STR sequences and determine STR copy number by searching NCBI reference sequences; (ii) predict combinations of microsatellite patterns using the Federal Bureau of Investigation Combined DNA Index System (CODIS); (iii) determine human papilloma virus (HPV) genotypes by searching current viral databases in cases of double infections; (iv) estimate the copy number of paralogous genes, such as \u03b2-defensin 4 (DEFB4) and its paralog HSPDP3.The direct sequencing of PCR products generates heterozygous base-calling fluorescence chromatograms that are useful for identifying single-nucleotide polymorphisms (SNPs), insertion-deletions (indels), short tandem repeats (STRs), and paralogous genes. Indels and STRs can be easily detected using the currently available In The detection of genomic variations is important in studying the relationships between causative genes and diseases and the relationships between predisposing genes and complex trait diseases, such as type 2 diabetes, coronary heart disease, and cancers \u20134. Strucdelligent program uses dynamic programming optimization to decode the heterozygous indels with International Union of Pure and Applied Chemistry DNA code system (IUPAC code)  Another type of \u201cmixed\u201d sequence is represented by viral coinfection in the same specimen. For example, double HPV genotypes within one sample could be analyzed by EasyChip using probes designed to amplify the variable regions that are unique to each HPV genotype . To valiDEFB4 gene, which is well known for its multiple copy number variations. The PCR primers used amplified DEFB4 and its paralog, the pseudogene HSPDP3  and chromosome 8 . The LRi value of each chromatography peak was used to estimate the ratio between DEFB4/HSPDP3 and calculate the DEFB4 copy number  . Second,delligent, which only processes IUPAC code data. Only MSR can map sequence data to a reference database and report the most possible mixed sequence. MSR and CHILD can estimate the ratio of sequences in a mixture. Only PolyScan can process next-generation sequencing data  STR repeat structure and those of plasmid cloning, (B) MSR analyzed results are shown as the IUPAC code and decomposed sequence.Supplementary Figure 2: (A) Chromatography trace of a combined two CODIS D21S11 Locus subtype, (B) there were two 4-bp gaps in the alignment of two subtypes in CODIS D21S11 Locus.Click here for additional data file."}
+{"text": "While considerable research has evaluated the effects of joint mobilisation on spinal, pelvic and shoulder biomechanics, there is a paucity of research evaluating the effects of foot mobilisation techniques (FMT) on gait. This pilot study evaluated the immediate effects of FMT on plantar pressures and temporal-spatial gait parameters.Fifteen adults (48\u00b121.4 years) that had no known balance problems or falls history participated. An instrumented treadmill system  was used to measure plantar pressure and temporal-spatial gait parameters. Data were recorded for 30 seconds of steady state walking immediately before and after intervention using a standardised protocol of FMT. Repeated measures ANOVAs were used to assess the effect of FMT on gait parameters at an alpha level of .05.Of the 34 gait parameters measured, only three changed significantly after FMT. Peak pressure beneath the lateral heel (4%) and lateral forefoot (9%) was increased immediately following FMT (p<.05) and was accompanied by a delay (3%) in the time to peak pressure beneath the lateral forefoot (p<.05).Changes in plantar pressure following FMT were small and less than the reported measurement error of the treadmill system. Therefore, in this pilot study the immediate effect of FMT on gait parameters was negligible. Further research evaluating short and long term effects of FMT on specific aspects of the locomotor system are needed."}
+{"text": "To the Editor: The recent article by Helms et al. described the distribution of Salmonella enterica serovar Typhimurium definitive page type 104 (DT104) infections in 29 countries from 1992 to 2001 (According to the Colindale scheme for phage typing (Emergence of phage subtype DT104A was identified in June 2004 during an outbreak of salmonellosis in Rome. This subtype had never been previously identified in Italy. All DT104A isolates were susceptible to the Enter-net panel of antimicrobial drugs (The incidence of DT104 in Italy has remained stable from 2002 through 2004. However, emergence of subtype DT104A during a recent outbreak highlights the need for subtyping in identifying communitywide outbreaks and in monitoring changing subtype patterns."}
+{"text": "Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-\u03b2) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as \u03b1 smooth muscle actin (\u03b1-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders. It is generally accepted that activated mesenchymal cells or myofibroblasts play a crucial role in the pathogenesis of various fibrotic diseases including interstitial pulmonary fibrosis, systemic sclerosis and liver or cardiac fibrosis being responsible for the exaggerated production and accumulation of extracellular matrix proteins in various organs affected by these diseases -4. AlthoThe occurrence of EndoMT in experimentally induced cardiac fibrosis was originally described by Zeisberg et al.  employinin vitro. The treated cells displayed a progressive loss and the eventual disappearance of endothelial-specific cell markers (CD-31 and VE-cadherin) and a parallel acquisition of mesenchymal cell markers including vimentin, collagen I and N-cadherin. These results suggested that intestinal endothelial cells exposed to an inflammatory environment may participate in the intestinal fibrotic process which accompanies intestinal inflammatory diseases. The in vitro observations were confirmed by studies of molecular co-localization in human colonic mucosa [In contrast with the extensive evidence from experimental animal models demonstrating the important participation of EndoMT in the development of tissue fibrosis studies with human endothelial cells are just beginning to appear. One such study  examinedc mucosa .Another study examined the expression of cell surface markers specific for endothelial cells in mesenchymal/fibroblastic cells present in the subendothelial compartment of small vessels in lungs from patients with Systemic Sclerosis-associated pulmonary fibrosis . ConfocaIn contrast to the very extensive studies conducted to unravel the molecular mechanisms and the regulatory pathways that modulate epithelial mesenchymal transition -31, the Besides TGF-\u03b2 it has been shown that endothelin-1 (ET-1) may also participate in EndoMT. In one study, Widyantoro et al.  showed tAlthough there are numerous studies which have conclusively shown the crucial involvement of members of the TGF-\u03b2 family of growth factors in initiation of EndoMT, the detailed molecular events and the intracellular cascades activated by TGF-\u03b2 that result in the remarkable phenotypic change of endothelial cells to mesenchymal cells have not been entirely elucidated. Recent studies in primary cultures of murine pulmonary endothelial cells  and in cde novo mesenchymal phenotypes. These studies identified the c-Abl protein kinase (c-Abl), protein kinase C\u03b4 (PKC-\u03b4), and glycogen synthase kinase 3\u03b2 (GSK-3\u03b2) as important participants and that GSK-3\u03b2 kinase phosphorylation was a crucial event in this process [Several studies explored the underlying molecular pathways that may cause the significant loss of endothelial-specific markers while inducing strong  process ,42. It i process ,44 as ilIn summary, numerous recent studies have provided strong evidence for the prominent participation of EndoMT in the generation of activated myofibroblasts during the development of experimentally induced tissue fibrosis suggesting that EndoMT plays a crucial role in fibrotic diseases. There is some early experimental evidence providing support and validation for the participation of EndoMT in the development of human intestinal fibrosis and of Systemic Sclerosis-associated pulmonary fibrosis. The firm demonstration of the occurrence of EndoMT in human fibrotic diseases and further understanding of the molecular mechanisms involved may lead to the pharmacologic modulation or abrogation of this pathway in human fibrotic disorders and may represent a novel therapeutic approach for these devastating diseases.The authors declare that they have no competing interests."}
+{"text": "It has been shown in in-vitro experiments that \"withdrawal\" of tamoxifen inhibits growth of tumor cells. However, evidence is scarce when this is extrapolated into clinical context. We report our experience to verify the clinical relevance of \"withdrawal therapy\".Breast cancer patients since 1998 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: (1) estrogen receptor positive, operable primary breast cancer in elderly (age > 70 years), locally advanced or metastatic breast cancer; (2) disease deemed suitable for treatment by hormonal manipulation; (3) disease assessable by UICC criteria; (4) received \"withdrawal\" from a prior endocrine agent as a form of therapy; (5) on \"withdrawal therapy\" for \u2265 6 months unless they progressed prior.Seventeen patients with median age of 84.3 (53.7-92.5) had \"withdrawal therapy\" as second to tenth line of treatment following prior endocrine therapy using tamoxifen (n = 10), an aromatase inhibitor (n = 5), megestrol acetate (n = 1) or fulvestrant (n = 1). Ten patients (58.8%) had clinical benefit (CB)  with a median duration of Clinical Benefit (DoCB) of 10+ (7-27) months. Two patients remain on \"withdrawal therapy\" at the time of analysis.\"Withdrawal therapy\" appears to produce sustained CB in a significant proportion of patients. This applies not only to \"withdrawal\" from tamoxifen, but also from other categories of endocrine agents. \"Withdrawal\" from endocrine therapy is, therefore, a viable intercalating option between endocrine agents to minimise resistance and provide additional line of therapy. It should be considered as part of the sequencing of endocrine therapy. Estrogen receptor (ER) positive breast cancers after a period of response to anti-estrogens develop resistance and clinically the disease progresses. Besides the predominant role of alternative signalling pathways, domination of partial agonistic activity of tamoxifen over its antagonist activity has been implicated for acquired resistance . RegressCase-notes of the breast cancer patients treated in the Nottingham breast unit since 1998 fulfilling the following criteria were studied retrospectively:\u2022 ER positive invasive breast carcinoma proven by histology  \u2022 Primary operable cancer in elderly (age > 70 years) (who were frail or refused to undergo surgery), locally advanced or metastatic\u2022 Disease deemed suitable for further hormonal manipulation\u2022 Disease progressed on a hormonal agent and thus suitable for \"withdrawal\" from an endocrine agent as a therapeutic option \u2022 Assessable lesions were deemed to have shown CB when they either had objective response in the form of complete response (CR) or partial response (PR); or had stable disease (SD) for \u2265 6 months in accordance with UICC criteria ,10\u2022 Metastatic lesions were assessed radiologically (CT scan/X-rays/bone scan) every 3 months as routine protocol in the unit\u2022 On \"withdrawal therapy\" for at least 6 months unless disease progressed priorDuration of CB (DoCB) is the duration of therapy in months only in patients who have derived CB and including patient still on treatment. Duration of treatment (DoT) is the duration of therapy in months of all patients (regardless of the type of response) and including patient still on treatmentSeventeen patients with either locally advanced primary (n = 3) or metastatic n = 14) breast cancer had \"withdrawal\" treatment as 2nd to 10th line of treatment. Patient and tumor characteristics are shown in Table 4 breast Tamoxifen may continue to provide antagonistic activity on ER nuclear signalling activity but may act as an agonist on the ER membrane signalling activity which could explain the loss of continuing CB to some patients on long-term tamoxifen therapy . There iIn an in-vivo study , athymicThe lack of response in the remaining patients on withdrawal of tamoxifen could partly be explained by the growth promoting action of natural estrogen in the body as seen in the above in-vivo study . Therefo-11 M/L or more of estradiol. This is again possible due to activation of cross-talk mechanisms and domination of mitogen-activated protein kinase or growth factors [In our study, as seen in table st 4 years followed by 12 months in year 5)[The above in-vitro concept is being explored further in clinical settings. There is ongoing recruitment to a phase III trial  wherein node positive early stage patients who have completed 4-6 years of prior adjuvant endocrine therapy (a SERM/AI/both) are randomised to receive either 5 years of daily letrozole or receive intermittent letrozole regime (daily for first 9 months of 1n year 5). The ratIn locally advanced and advanced breast cancer, ideally, inhibitors of the alternative pathways would be the subsequent logical therapy following resistance to other endocrine agents. However, if the patient is unfit to receive any further anti-estrogen therapy then it is very likely that they would not be suitable for further growth factor inhibitors or indeed chemotherapeutic agents. In this circumstance, withdrawal of therapy may be the only feasible option or alternating regime of endocrine therapy and withdrawal therapy as is being tested in the adjuvant setting in the SOLE trial.Our data therefore provides some clinical evidence and emphasises the relevance of withdrawal therapy. The concept is being tested in large randomised trials in adjuvant settings. However, larger datasets and results of ongoing adjuvant trials are needed to provide confirmatory evidence for or against the concept and feasibility of withdrawal therapy in locally advanced and metastatic breast cancer.The authors declare that they have no competing interests.KLC conceived this study. Patients were under care of JFR and KLC. AA collected data, performed analysis, drafted, revised and finalised the manuscript. KLC and JFR revised and approved of the contents of the manuscript. All authors read and approved the final manuscript."}
+{"text": "Diabetes related foot ulcers (DRFU) frequently require surgical debridement or limb saving, partial foot amputation. The resultant wounds are generally deep and associated with prolonged healing times. Negative pressure wound therapy (NPWT) is increasingly used to facilitate healing of these complex wounds. This retrospective audit provides outcome data on patients with post-surgical wounds managed with NPWT within our High Risk Foot Service (HRFS). There is a paucity of data on clinical outcomes of DRFU treated with this therapy.Data from patients treated for post-surgical wounds within the HRFS was extracted from our electronic data base. A manual review of the patients records treated with NPWT was conducted to determine wound severity (University of Texas grading system), time to healing (from date of surgery), duration of NPWT and complications including new or recurrence of wounds and the need for further surgical management.155 patients with post surgical wounds were managed by the HRFS between September 2006 and November 2010. Many (83%) of these were superficial ulcers (grade 1), the remainder involved tendon and or bone (Grade 2 and 3). Thirty seven patients (37 wounds) were treated with NPWT. Two were superficial (grade 1), 19 were to tendon (grade 2) and 16 were to bone (grade 3). Most (34) were clinically infected at baseline and 13 were ischaemic. Median time to healing (from the date of surgery) was 121 days. Twenty one healed and 5 cases are ongoing. NPWT was used for a median of 30 days. Two required further foot surgery before healing, 14 patients developed new ulcers (unrelated to NPWT), 3 patients who healed required below knee amputation within 2 years and 1 died during the follow-up period.NPWT is often used in our service for the management of complex post surgical wounds with close to 60% achieving complete wound closure and a low rate of major amputation. While many factors may influence this result, the increasing use of NWPT is supported in this setting. Data collection is ongoing and we plan to compare these outcomes to a historical control group and hope that this sets a benchmark for appropriate use of NPWT."}
+{"text": "Cancer remains a major health concern in the management of HIV infection in areas of the world with and without access to highly active antiretroviral therapy. In the USA alone, approximately 56,000 people were newly diagnosed with HIV infection in 2006; 53% of these new diagnosis occurred in gay and bisexual men but Black/African American men (45%) ,women (27%) , and Hispanics 17%) were also strongly affected [7% were aAMC-PNs conducted activities that raised awareness in their local communities of AIDS-related malignancies, developed partnerships with local health community organizations and identified areas where further communication was needed. PNs took the lead in developing a PN brochure and in the design of several tailored recruitment strategies. The PN program is making important inroads into behavioral interventions to increase participation of minorities and underserved populations in AMC trials."}
+{"text": "Addressing the problem of preventable drug related morbidity (PDRM) in primary care is a challenge for health care systems internationally. The increasing implementation of clinical information systems in the UK and internationally provide new opportunities to systematically identify patients at risk of PDRM for targeted medication review. The objectives of this study were (1) to develop a set of explicit medication assessment criteria to identify patients with sub-optimally effective or high-risk medication use from electronic medical records and (2) to identify medication use topics that are perceived by UK primary care clinicians to be priorities for quality and safety improvement initiatives.For objective (1), a 2-round consensus process based on the RAND/UCLA Appropriateness Method (RAM) was conducted, in which candidate criteria were identified from the literature and scored by a panel of 10 experts for 'appropriateness' and 'necessity'. A set of final criteria was generated from candidates accepted at each level. For objective (2), thematically related final criteria were clustered into 'topics', from which a panel of 26 UK primary care clinicians identified priorities for quality improvement in a 2-round Delphi exercise.(1) The RAM process yielded a final set of 176 medication assessment criteria organised under the domains 'quality' and 'safety', each classified as targeting 'appropriate/necessary to do'  or 'inappropriate/necessary to avoid' (safety) medication use. Fifty-two final 'quality' assessment criteria target patients with unmet indications, sub-optimal selection or intensity of beneficial drug treatments. A total of 124 'safety' assessment criteria target patients with unmet needs for risk-mitigating agents, high-risk drug selection, excessive dose or duration, inconsistent monitoring or dosing instructions. (2) The UK Delphi panel identified 11 (23%) of 47 scored topics as 'high priority' for quality improvement initiatives in primary care.The developed criteria set complements existing medication assessment instruments in that it is not limited to the elderly, can be implemented in electronic data sets and focuses on drug groups and conditions implicated in common and/or severe PDRM in primary care. Identified priorities for quality and safety improvement can guide the selection of targets for initiatives to address the PDRM problem in primary care. Systematic reviews have demonstrated deficits in the quality and safety of medication use in primary care to an extent sufficient to constitute a public health threat. Three to four percent of all unplanned hospital admissions are due to preventable drug related morbidity (PDRM), with the majority attributed to high-risk prescribing and inconsistent monitoring -4. AntipThe 'Data-driven Quality Improvement in Primary care (DQIP)' research programme is designing and testing a complex intervention to improve the quality and safety of medication use in UK primary care. It is based on encouraging and facilitating primary care medical practices to systematically and continuously identify, correct or otherwise manage drug therapy risks that are potential pre-cursors to PDRM . The DQIA number of explicit medication assessment tools have been developed in recent years. The Beers criteria set  lists potopics, are perceived to be priorities for quality improvement by professionals working in UK primary care.The study had two aims. First, we aimed to develop and classify by clinical importance a set of up-to-date medication assessment criteria that can be implemented in routine primary care clinical datasets to identify instances of (a) sub-optimally effective medication use for conditions commonly encountered in primary care and (b) high-risk use of drugs that have been shown to either commonly cause harm and/or cause severe harm in primary care. Second, we aimed to elicit the extent to which thematically-related medication assessment criteria, subsequently referred to as The study was conducted in three stages. First, an extensive list of candidate medication assessment criteria was generated based on a structured literature review. Second, an expert panel participating in a modified RAND/UCLA (University College of Los Angeles) Appropriateness Method (RAM) study scored these items by clinical importance based on a summary of research evidence and their clinical judgement. Candidate criteria with high importance scores were translated into a final criteria set by removing redundancies (see below). Final criteria were characterised by the type of medication use targeted, informed by available taxonomies -15. ThirPrescribing is a ubiquitous feature of medical care which makes a systematic evaluation of the literature on prescribing quality or safety unfeasible in a single research project. We therefore focussed on medication use for conditions commonly encountered in primary care and drugs with clear evidence of significant benefit or harm. The literature review drew initially on UK national clinical guidelines, prescribing advice, and safety alerts, supplemented by European or other clinical guidelines and targeted primary literature review in selected areas as detailed below.Candidate medication assessment criteria either described potentially beneficial medication use  or the use of potentially harmful treatments ('safety'). Candidate 'quality' criteria targeted common conditions where there are compelling indications for drug therapy based on UK and European guidelines -25. CommIn order to identify candidate safety criteria, the drug groups reported to be most frequently implicated in PDRM hospital admissions were identified from systematic reviews and large scale studies -4,34. FoThe RAND/University of California Los Angeles (UCLA) appropriateness method is a rigorous way of combining research evidence with expert opinion , and hasimproper' not to be offered or avoided, whereas 'appropriate' is a more neutral balancing of net benefit or harm [The questionnaire aimed to classify candidate medication assessment criteria derived from the literature as either 'necessary' or 'appropriate' care table . 'Necess or harm -45. Foll or harm ,46.and three or more ratings of 1 to 3) on the appropriateness scale were rejected. Those items with median ratings of 7 to 9 were accepted as 'appropriate' and those with median ratings of 1 to 3 as 'inappropriate'.All candidate quality and safety assessment criteria were scored for 'appropriateness'. Candidate criteria with a median rating of 4 to 6 ('uncertain') or disagreement  were accepted. Candidate safety assessment criteria were additionally scored on a 'necessary to avoid' scale, where items with a median rating of 1 to 3 (= clearly necessary to avoid) were accepted. Candidate criteria with median ratings of < 7 on the 'necessary to do' and > 3 on the necessary to avoid scale and those showing disagreement (defined as above) were rejected. The concept of 'necessary to avoid' was an extension to the original RAM method to differentiate between prescribing that is 'generally not worthwhile' from 'improper' in safety terms (see box 2).The ten RAM panel members were emailed the first round questionnaire and a summary of the supporting evidence base. Panellists were asked to rate each item with reference to an 'average' patient consulting an 'average' primary care clinician in 2009 based on both the evidence summary and their clinical judgement . PanelliA random sample of general medical practitioners (GPs) and eligible pharmacists in Scotland and England was invited to participate by e-mail. In order to be eligible, pharmacists had to have experience of working in medicines governance, as a prescribing advisor or as a practice pharmacist. Twenty three (64%) GPs and 13 (36%) pharmacists agreed to participate.'The described topic is a priority for collaborative quality improvement in primary care'. The term 'collaborative' was used in order to emphasise that the intended purpose of this study was to identify priority topics for quality improvement rather than measures for judging practitioners or practices as part of performance management.The Delphi questionnaire listed the medication improvement topics to be scored together with a short summary of the scientific rationale for each topic. For each item, panellists were asked to state their level of agreement with the statement and 30% or more ratings of 7 to 9) were accepted as 'priority', with median ratings of 8 or 9 defined as 'high priority'. All findings reported in this paper refer to second round ratings.As in the RAM study, all ratings used an ordinal scale of 1 to 9 (1 = strongly disagree and 9 = strongly agree). Panellists were instructed to rate topics in relation to primary care in general, rather than their own practice. The first round ratings were summarised and returned to participants by email for a second round of scoring. Topics with second round median ratings of 7 to 9 without disagreement  candidate assessment criteria. Upon completion of the second rating round, 318 (82%) candidates  were accepted at the 'appropriate' and 275 (71%) items  at the 'necessary' level. A number of candidate criteria were duplicates, in the sense that they were designed to determine thresholds beyond which care was judged appropriate and necessary. For example, 18 candidate quality assessment criteria related to glycated haemoglobin (HbA1c) levels beyond which treatment intensification was appropriate or necessary. Removing redundant candidate criteria yielded 52 quality and 124 safety assessment criteria to be included in the final set. Forty (77%) final quality assessment criteria and 107 (86%) final safety assessment criteria were derived from candidates accepted at the 'necessary' level. The results of the RAM study are summarised in tables Table Similarly, table The majority of safety assessment criteria are drug-focussed (74%), either targeting drugs reported to be frequently implicated in PDRM hospital admissions (54% - section A) or others implicated in severe preventable harm (20% - section B). The remainder (26% - section C) target medication use in particularly vulnerable groups, namely the elderly 15%), patients with heart failure (8%) and children (4%). Over a third (36%) of final safety assessment criteria focus on potentially harmful use of NSAIDs, antiplatelets, anticoagulants and diuretics, the drug groups most frequently implicated in PDRM hospital admissions [5%, patieOver half (52%) of safety criteria target the selection of high-risk drugs (MS2 to 4), either for indications where safer  alternatives exist (MS2) or in patients particularly susceptible to adverse reactions because of age/co-morbidity (MS3) or co-prescription (MS4). A further 15 (12%) criteria target omissions of drugs indicated to mitigate the risk of adverse events from high-risk treatments (MS1), while twenty (16%) criteria target inconsistent laboratory monitoring (MS8). Two (2%) criteria focus on prescribing that may jeopardise patient compliance with methotrexate dosing schedules (MS7).The majority of quality (81%) and safety (71%) assessment criteria are not restricted to the elderly (patients aged 65 years or older).Grouping of thematically related assessment criteria that were derived from candidates accepted at the 'necessary' level yielded a total of 47  medication improvement topics to be rated by the Delphi panel. Thirty-six Delphi study participants completed a first round and 26 (73%) a second round questionnaire  and high-risk use, inconsistent monitoring or patient instructions for drugs implicated in preventable harm (medication use safety) in primary care. All items are classified by clinical importance (appropriateness and necessity) as the output of an extended RAM process. Key professionals in UK primary care identified eleven clusters of thematically related medication assessment criteria (topics) as 'high priority' for quality improvement initiatives. The three highest rated topics related to methotrexate dosing instructions, high-risk prescribing of NSAIDs and antiplatelets and underuse of corticosteroids in asthma.The RAM approach had advantages over the Delphi technique as an initial step in the criteria development process, because the face-to-face meeting ensured the necessary commitment of panellists to place ratings on an extensive and thematically broad list of candidate criteria that were grounded in the evidence base. The original RAM approach was extended in this study by introducing the concept of 'necessary to avoid', in order to distinguish between inappropriate ('not worthwhile') and 'improper' medication use in safety terms  results in the UK are often held in bespoke systems which hinder the implementation of meaningful measures for monitoring anticoagulant use -4. SimilAlthough the DQIP criteria set has been developed for application in UK primary care, the drug groups reported to be implicated in PDRM events in primary care are similar internationally -52, and The Delphi approach allowed stakeholders in primary care to prioritise the chosen medication use topics for improvement initiatives in UK primary care. The Delphi panel was deliberately chosen to include both day to day prescribers  and those involved in prescribing governance and improvement (predominately pharmacists but including GPs with a more strategic role). A limitation is that our focus on professionals involved in primary care prescribing meant that we did not seek to include either specialist or patient/public perspectives in the Delphi panel. Since there is evidence that practitioners' perceptions of a targeted behaviour as meaningful is a pre-requisite to changing behaviour  we aimedIt is important to note that even those topics that were not considered to be priorities  contain individual criteria that were agreed to be 'necessary' to do or avoid by the RAM panel. Examples are 'inadequate dose titration of ACEI, ARBs and beta blockers in chronic heart failure', and the 'using of warfarin without a compelling indication in atrial fibrillation with low risk of stroke'. These should therefore not be neglected. Lower priority ratings nevertheless indicate that changing and improving the corresponding medication use aspects may require targeted effort (or resources) in order to influence prescribing behaviour.NCT01425502).The DQIP medication assessment criteria set presented here has been developed using established consensus methods and complements existing medication assessment instruments by not being limited to the elderly and by targeting a wide spectrum of medication use practices implicated in common and/or severe PDRM events in primary care. As all previously published explicit medication assessment tools, the criteria set presented here does not, however, provide comprehensive coverage of all situations that put patients at risk of PDRM, reflecting the large scope and high complexity of medication use in primary care and the limitations of current UK clinical information systems. The best choice of criteria set will therefore depend on the main purpose to be addressed and will be guided by local priorities. Informed by the priority ratings of a panel of UK primary care professionals, we have selected a subset of the DQIP criteria to serve as outcome measures in a cluster randomised trial evaluating the effectiveness of a complex intervention to improve prescribing safety  and the extent to which any improvements in prescribing or monitoring translate into improved patient outcomes  therefore deserve further study.ACEI: Angiotensin converting enzyme inhibitor; ACOVE: Assessing care of vulnerable elders; ACS: Acute coronary syndrome; ADE: Adverse drug event; AF: Atrial fibrillation; ARB: Angiotensin receptor blocker; BB: Beta blocker; BP: Blood pressure; CCB: Calcium channel blocker; 2: CHADSScore for stroke risk assessment in atrial fibrillation based on the following risk factors: cardiac failure, hypertension, age > 75, diabetes and stroke; CHD: Coronary heart disease; CHD: Coronary Heart Disease; CHF: Chronic heart failure; CKD: Chronic kidney disease; CKD: Chronic kidney disease; COPD: Chronic obstructive pulmonary disease; COX: Cyclo-oxygenase; CVD: Cardiovascular disease; DM: Diabetes mellitus; DMARD: Disease modifying antirheumatic drug; DQIP: Data driven quality improvement in primary care; eGFR: Estimated glomerular filtration rate; FBC: Full blood count; GIP: Gastro-intestinal protective agents; GP: General practitioner; HbA1c: Glycated haemoglobin; HIV: Human immunodeficiency virus; HRT: Hormone replacement therapy; HTN: Hypertension; INR: International normalised ratio; IT: Information technology; MI: Myocardial infarction; MTX: Methotrexate; NSAID: Non-steroidal anti-inflammatory drug (includes non-selective and COXII selective agents unless stated otherwise); NS NSAID: Non-selective NSAID NYHA: New York Heart Association; PDRM: Preventable drug related morbidity; RAM: RAND appropriateness method; SABA: Short acting beta 2 receptor agonist; SD: Standard deviation; START: Screening tool to alert doctors to right treatment; STOPP: Screening tool of older person's prescriptions; TCA: Tricyclic antidepressant; TIA: Transient ischaemic attack; U&E: Urea and electrolytes; UCLA: University College of Los Angeles; UK: United Kingdom; Z-drug: zopiclone, zolpidem or zaleplone.The authors declare that they have no competing interests.The study is part of the Data-driven Quality Improvement in Primary Care (DQIP) research programme, which is led by BG. TD led the literature review, conduct of RAM and Delphi studies, data analysis and wrote the first draft of the manuscript. All co-authors contributed to subsequent drafts. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6904/12/5/prepub"}
+{"text": "The purpose of this study was to determine whether the duration of antiarrhythmic therapy after discharge from the hospital following abdominal surgery is related to the incidence of atrial fibrillation (AF) recurrence in elderly patients with the occurrence of peri-operative AF.The occurrence of peri-operative AF after abdominal surgery is a clinical condition burdened by several complications, especially in the elderly -3. When The recurrence of AF needs different kind of treatment. Medical therapy includes various antiarrhythmic drugs to control heart rate and restore sinus rhythm and anticoagulation to reduce the tromboembolic risk . OveractA pilot study was conducted in 19 elderly patients (age > 65 years) who underwent abdominal surgery  and with occurrence of peri-operative AF that successfully reverted to sinus rhythm. They were prospectively randomized at dismissal to receive antiarrhythmic therapy for 1 week (six patients in group A), 3 weeks (seven patients in group B), or 6 weeks (six patients in group C). Patients were followed up for an additional 4 weeks after discontinuation of antiarrhythmic therapy for detection of recurrence of AF.There was no significant difference in the recurrence of AF among groups .In elderly patients with peri-operative AF after abdominal surgery, converted to normal sinus rhythm before hospital discharge, have a benign course and the duration of antiarrhythmic therapy shorter than one week is appropriate."}
+{"text": "To the Editor: The biologic role of amino acid variants at position 222 of the hemagglutinin (HA) gene of pandemic (H1N1) 2009 virus in severe infections has been extensively discussed. A recent series of studies , confirming the clustering of all the worldwide 222E variants in a well-defined subclade . The same analysis showed that D222G variants could be reconciled with 2 different phylogenetic patterns. The first less frequent pattern includes sequences appearing sparsely throughout the tree, confirming the mentioned hypothesis of sporadic mutation. In contrast, the second pattern (the majority) relates to small groups of sequences appearing in monophyletic microclusters. Among these microclusters, 2 are particularly interesting because they include only 222G sequences, isolated in different parts of the world  to 2,492 complete HA sequences from the Global Initiative on Sharing All Influenza Data database (expanded Figure online,"}
+{"text": "Early results of an international RCT comparing drainage, irrigation &fibrinolytic therapy (DRIFT)for prematurity-associated post-ventricular dilatation (PHVD), with standard treatment suggested no benefit in terms of avoidance of shunt dependency. There was also an increased rate of secondary bleeds in those having DRIFT. The longer term benefits or otherwise of DRIFT treatment were unknown.We randomly allocated 77 preterm infants with PHVD to either DRIFT or standard treatment . Severe disability was assessed at 2 years\u2019 corrected age.Of 39 infants assigned to DRIFT, 21 (54%) died or were severely disabled versus 27 of 38 (71%) in the standard group . Among the survivors, 11 of 35 (31%) in the DRIFT group had severe cognitive disability versus 19 of 32 (59%) in the standard group . Median Mental Development Index was 68 with DRIFT and_50 with standard care.Despite inducing an increased rate of secondary intraventricular bleeding, DRIFT reduced severe cognitive disability in survivors and overall rates of death or severe disability. A modification of DRIFT involving simple ventricular lavage and fibrinolytic therapy (limited to unblocking clogged-up drainage catheters) will now be employed in clinical practice at our unit."}
+{"text": "When patients with a rheumatic disorder reach adulthood, transfer to adult-focused care is advocated (1). A successful continuation of rheumatology follow-up beyond childhood depends on how clinicians think about transfer and transition (2).To explore the attitudes of rheumatology practitioners on transfer and transition from pediatric to adult health care of adolescents with a rheumatic disorder.A survey  among rheumatology practitioners attending the Pediatric Rheumatology European Society congress in 2010. Overall, 138 individuals participated, of which 59 were medical doctors (MDs) with paediatric and rheumatology background; 30 MDs with pediatric background; and 21 MDs with rheumatology background.Participants judged that, when patients with active rheumatic disorder reach adulthood, they should receive medical follow-up from an adult rheumatologist (87%). Only 19% thought that patients should stay under surveillance of a paediatric rheumatologist. Several initiating factors for transfer were marked as important: readiness of the patient according to the caregiver (62%), age (61%) and psychosocial maturity (49%). A transfer meeting with the patient (76%), a referral letter (73%), or a medical transfer file (64%) were most preferred transfer communication tools with adult healthcare. Joint outpatient clinic, phone calls, and transfer meetings without the patient were considered to be less useful. The pediatric (94%) or adult rheumatologist (83%), parents (81%) and the nurse specialist (74%) were stated as most important active participants in the transition process.This study emphasized the importance of transfer to specialized rheumatology care of adolescents with an active rheumatic disease and highlighted transfer initiators and transfer communication tools."}
+{"text": "We analysed the responses using descriptive statistics; 660 individuals responded to the public and 303 individuals responded to the expert survey. We found evidence of public skepticism about the use of neuroimaging for applications such as lie detection or to determine consumer preferences and considerable disquiet about use by employers or government and about how their data would be stored and used. While also somewhat skeptical about new applications of neuroimaging, experts grossly underestimated how often neuroimaging had been used as evidence in court. Although both the public and the experts rated highly the importance of a better informed public in limiting the inappropriate uses to which neuroimaging might be put, opinions differed on the need for, and mechanism of, actual regulation. Neuroscientists recognized the risks of inaccurate reporting of neuroimaging capabilities in the media but showed little motivation to engage with the public. The present study also emphasizes the need for better frameworks for scientific engagement with media and public education.Emerging applications of neuroimaging outside medicine and science have received intense public exposure through the media. Media misrepresentations can create a gulf between public and scientific understanding of the capabilities of neuroimaging and raise false expectations. To determine the extent of this effect and determine public opinions on acceptable uses and the need for regulation, we designed an electronic survey to obtain anonymous opinions from as wide a range of members of the public and neuroimaging experts as possible. The surveys ran from 1 Am I politically right or left wing? Which of sex or money interests me most? Should I take an fMRI lie detector test? Can other people see my dreams? Can neuroimaging help me chose the right career? Can imaging identify future criminals amongst young children? The potential for new technologies to improve the health, living and economic prospects of society quite rightly attract public curiosity We are exposed, almost weekly, to reports of new, thrilling and increasingly fantastical applications of neuroimaging to unravel the complexities of our minds \u2013 Misinterpretations of neuroimaging research by the public may arise in several ways: the distortion of findings by scientists or the media to enflame interest, through commercial interests, or poor engagement of the public by researchers. Promotion of the level of public understanding of neuroscience concepts Motivated by the need for evidence-based solutions to these challenges, we surveyed the public for their thoughts on the current uses, communication of, and need for regulation of, neuroimaging research. In parallel, we also surveyed experts in neuroimaging to provide a benchmark of the scientifically accepted uses and identify where public and professional opinions might differ.We designed two short questionnaires, one for the public and one for neuroimaging experts, suitable for delivery online or on paper. The public and expert surveys were modified to reflect the respondents' likely knowledge of and degree of personal relevance in determining their opinion on each issue. There were 10 questions in the public survey and 21 questions in the expert survey , websites , tweets , and science blogs  as well as to attendees at meetings (e.g. Scottish Parliament Futures Forum) and societies for public engagement (Beltane http://www.publicengagement.ac.uk/about/beacons/edinburgh-beltane). The Expert Survey was distributed via university mailing lists , professional interest websites  and individual imaging research centre websites) to target individuals who routinely used neuroimaging methods . Ethics approval was not sought. A level one self-assessment indicated that there was no risk to the respondent or the researcher.The survey was posted online, using the Survey Monkey Pro web survey template, between 31p<0.05). All available data were included. Percentages are based on samples of completed response, as opposed to the entire potential sample. After main effects were examined, we examined for trends within demographic profiles. The public sample was divided into groups based on scientific interest. The expert sample was divided based on the capacity in which they used neuroimaging technology .We used descriptive statistics to characterize the composition of the sample, t-tests to examine differences between the samples and chi-squared tests to analyse main effects  and the majority described themselves as professionals (60%), students (16.5%), administrator (9.8%), not working (9.8%), skilled manual (2.7%) or manual workers (1.1%). The highest educational attainment was university undergraduate degree (30%), a Masters degree (21.3%), a PhD (15.9%), a professional qualification (15.5%), minimum school leaver's exam (8.9%) or final school leaver's exam (8.1%). Most respondents to the Expert Survey were neuroscientists (27%), followed by psychologists (17%), neuroradiologists (12.5%), psychiatrists (12.5%) or medical physicists (10.5%); had been using neuroimaging for 5\u201310 years (31%), <5 years (28%) or 10\u201320 years (26%); and were based in Scotland (34%), elsewhere in the United Kingdom (32%), Europe (16%) or the United States (15%).n\u200a=\u200a39, 5%) who said that their professions involve neuroimaging and may therefore not be representative of the public profile was identified, but no differences were found between the groups (p>0.05).Almost half the sample reported themselves as at least \u2018a little\u2019 aware of neuroimaging uses (47%), followed by \u2018quite aware\u2019 (26%), \u2018no awareness\u2019 (17%) and \u2018very aware\u2019 (10%). A subgroup , but few had the same confidence in use of neuroimaging to diagnose mental illness , some thought that neuroimaging could detect lies  or consumer preferences , but had less confidence in detecting racial attitudes , political views  or reading minds , Most respondents reported that they would be comfortable having their brain scanned for medical purposes (96%), for scientific research (90%), but were less inclined as part of a criminal investigation (36%), for insurance purposes (9%), for marketing research (16%) or as part of a job interview (11%) Most respondents were \u2018very\u2019 or \u2018quite\u2019 concerned about the confidentiality and storage of scans (82%) and that \u2018people would know what they were thinking\u2019 (55%), being forced to have a scan (70%) or that there would be \u2018something wrong with their brain\u2019 (57%). Most were \u2018not at all \u2018or\u2019 only a little \u2018worried that having a scan would make them vulnerable to thought control (61%), Most respondents reported that newspapers (65%) and popular science publications (64%) were the most common sources for information about neuroimaging, followed by television documentary (62%), television or film fiction (59%) and online sources (46%). Of those who reported using online sources, twitter and blogs were the most popular. When asked how often they encountered information on brain imaging, responses were highly varied with about a third reporting a little , often  and very often .When asked about the regulation of brain imaging, most public respondents chose legislation (85%) and professional regulatory bodies (86%), followed by increased public awareness (84%). The least favoured response was the self-regulation of brain imaging research by the scientists themselves (53%), followed by the licensing of the scientists to conduct neuroimaging research (66%).Most expert survey respondents reported using neuroimaging for neuroscience research (66%), followed by clinical research (47%), medical diagnosis (35%), neuromarketing (4%), forensic purposes (3%) and security purposes (1%). The majority of respondents were aware of the use of neuroimaging outside traditional research (86%), particularly for neuromarketing (67%) and lie-detection (68%). Moderate awareness was reported for legal uses (48%), neuroaesthetics (56%), cognitive enhancement (55%) and mind reading (45%). Few were aware that neuroimaging was being used for security purposes (11%).Most respondents report specialist peer-reviewed literature as their main source of information on neuroimaging (84%), followed by general literature (65%), popular science media (50%), research conferences (54%), science blogs (25%), newspapers (25%) and popular science websites (23%).Most respondents thought that neuroimaging could improve the understanding of cognition , or improve treatment of psychiatric illness . However, most experts thought that the ability of neuroimaging to detect lies, read minds, understand consumer or criminal behaviour was largely a thing of the future or unlikely ever to occur : 29% of When asked how often neuroimaging evidence has been presented in U.S. courts in the last 5 years, most believed it was between 10 and 30 times (24%), followed closely by 6\u201310 times (22%) and between 1 and 5 times (23%). The lowest rates were reported for greater than 100 times (15%), between 30\u201360 times (8%) and between 60 and 100 times (8%).development of new applications, changing the legal system, changing views on responsibility for criminal behavior and enhancement of mental abilities, although changing the legal system and enhancing mental abilities were considered the least likely amongst these options (innovative applications (45%), cognitive enhancement (46%), change views of criminal responsibility (34%) and change the legal system (47%).Most respondents thought that wider uses of neuroimaging would, to some extent, lead to  options . These vIn terms of strategies for regulating use of neuroimaging, respondents ranked professional guidelines first (66% ranked first or second choice), followed by more funding for interdisciplinary projects integrating neuroscience and law (50%) and improved public awareness (51%), with legal regulation (16%) and self regulation (15%) being placed last.A substantial majority (87%) felt that neuroimaging was not accurately portrayed in the media. When asked why, most cited poor journalism (54%) as either a quite or very important factor, followed by exaggerated results by researchers (51%), a lack of effective scientific communication (38%) and poorly conducted research (44%). Most respondents believe that increased exposure to neuroimaging research would raise its public profile as a beneficial technology (96%), whereas 80% foresaw a public backlash on the widespread use of the technology. 92% predicted an increase in funding opportunities, but 44% anticipated the opposite trend. 69% feared the over regulation of neuroimaging in research.Having said that, although most respondents thought it was important to communicate with the public (69%), most do not regularly engage with the media (52%). Of those that do communicate their results to the public, most used media and peer-reviewed publication to do this (78%), followed by public seminars (49%), the internet (39%) and television (28%). Among those that did not engage with the public, the majority gave little opportunity (58%), little incentive (38%) and distrust of media (27%) as their main reasons, followed by a lack of public speaking training (15%) and a fear of criticism (5%). When asked how this situation might be improved, most rated as \u2018quite\u2019 or \u2018very effective\u2019: professional credit for public engagement (75%), making public communication a funding requirement (72%), increased public exposure of research (76%), and outlets for a career in the media (25%).This survey of members of the public and neuroimaging experts revealed a range of similarities and differences of opinions. About a third of the public saw articles on neuroimaging in the media once or twice a month indicating, in line with previous research Although the public and experts were generally in agreement about some points, e.g. both had little faith in uses of neuroimaging in non-medical applications and both agreed on some methods to use for regulation, the results also suggest that extensive media coverage has moderated viewpoints and awareness differentially among the public and experts. The public were concerned about data protection issues. The experts had little awareness of how often neuroimaging had been used in court in the USA  and one in three experts reporting no familiarity with neuromarketing or commercial lie-detection, although the public were aware of these uses. Although the experts thought that neuroimaging results were not well communicated in the media, and recognised the dangers of public loss of trust, few experts seemed motivated to improve the situation.Who can say which, if any, of the current legal, commercial or governmental uses of neuroimaging may become in future years routine, reliable tools? Neuroimaging is a rapidly evolving discipline; insights gained from well-conducted neuropsychological imaging research are in turn influencing knowledge of human behavioural traits on which many of society's attitudes are based. Consequently, it is entirely possible that society will need to adjust its views on behaviour, culpability, consciousness, etc. in future. However, a major focus of the present study was to determine how the public perceived the current capability of neuroimaging. Limited confidence in diagnosing psychiatric illness, lie-detection and neuromarketing was found, and to a far lesser degree in revealing racial and political attitudes and inner thoughts. Interestingly, the evidence base that complex social behaviours, such as racial attitudes and basic forms of mental representation, can be inferred using neuroimaging  especially with regards privacy and human rights (e.g. \u201cAnything that is voluntary is acceptable. Mandatory brain scans are not\u2026\u201d). The public distrust of other technologies used to extract sensitive information for non-health related uses has been echoed in a public survey on the acceptability of genetic testing in insurance and employment settings One of the clearest trends identified in the survey is the public disapproval of the use of neuroimaging in non-medical or scientific settings, such as in marketing research, and in employment screening. Indeed, respondents who made specific comments cited moral and ethical grounds as explanations for this standpoint Click here for additional data file."}
+{"text": "The recommendations are presented with supporting level of evidence.In this report, guidelines for the evaluation, medical and surgical management of transitional cell carcinoma of testicular germ cell tumors is presented. It is categorized according to the stage of the disease using the tumor node metastasis staging system, 7 A total of 38 cases have been diagnosed in 2006, with an age standardized rate (ASR) of 0.5 cases per 100,000 representing 1% of all diagnosed cancer in Saudi Arabia  High level: well-conducted phase III randomized trials or meta-analysis.(EL2) intermediate level: good phase II trials or phase III with limitations.(EL3) low level: Observational/retrospective studies or expert opinion.thedition 2010) was used.The American Joint Committee on Cancer (AJCC) TNM staging for testis cancer (7 The international Germ Cell Cancer Collaborative Group Risk Classification should bWill depend on the histological subtype as follows:"}
+{"text": "Most patients undergoing cardiac surgeries are exposed to red blood cell (RBC) transfusions, in the operating room or in the postoperative period. One of the main beliefs of this therapy is the ability of the RBCs to improve tissue perfusion through oxygen supply. However, recently, this concept is being questioned by some evidence as RBC storage lesion and adverse outcomes in transfused patients. The aim of this study was to determine if RBC transfusion after cardiac surgery results in improvement of tissue perfusion.2) were collected immediately at the beginning and end of the procedure, immediately postoperative (POI), after 24 hours (1PO), 48 hours (2PO), 72 hours (3PO) and at ICU discharge. Mean values of these above-mentioned parameters were compared in patients exposed to RBC transfusions and patients not exposed through repeated-measures variance analysis.From February 2009 to February 2010, a total of 502 patients underwent cardiac surgery with cardiopulmonary bypass at InCor - University of S\u00e3o Paulo. Arterial lactate, standard base deficit (SBD), arterial bicarbonate and oxygen central venous saturation (ScVOHemoglobin values were different between groups since before surgery until just before ICU discharge and in all periods, the group not exposed to RBC transfusions presented higher values compared with the exposed group (see Figure In this prospective study, red blood transfusion did not result in improvement of tissue perfusion parameters. This finding brings to discussion the real role of blood transfusion in cardiac patients."}
+{"text": "We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol.We conducted a meta-analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta-analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin.In a meta-analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD . Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers  agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy .The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol. A common single nucleotide polymorphism (rs20455) results in an argine to tryptophan substitution at position 719 (Trp719Arg) in the gene encoding kinesin-like protein 6 (KIF6). Some One possible explanation is that the KIF6 719Arg allele may increase the risk of cardiovascular disease (CVD), and that treatment with a statin may ameliorate this increased risk through a pleiotropic effect A biologically plausible hypothesis that can potentially reconcile these apparently conflicting findings is that the KIF6 719Arg allele may increase vulnerability to LDL cholesterol. If carriers of the 719Arg allele are more vulnerable to the deleterious effects of LDL cholesterol, then they should experience a greater increase in the risk of CVD per unit increase in LDL, and a correspondingly greater reduction in the risk of CVD per unit decrease in LDL, as compared to non-carriers. Therefore, if KIF6 carriers are more biologically vulnerable to LDL cholesterol, they should derive a greater clinical benefit per unit reduction in LDL cholesterol than non-carriers in response to therapies that lower serum LDL cholesterol levels.The primary aim of our study was to test the hypothesis that a common polymorphism can influence biological vulnerability to LDL cholesterol, and thereby influence the expected clinical benefit of therapies that reduce serum LDL cholesterol levels. To test this hypothesis, we first conducted a systematic review and meta-analysis of the association between the KIF6 719Arg allele and the risk of CVD. We then conducted a meta-regression analysis to measure the effect of the KIF6 719Arg allele on the association between LDL cholesterol on the risk of CVD. We used this measure of effect modification to estimate the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower serum LDL cholesterol level. We then conducted a systematic review and meta-analysis of the effect of the KIF6 719Arg allele on the clinical efficacy of statin therapy. Finally, we compared the expected difference in clinical benefit predicted by the meta-regression analysis with the observed difference in clinical benefit among KIF6 carriers and non-carriers in the meta-analysis of statin trials.We searched Pubmed, Embase, Index of Science, HUGEnet, and Google Scholar, using the search terms: KIF6, rs20455, 719Arg, and Trp719Arg without language restriction; we also checked the abstracts and presentations from major cardiovascular medicine meetings held from 2004 to present First, we conducted an updated systematic review and meta-analysis of the association between KIF6 719Arg carrier status and the risk of CVD. For this analysis, we included case-control studies, epidemiologic cohort studies, and the treatment allocation arms of randomized trials of statin therapy that have reported data separately among KIF6 719Arg allele carriers and non-carriers, but excluded family-based studies. We included both the placebo allocation and statin allocation arms of the placebo controlled trials, as well as both the less intensive and more intensive treatment allocation arms of the trials that compared different treatment intensities of statin therapy. Each treatment allocation arm was considered as a separate prospective cohort study for the purposes of this analysis. For study samples that were included in more than one report, we used data from only the most recent report. In each study, Hardy-Weinberg equilibrium was assessed, as appropriate, using a chi-square test. For each prospective cohort study , we extracted the total number of KIF6 719Arg allele carriers and non-carriers, as well as the number of KIF6 carriers and non-carriers who experienced an incident CVD event during study follow-up. From each case-control study, we extracted the total number of prevalent cases and controls for both KIF6 719Arg allele carriers and non-carriers. We used these data to create 2\u00d72 tables to calculate the unadjusted relative risk (RR), and 95% confidence interval (CI), for each prospective cohort study, and the unadjusted odds ratio (OR), and 95% CI, for each case-control study (as an approximation of the RR) 2) by the effect modification was calculated as the difference in tau2 between the regression model with and without a regression term, expressed as a percentage.Next, we performed a random effects meta-regression analysis to measure the effect modification of study baseline LDL cholesterol level on the association between KIF6 carrier status (and separately KIF6 genotype) and the risk of CVD Finally, we conducted an updated systematic review and meta-analysis of statin trials that have reported results stratified by KIF6 carrier status (or KIF6 genotype). From the report of each randomized trial, we extracted data on the number of persons assigned to either treatment allocation arm and the number of incident CVD events that occurred during study follow-up in each arm, stratified by KIF6 carrier status. We used these data to create 2\u00d72 tables to calculate an unadjusted RR (and 95% CI) for the effect of statin therapy as compared to placebo (or more intensive statin therapy as compared to less intensive statin therapy) on the risk of incident CVD events, separately among KIF6 carriers and non-carriers in each study. All analyses were by the intent-to-treat principle. We then standardized the estimate of the effect of statin therapy per mmol/L reduction in LDL cholesterol across trials by multiplying the natural logarithm of the RR for each trial (and its standard error) by 1\u00f7 Y, where Y is difference in average LDL cholesterol during follow-up between the two treatment allocation arms . We then combined the adjusted RR for each trial using an inverse variance weighted random effects model We standardized the effect of statin therapy per mmol/L reduction in LDL cholesterol in order to compare the observed difference in clinical benefit in the meta-analysis with the expected difference in clinical benefit estimated from the meta-regression analysis using the same scale. Standardizing the effect of statin therapy also allowed us to include both the trials that compared statin with placebo and the trials that compared more intensive and less intensive statin therapy. In the meta-analysis, therefore, the primary measure of effect is not the clinical benefit of statin therapy per se, but rather the clinical benefit per mmol/L reduction in LDL cholesterol during treatment with a statin.2 metric Heterogeneity was measured using Cochran's Q, and the IA total of 37 case-control studies, prospective cohort studies, or randomized trial treatment allocation arms (each considered as a separate cohort), including 144,931 participants and 27,465 CVD events, were included in our meta-analysis of the association between the KIF6 719Arg allele and the risk of CVD  [1]\u2013[6],2\u200a=\u200a58.7%).Among the 37 study samples included in our meta-analysis, 19 prospective cohort studies  involving a total of 88,535 participants and 9,692 incident CVD events, provided information on the average baseline LDL cholesterol level of the population under study and therefore were included in our meta-regression analysis Relying on the symmetrical nature of the effect modification between any two epidemiologic exposures A total of 8 randomized trials, involving 50,060 participants and 7,307 incident cardiovascular events, were included in our meta-analysis of the effect of statin therapy, stratified by KIF6 carrier status  [1]\u2013[6],The magnitude of the difference in clinical benefit per mmol/L reduction in LDL cholesterol observed among KIF6 719Arg carriers and non-carriers in response to treatment with a statin  was nearly identical with the expected difference in clinical benefit per mmol/L reduction in LDL cholesterol predicted by the increased vulnerability to LDL cholesterol among KIF6 719Arg carriers from the meta-regression analysis .Our study demonstrates that the common KIF6 719Arg allele appears to increase vulnerability to LDL cholesterol, and thereby influences the expected clinical benefit from therapies that lower serum LDL cholesterol levels. Persons who inherit one or more copies of the 719Arg allele appear to be more biologically vulnerable to the deleterious effects of LDL cholesterol than non-carriers. As a result, KIF6 719Arg carriers appear to derive a greater reduction in the risk of CVD per mmol/L reduction in LDL cholesterol than non-carriers. The results of our study resolve several apparently conflicting lines of evidence to provide a biologically plausible explanation for how KIF6 carriers can derive a greater clinical benefit from treatment with a statin than non-carriers, even though this polymorphism does not have any impact on the LDL cholesterol lowering effect of statins, and is not independently associated with the risk of CVD.More generally, our study demonstrates that a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the expected clinical benefit from therapies designed to lower serum levels of LDL cholesterol. The concept of genetically-mediated differential vulnerability to LDL cholesterol is illustrated in Our study shows that, on average, KIF6 719Arg allele carrier status is not associated with the risk of CVD. Our study also shows, however, that this association varies significantly according to the average baseline LDL cholesterol level of the population under study . FurtherOur findings do not challenge the results of a large-scale meta-analysis of statin randomized trials that found that the clinical benefit of statin therapy is determined largely by the magnitude of LDL cholesterol reduction achieved during treatment Importantly, our study shows that the KIF6 719Arg allele increases vulnerability to LDL cholesterol even though it is not, on average, associated with an increased risk of CVD. This means that all 2.5 million directly genotyped and imputed polymorphism measured in previously conducted genome-wide association studies of CVD, very few of which have been shown to be reliably associated with the risk of CVD Our study has several limitations. Most importantly, we did not have any data on the association between LDL cholesterol and the risk of CVD, stratified by KIF6 carrier status. Therefore, we could not estimate the effect modification of KIF6 on the association between LDL cholesterol and the risk of CVD directly. Instead, we estimated this effect from the meta-regression estimate of the effect modification of LDL cholesterol on the association between the KIF6 719Arg allele and the risk of CVD. We believe this approach is valid because these two estimates of effect modification are equivalent as shown in In conclusion, we found that the common KIF6 719Arg allele appears to increase vulnerability to LDL cholesterol, and thereby influences the expected clinical benefit from therapies that lower serum LDL cholesterol levels. More generally, our study demonstrates that a common polymorphism can influence vulnerability to a common modifiable risk factor for CVD even if it is not independently associated with the risk of CVD. Our study provides a roadmap for further research that could potentially lead to the discovery of polymorphisms that cause large differences in vulnerability to common modifiable risk factors for CVD and thus lead to correspondingly large differences in the clinical benefit derived from therapies used to treat these risk factors. Incorporating such polymorphism into the care of individual patients may help to guide the selection of optimal medical therapies for each individual person based on their genetic background and therefore introduce a practical clinical strategy to personalize the prevention of CVD.Table S1A list of studies included in the meta-analysis of the KIF6 719Arg allele and the risk of cardiovascular disease. The included studies are Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology study (ADVANCE); Acute Myocardial Infarction Gene Study, Dortmund Health Study (AMI Gene Study); CATHGENE Research Project (CATHGENE); deCODE CAD Study (deCODE); National FINRISK studies (FINRISK); German Myocardial Infarction Family Study I (GerMIFS I); German Myocardial Infarction Family Study II (GerMIFS II); Heart Attack in Puget Sound study (HARPS); International Heart Study (INTERHEART); Malmo Diet and Cancer Study (MDS); Washington Hospital Center catheterization study (MEDSTAR); Massachusetts General Hospital study of premature CAD (MGH PCAD); Mid-America Heart Institute (MAHI); Penn-CATH study; Registre Gironi de Cor (REGIGOR); Verona Heart Study (VHS); Wellcome Trust Case Control Consortium CAD Study (WTCCC); Ottawa Heart Study; Cholesterol and Recurrent Events (CARE); West of Scotland Coronary Prevention Study (WOSCOPS); Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI22); Prospective Study of Pravastatin in the Elderly at Risk (PROSPER); Heart Protection Study (HPS); Justification for the Use of Statins in Primary Prevention trial: An Intervention Trial Evaluating Rosuvastatin (JUPITER); Treat to New Targets (TNT); Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL); Atherosclerosis Risk in Communities study (ARIC); Cardiovascular Health Study (CHS); Women's Health Study (WHS).(PDF)Click here for additional data file.Table S2A description of the baseline characteristics of the randomized trials included in the meta-analysis of the clinical benefit of statin therapy stratified by KIF6 carrier status. The Difference in average LDL (mmol/L) is the difference between either treatment allocation arm. Study acronyms are defined in (PDF)Click here for additional data file.Text S1Equivalent measures of effect modification.(PDF)Click here for additional data file."}
+{"text": "Despite the use of hepatitis B virus (HBV) vaccines and preventive mDespite the use of hepatitis B virus (HBV) vaccines and preventive measures, infection with HBV remains a major global health problem. Patients with chronic kidney disease (CKD) are at an increased risk of acquiring HBV infections from shared dialysis equipment, increased exposure to blood products, and immunodeficiency associated with CKD 2]. In a. In a2]."}
+{"text": "Differentiation of acute heart failure from infection in patients with respiratory symptoms and a history of congestive heart failure (CHF) is challenging due to overlap of clinical symptoms and X-ray findings. The BACH study found higher mortality rates if patients presenting with dyspnea were treated with antibiotics and their procalcitonin (PCT) levels were low indicating absence of bacterial infection. Yet the BACH study was observational and causal inference cannot be drawn. Herein, we analyzed the effects of PCT-guided antibiotic stewardship in CHF patients from a previous trial (ProHOSP).This is a secondary analysis of a previous randomized trial of adult ED patients with respiratory symptoms and a history of CHF. Patients were randomized to administration of antibiotics based on a PCT algorithm (PCT group) or standard guidelines without knowledge of PCT levels (control group). The primary endpoint of this analysis is the risk of adverse outcome defined as death or ICU admission within 30 days after ED admission.n = 110), PCT-guided patients had a significant reduction in antibiotic exposure , P <0.001). Furthermore, PCT-guided patients had a significant lower risk for death and ICU admission , P = 0.02). See Figure A total of 233 patients met the inclusion criteria, with 116 in the PCT-guided group and 117 in the control group. In the subgroup of patients with low initial PCT levels <0.25 ng/l (In CHF patients with suspicion of respiratory infection, use of a PCT protocol resulted in a significant decrease of antibiotic exposure and significantly improved outcomes in patients with low PCT levels indicating absence of bacterial infection. Whether inadequate antibiotic therapy in these CHF patients requiring diuretic treatment explains this difference in clinical outcomes needs verification."}
+{"text": "Anser albifrons) in South Korea. Phylogenetic analyses of the complete genome sequence showed that polymerase acidic (PA) and neuraminidase (NA) genes belonged to the Eurasian lineage AIV, but polymerase basic 2 (PB2), PB1, hemagglutinin (HA), nucleoprotein (NP), matrix (M), and nonstructural (NS) genes belonged to the North-American lineage AIV. These data are beneficial for understanding the ecology and epidemiology of AIVs.In 2007, we isolated a natural recombinant H9N2 avian influenza virus (AIV) from the fecal droppings of a white-fronted goose ( Influenzavirus A genus of the Orthomyxoviridae family (Avian influenza virus (AIV) belongs to the e family . The AIVe family .Anser albifrons) in South Korea in 2007. Species identification of the fecal droppings was done by DNA barcoding using the cytochrome oxidase I gene, as described previously  was isolated from the fecal droppings of a white-fronted goose  virus were derived from North American lineages but that PA and NA genes were derived from Eurasian lineages. It seems that continuous reshuffling of AIV genes between North American and Eurasian lineages has been occurring in wild bird populations, producing the reassortant North American-Eurasian lineage AIV.In the present study, our results provide crucial information on the epidemiology of AIV in wild birds by increasing understanding of the role of migratory birds in exchanging AIV genes between the Eurasian and North American continents. Enhanced surveillance of the wild bird population is required to improve our understanding of the natural history of AIV in wild birds.KC693639 to KC693646.The genome sequences of A/white-fronted goose/Korea/20-36/2007 (H9N2) have been deposited in GenBank under accession no."}
+{"text": "Geologic process, including tectonics and global climate change, profoundly impact the evolution of life because they have the propensity to facilitate episodes of biogeographic differentiation and influence patterns of speciation. We investigate causal links between a dramatic faunal turnover and two dominant geologic processes operating within Laurentia during the Late Ordovician: the Taconian Orogeny and GICE related global cooling. We utilize a novel approach for elucidating the relationship between biotic and geologic changes using a time-stratigraphic, species-level evolutionary framework for articulated brachiopods from North America. Phylogenetic biogeographic analyses indicate a fundamental shift in speciation mode\u2014from a vicariance to dispersal dominated macroevolutionary regime\u2014across the boundary between the Sandbian to Katian Stages. This boundary also corresponds to the onset of renewed intensification of tectonic activity and mountain building, the development of an upwelling zone that introduced cool, nutrient-rich waters into the epieric seas of eastern Laurentia, and the GICE isotopic excursion. The synchronicity of these dramatic geologic, oceanographic, and macroevolutionary changes supports the influence of geologic events on biological evolution. Together, the renewed tectonic activity and oceanographic changes facilitated fundamental changes in habitat structure in eastern North America that reduced opportunities for isolation and vicariance. They also facilitated regional biotic dispersal of taxa that led to the subsequent establishment of extrabasinal (=invasive) species and may have led to a suppression of speciation within Laurentian faunas. Phylogenetic biogeographic analysis further indicates that the Richmondian Invasion was a multidirectional regional invasion event that involved taxa immigrating into the Cincinnati region from basins located near the continental margins and within the continental interior. Late Ordovician (~450 Ma) shallow marine deposits of Laurentia record a series of dramatic faunal and biogeographic shifts including a rapid change from predominantly warm to cool water adapted taxa during the middle Mohawkian (late Sandbian) and a major regional biotic immigration event into the Cincinnati Basin during the early Richmondian (Katian) ,2. TheseDuring the Late Ordovician, the Taconian orogeny developed along the eastern margin of Laurentia as a result of diachronous collisions with an island arc and/or microplates \u20135 , carbonate deposits of eastern Laurentia reflect a heterozoan assemblage typified by cool water and/or non-photosynthetic organisms, whereas tropical-style carbonates became restricted to the continental interior and marginal basins ,7. This  sequenceAlso during the M5 sequence, faunas of the Appalachian Basin transitioned from predominantly warm to cool water adapted. The biotic overturn was accomplished primarily through immigration of extra-basinal taxa into a region following regional generic extinction . For exaThe Richmondian Stage   was employed as described in Wiley & Lieberman . SpeciesBecause different geologic processes operated before and after the M4/M5 sequence boundary, LBPA was employed in a time-stratigraphic framework to more accurately discern patterns of biogeographic differentiation. Stratigraphic dimension was incorporated based on equal phylogenetic split using first and last appearances of species at the level of depositional sequence. Cladogenetic events were separated into Time Slice 1 (T1), approximately corresponding to the Blountian tectophase (W-b through M4 sequences), and Time Slice 2 (T2), approximately corresponding to the Taconic tectophase (M5 though C6 sequences) . AdditioGlyptorthis indicates that the genus originated in the Southern Midcontinent region and subsequently underwent a major dispersal event into the Appalachian and Central Basins  with frequent episodes of speciation via dispersal into neighboring tectonic basins during T2 , whereas the other tree is consistent with a more recent exchange of taxa between Anticosti Island and the Midcontinent region (supported by biogeographic affinities of Psubquadratus. ). These data indicate that both dispersal pathways were operational during the Richmondian Invasion.The diametrically opposed patterns of speciation and biogeographic differentiation between T1 and T2 reflect different biogeographic controls operating before and after the M4/M5 sequence boundary. This discrepancy is clearly illustrated by the divergent topology of vicariance trees between times slices and the dissimilarity of the geodispersal and vicariance trees within each time slice , 3. The The level of congruence between vicariance and geodispersal trees is indicative of the style of geologic processes impacting macroevolutionary patterns . CongrueDuring T1, the Blountian tectophase introduced siliciclastics into eastern Laurentia yet did not inhibit the production of tropical carbonates ,6. The hDispersal became the dominant mode of speciation during the Taconic tectophase of the Taconian Orogeny T2). The combination of flexural downwarping of the craton and GICE related oceanographic changes facilitated the upwelling of cool, nutrient rich water into the shallow epieric seas of eastern Laurentia ,5,9. Thi. The comThe shift in speciation regime across the M4/M5 boundary is significant because high rates of vicariance are typically associated with high rates of speciation, whereas high rates of dispersal are associated with reduced speciation . The negThe main pulse of the Richmondian Invasion into the Cincinnati Basin occurred during the C5 sequence . The retPhylogenetic biogeographic analysis of species-level patterns in Middle to Late Ordovician brachiopods indicates a shift in biogeographic patterns and macroevolutionary dynamics between the Blountian and Taconic tectophases of the Taconian orogeny . These patterns were driven largely by geologic processes related to the Taconian Orogeny and global cooling at the boundary between the Sandbian and Katian stage boundary (M4/M5 sequence boundary). Prior to the M5 sequence, tectonic activity associated with the Blountian tectophase produced increased habitat fragmentation in tropical carbonate environments, thereby facilitating high levels of vicariant speciation. In contrast, the post-M5 sequence interval corresponds to a shift in paleoceanographic conditions related to the combined effect of structural deformation from the Taconic tectophase and GICE related global cooling, whereby cool, nutrient rich water from the Sebree Trough was introduced into shallow intracratonic seas. Dispersal became the dominant form of speciation and the increased number of invasive species may have led to increased faunal homogenization between basins. High rates of dispersal in the T2 interval and a return to tropical conditions within the Cincinnati Basin facilitated the Richmondian Invasion into the Cincinnati Basin. Species-level phylogenetic biogeographic patterns suggest both intracratonic seas and marginal basins supplied invasive species into the Cincinnati Basin.Figure S1The division between TS1 and TS2 is indicated by the horizontal line.(TIF)Click here for additional data file.Table S1Numbered columns refer to nodes and tips on the stratocladograms . Coding as in Wiley & Lieberman [31].(PDF)Click here for additional data file."}
+{"text": "Dear Editor,We read with great interest the report of Alcelik et al.This 64-year old woman with chronic kidney disease due to nephrosclerosis, commencing on hemodialysis before 3 years, desired to candidate for kidney transplantation. Her medical history limited to hypertension of 10 years duration and end stage renal disease with well controlled secondary hyperparathyroidism [intact parathyroid hormone (iPTH): 17O pg/ml], but increased calcium phosphorus product (about 62 over the last 6 months) due to non compliance with absorption of phosphorus binders. No signs of osteoporosis have been identified on Dexa scan. Pretransplantation evaluation of the hands (plain radiograph) identified subperiostal bone resorption at the inner part of the terminal thumb phalanges symmetrically at both hands, with preservation of peripheral cortex . MoreovePublished data point out that the earliest subperiostal bone resorption due to secondary hyperparathyroidism is demonstrated at the phalangeal tufts and the radial aspects of the middle phalanges of the second and the third hand fingers. Whereas previously, radiologic findings were more intense, improvements in therapeutic management of secondary hyperparathyroidism in hemodialysis result in significant decrease of radiologic evidence."}
+{"text": "The current methods utilized to track stem cells by cardiac MR are affected by important limitations, and new solutions are needed.In vivo cine and in vivo and ex vivo multiecho T2 weighted images were obtained by 9.4T cardiac MR.We tested human ferritin heavy chain (hFTH) tagged with both myc and green fluorescence protein (GFP) as a reporter gene for in vivo tracking of stem cells by cardiac MR. Rat mesenchymal stem cells (rMSCs) were transduced with lentiviurs to overexpress hFTH. Myocardia infarction was induced by cryoinjury in rats, and the animals were immediately subjected to intramyocardial injection of 100 \u00b5l of 106 rMSCs (experiment group) or buffer solution (control group) in the border zone. ex vivo images was significantly decreased in the infarct area compared to remote normal myocardium in the experiment group, but not in the control group. GFP and myc immune-staining confirmed the presence of differentiated rMSCs around infarct area in the experiment group.Four-week follow-up cine MR showed that marked left ventricular remodeling developed in the control group. T2 relaxation time of in vivo and hFTH can be used as a MR reporter gene to track dividing and differentiating stem cells in the beating heart while simultaneously monitoring cardiac morpho-functional changes.This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (No.A100131) and partly by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) ."}
+{"text": "Chronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterised by bilateral progressive ptosis and ophthalmoplegia. These ocular features can develop either in isolation or in association with other prominent neurological deficits (CPEO+). Molecularly, CPEO can be classified into two distinct genetic subgroups depending on whether patients harbour single, large-scale mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair. The aim of this magnetic resonance imaging (MRI) study was to investigate whether the ophthalmoplegia in CPEO is primarily myopathic in origin or whether there is evidence of contributory supranuclear pathway dysfunction.POLG, PEO1, OPA1, and RRM2B. All subjects underwent a standardised brain and orbital MRI protocol, together with proton magnetic resonance spectroscopy in two voxels located within the parietal white matter and the brainstem.Ten age-matched normal controls and twenty patients with CPEO were recruited nine patients with single, large-scale mtDNA deletions and eleven patients with multiple mtDNA deletions secondary to mutations in There was evidence of significant extraocular muscle atrophy in patients with single or multiple mtDNA deletions compared with controls. There was no significant difference in metabolite concentrations between the patient and control groups in both the parietal white matter and brainstem voxels. Volumetric brain measurements revealed marked cortical and cerebellar atrophy among patients with CPEO+ phenotypes.The results of this study support a primary myopathic aetiology for the progressive limitation of eye movements that develops in CPEO. Chronic progressive external ophthalmoplegia (CPEO) is a slowly progressive extraocular muscle disorder characterised by bilateral, usually symmetrical, limitation of eye movements and ptosis The aim of this magnetic resonance imaging (MRI) study was to investigate whether the limitation of eye movements in CPEO is myopathic in origin or whether there is evidence of contributory brainstem dysfunction with magnetic resonance spectroscopy (MRS). Brain volumetric measurements were also performed to assess the extent of central nervous system involvement and whether this correlated with the development of extraocular neurological features in patients with CPEO+ phenotypes.The study cohort included: (i) nine patients with single, large-scale mtDNA deletions \u200a=\u200a3.0 years), (ii) eleven patients with multiple mtDNA deletions , and (iii) ten age-matched normal controls  Table 1.POLG mutations (n\u200a=\u200a4) PEO1 mutations (n\u200a=\u200a3) OPA1 mutations (n\u200a=\u200a1) RRM2B mutations (n\u200a=\u200a1) c oxidase-deficient fibres in addition to prominent ragged red fibres.All patients were assessed by an experienced multi-disciplinary team of neurologists and ophthalmologists to define the clinical phenotype and disease severity Table 1.Text S1), with a high degree of intra- and inter-observer reliability (Table S1).MRI and MRS data were acquired on a 3-Tesla Philips Achieva clinical MR system using an 8-channel head coil. Proton MRS analysis was performed by an experienced research physicist (FES) to derive brain metabolite concentrations in the parietal white matter and brainstem regions: (i) choline; (ii) creatine; (iii) total glutamate and glutamine (Glx); (iv) myo-inositol; and (v) N-acetyl-aspartate (NAA). Extraocular and brain compartment volumes were measured using standardised semi-automated segmentation protocols . Group comparisons were made using the unpaired t-test. Intra-observer and inter-observer variability for the measurement of extraocular muscle and brain volumes was assessed with Pearson correlation coefficient (r). and  and There was a significant reduction in extraocular muscle volumes in the CPEO group compared with normal controls for all four recti muscles Figure 1There was no significant difference in metabolite concentrations between the patient and control groups in both the parietal white matter and brainstem voxels Table 4.Carlow and colleagues observed a significant reduction in extraocular muscle volumes for the inferior rectus, medial rectus and lateral rectus Ortube and colleagues measured extraocular muscle volumes in five patients with a clinical diagnosis of CPEO Ortube and colleagues, including the relatively small number of patients that were recruited and the lack of a confirmatory molecular diagnosis. Furthermore, only a relatively small portion of the extraocular muscle belly was sampled, which could have underestimated the degree of atrophy in the recti muscles.This study has shown clear evidence of significant extraocular muscle atrophy involving all four recti muscles in CPEO. This striking observation was noted for both patients with single, large-scale mtDNA deletions and for those harbouring multiple mtDNA deletions secondary to an underlying nuclear genetic defect. In a previous report of nine patients with CPEO, Our study is the first to demonstrate objectively that the extent of extraocular muscle atrophy in CPEO is highly symmetrical between the two eyes of the same patient, reflecting the ophthalmoplegia pattern observed clinically A variable decrease in N-acetyl-aspartate (NAA) has previously been reported in the brain of patients with the Kearns-Sayre syndrome \u2013 a particularly severe clinical phenotype characterised by the development of CPEO and pigmentary retinopathy before the age of twenty years, often in association with progressive cardiac conduction block Patients with CPEO+ features had significantly reduced total grey matter and cerebellar volumes compared with controls, in keeping with the higher burden of neurological disease in this specific patient population. The prominent degree of atrophy seen in the cerebellum further highlights the particular vulnerability of this specific brain region to the deleterious consequences of mtDNA defects This comprehensive magnetic resonance study of patients with molecularly confirmed CPEO has revealed a number of important findings that are directly relevant to our understanding of the underlying pathophysiology in this mitochondrial ocular disorder. In addition to marked generalised extraocular muscle atrophy, there was clear evidence of significant CNS involvement in this disorder, which becomes clinically manifest in a subgroup of patients.Figure S1Voxel placements and proton magnetic resonance spectra.(PDF)Click here for additional data file.Figure S2Boundary delineation of extraocular muscle cross-sections.(PDF)Click here for additional data file.Figure S3Measurement protocol for brainstem and cerebellar volumes.(PDF)Click here for additional data file.Table S1Validation of extraocular muscle and brain volume measurements.(DOC)Click here for additional data file.Text S1Supplementary methods.(DOC)Click here for additional data file."}
+{"text": "Malaria prevalence has recently declined markedly in many parts of Tanzania and other sub-Saharan African countries due to scaling-up of control interventions including more efficient treatment regimens (e.g. artemisinin-based combination therapy) and insecticide-treated bed nets. Although continued molecular surveillance of malaria parasites is important to early identify emerging anti-malarial drug resistance, it is becoming increasingly difficult to obtain parasite samples from ongoing studies, such as routine drug efficacy trials. To explore other sources of parasite DNA, this study was conducted to examine if sufficient DNA could be successfully extracted from malaria rapid diagnostic tests (RDTs), used and collected as part of routine case management services in health facilities, and thus forming the basis for molecular analyses, surveillance and quality control (QC) testing of RDTs.Plasmodium species detection. Additionally, 165 archived RDTs obtained from ongoing malaria studies were analysed to determine the amplification success and test applicability of RDT for QC testing.One hyper-parasitaemic blood sample  was serially diluted in triplicates with whole blood and blotted on RDTs. DNA was extracted from the RDT dilution series, either immediately or after storage for one month at room temperature. The extracted DNA was amplified using a nested PCR method for DNA was successfully extracted and amplified from the three sets of RDT dilution series and the minimum detection limit of PCR was <1 asexual parasite/\u03bcl. DNA was also successfully amplified from (1) 70/71 (98.6%) archived positive RDTs (RDTs and microscopy positive) (2) 52/63 (82.5%) false negative RDTs (negative by RDTs but positive by microscopy) and (3) 4/24 (16.7%) false positive RDTs (positive by RDTs but negative by microscopy). Finally, 7(100%) negative RDTs (negative by RDTs and microscopy) were also negative by PCR.This study showed that DNA extracted from archived RDTs can be successfully amplified by PCR and used for detection of malaria parasites. Since Tanzania is planning to introduce RDTs in all health facilities , availability of archived RDTs will provide an alternative source of DNA for genetic studies such as continued surveillance of parasite resistance to anti-malarial drugs. The DNA obtained from RDTs can also be used for QC testing by detecting malaria parasites using PCR in places without facilities for microscopy. Malaria has for a long time remained a major cause of morbidity and mortality in most endemic countries particularly in sub-Saharan Africa. However, recent reports have indicated that malaria prevalence has declined drastically in some endemic countries -4. The dFollowing changes of malaria treatment guidelines in Tanzania in 2006, by introducing an ACT containing artemether and lumefantrine (ALu) ,8. HowevPlasmodium falciparum specific histidine rich protein 2 (PfHRP-2), Plasmodium lactate dehydrogenase (pLDH) or aldolase  districts of Tanga region, Tanzania.This study was conducted at Amani Biomedical Research Laboratory (AMBRELA) of the National Institute for Medical Research (NIMR) at Tanga Centre in Tanga region, northeastern Tanzania. Archived RDTs were obtained from ongoing studies in Muheza  and Korogwe . Other 94 RDT samples (on ParaHIT\u00aef), included 24 RDT false positive (positive by RDT but negative by microscopy), 63 false negatives (negative by RDTs but positive by microscopy) and seven negative samples (negative by both RDTs and microcopy) obtained from a cross-sectional survey conducted in May 2010 in four villages in Muheza district where high level of false positive and negative RDT results were observed in previous surveys . All 165 RDT samples were stored at room temperature in the field or laboratory for a duration of 6 - 95 days (Table The archived RDT samples included 71 RDTs (positive for both RDT and microcopy) collected at health facilities in Muheza and Korogwe districts and stored without any preservatives at room temperature (temperature ranging from 25 - 34\u00b0C). Out of these, 26 RDTs were obtained from patients enrolled in InterACT project in Muheza  were ParaHIT\u00aef (Table \u00aef), which failed to amplify by PCR, had a low parasitaemia detected by microscopy . Fifty-two (82.5%) of the 63 false negative RDTs  were positive by PCR. Eleven (17.4%) of the 63 false negative RDT samples which failed to amplify by PCR had low parasite density detected by microscopy .Table \u00aef Table . One posPfdhfr gene as a marker of pyrimethamine resistance using DNA extracted from RDTs was also successful and the results were similar to those observed when DNA was obtained from other sources such as cultured parasites or filter papers.Detection of microscopically negative samples was equally successful whereby, 20 out of 24 (83.3%) RDT false positive samples (which were positive by RDTs but negative by microscopy) were confirmed to be negative by PCR. Fourteen out of the 20 RDT false positive samples with negative PCR results were obtained from individuals who had taken anti-malarials (within seven days) before the survey. All seven negative RDTs (negative by both RDTs and microscopy) were also negative by PCR Table . Detectiet al, personal communication) and most likely, the decline is apparent in other parts of Tanzania as well . However, because of this current positive trend, recruitment of malaria positive patients for various studies, such as malaria drug efficacy trials has proved to be difficult. Since the region has been known as a hotspot for the emergence of anti-malarial drug resistance in Eastern Africa [Previously, malaria has consecutively been shown to be the main cause of morbidity and mortality in Tanga region, as for the rest of Tanzania -31. Howen Africa -36, it iIn this context, the study presented here has shown that archived RDTs used for malaria diagnosis in routine practice can be used as an alternative source of DNA for detection of malaria parasites and other molecular analyses. The RDTs can also be used as source of DNA as part of QC testing of RDTs instead of microscopic examination of Giemsa-stained blood smears, by comparing RTD results produced by health workers with those obtained in the laboratory based on detection of malaria parasite by PCR. Thus, after deployment of RDTs in the field, archived RDTs can also be used for QC of RDTs in addition to using Giemsa-stained blood smears, particularly in health facilities without capacity for performing malaria diagnosis by microscopy or lacking the skills and experience to prepare good blood smears as recently shown in Eastern Tanzania by McMorrow and colleagues ,25.Storage of RDTs (that were prepared in the laboratory) for one month either with or without silica gel as preservatives did not affect the quality of extracted DNA as determined by the detection limit of PCR in the diluted samples and band intensity of amplified products in comparison to known standard DNA samples which were used as control. Similarly, field samples stored at room temperature without preservatives for over 3 months were equally amplified. However, the impact of long term storage of RDTs beyond this duration on the quantity and quality of DNA is not clearly known, particularly if they are stored at room temperature without preservatives and under high ambient temperature, and humidity (as in most parts of Tanzania) which support growth of moulds that can degrade the parasite DNA. The period of three months or more shown in this and a previous study  should b\u00aef and Paracheck Pf\u00ae) examined provided DNA of sufficient quality with similar amplification success although the quantity of DNA was not assessed. This is in concordance to a previous study which showed that the type/brand of RDTs did not affect the quality of extracted DNA [Both types of PfHRP-2 based RDTs (ParaHITcted DNA . Furthercted DNA . Among tcted DNA .This study showed that DNA can be extracted from routinely used and archived RDTs, and successfully amplified by PCR; thus providing an alternative source of DNA for detection of malaria parasites and possibly other molecular analyses such as surveillance of parasite resistance to anti-malarial drugs and monitoring of insidious parasite reservoirs in different interventions, such as malaria elimination programmes. Furthermore, the RDTs can be used for QC testing of RDTs deployed in the field for malaria diagnosis based on comparing the results obtained by PCR genotyping of DNA extracted from archived RDTs with the test results produced by health workers, particularly from remotely located health facilities without the capacity of microscopic examination of blood smears. Thus, availability of archived RDTs after the tests are deployed in all health facilities in Tanzania as planned by the Ministry of Health and Social Welfare will provide a good source of parasite DNA for laboratory studies.Plasmodium falciparum; PfHRP-2: Plasmodium falciparum histidine rich protein 2; RDTs: Rapid diagnostic tests; WBCs: white blood cells; WHO: World Health Organisation; \u03bcl: microlitre.ACT: artemisinin combination therapy; DNA: deoxyribonucleic acid; pLDH: Plasmodium lactate dehydrogenase; NIMR: National Institute for Medical Research; NMCP: National Malaria Control Programme; PCR: polymerase chain reaction; Pf: The authors declare that they have no competing interests.DSI, MA conceived of the study, designed the experiments, supervised the laboratory analyses and wrote the manuscript. NN, OP and LV participated in study design and supplied archived RDTs while SL and RAM conducted the laboratory analyses. MML and ICB participated in study design and supervised the study. All authors read and approved the manuscript."}
+{"text": "In contrast to the RNA viruses, the genome of large DNA viruses such as herpesviruses have been considered to be relatively stable. Intra-specific recombination has been proposed as an important, but underestimated, driving force in herpesvirus evolution. Recently, two distinct field strains of infectious laryngotracheitis virus (ILTV) have been shown to have arisen from independent recombination events between different commercial ILTV vaccines. In this study we sequenced the genomes of additional ILTV strains and also utilized other recently updated complete genome sequences of ILTV to confirm the existence of a number of ILTV recombinants in nature. Multiple recombination events were detected in the unique long and repeat regions of the genome, but not in the unique short region. Most recombinants contained a pair of crossover points between two distinct lineages of ILTV, corresponding to the European origin and the Australian origin vaccine strains of ILTV. These results suggest that there are two distinct genotypic lineages of ILTV and that these commonly recombine in the field. Herpesviridae have genomes ranging in size from 124 to 241 kbp Alpha-, Beta- and Gammaherpesvirinae. Classically, sequences obtained from a single gene or multiple concatenated genes have been used for phylogenetic analyses of herpesviruses. More recently developments in high-throughput sequencing techniques have resulted in the availability of complete genome sequences for comparative complete genomic analyses of herpesviruses Herpesviruses are highly host-specific double stranded DNA viruses that have been isolated from most animal species, including mammals, birds, reptiles and fish. The Alphaherpesvirinae (genus Iltovirus) and causes acute upper respiratory tract disease in chickens Iltovirus genus (including psittacid herpesvirus 1 (PsHV1) and ILTV) separated from the mammalian alphaherpesviruses around 200 million years (Mys) ago, in agreement with the theory that herpesviruses have co-evolved with their hosts AlphaherpesvirinaeInfectious laryngotracheitis virus  belongs to the subfamily In Australia three commercial live ILTV vaccines  are registered for use. The SA2 vaccine strain  is an attenuated ILTV field strain isolated from South Australia in 1950 Australian ILTV field strains and vaccine strains have been classified into nine genotypes (classes 1 to 9) using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis th century) In a previous report we analysed and compared the complete genome sequences of two Australian origin ILTV vaccines and a European origin ILTV vaccine strain. The genome sequences of the two Australian origin vaccines differed by only 23 nucleotide substitutions, even though one of the strains was derived from the other after more than twenty-five serial passages in cell culture and embryonated eggs. Although similar to each other, these two Australian vaccine strains showed considerable divergence (0.8% nucleotide difference) from the genomic sequence of the European origin ILTV vaccine strain. This is higher than the 0.1\u20130.5% nucleotide difference reported between the most distantly related strains of varicella zoster viruses (VZV), which is a human alphaherpesvirus with the same genomic sequence arrangement as ILTV The aim of this study was to better understand the molecular epidemiology of ILTV by analysing a broader range of ILTV sequence data, including currently available complete or partial genomic sequences of ILTV. The complete genome sequences of two Australian ILTV field strains (V1-99 and CSW-1) were determined using high-throughput sequencing and included in these analyses. Additionally, we aimed to identify the origins of the parent strain of the Australian ILTV vaccines by searching for similar genotypes among publically available nucleotide sequences from ILTV strains isolated in other countries.de novo and mapped to the complete genome sequence of the Serva vaccine strain. Sequence gaps were filled and ambiguous sequences clarified using Sanger sequencing. The size of the ILTV genomes ranges from 150,335 to 153,952 bp . The size of the strain V1-99 genome was 153,631 bp, similar to that of the Serva strain . The V1-99 and Serva strains shared 99.6% nucleotide sequence identity. The CSW-1 strain genome was somewhat smaller  due to three large deletions within the unique long region  and both the internal and terminal repeat regions (463 bp) (Sequencing data from the V1-99 and CSW-1 strains of ILTV obtained by high-throughput sequencing were assembled (463 bp) . Excludi(463 bp) .In order to further understand the relationship between ILTV vaccine strains and Australian field strains of ILTV, complete genome sequence alignments were performed and phylogenetic trees were inferred using the six complete genomic sequences of ILTV currently available. This analysis included a European origin vaccine (Serva), an Australian origin vaccine (SA2), two Australian field strains (V1-99 and CSW-1) and two strains from the USA (63140 and USDAref). The sequences were examined in order to identify relevant genes that could be used to differentiate between all six strains .All predicted ORFs were extracted from the complete genome alignments and separate phylogenetic trees were inferred from the nucleotide sequences of each ORF. Similarly, alignments of amino acid sequences for all the predicted ORFs were performed separately and phylogenetic trees were inferred. The UL21, 32, 34 and 43 genes of all six ILTV strains were found to share 100% nucleotide and amino acid sequence identity. The UL3, 4, 13, 14, 18, 24, 31, 33, 40 and 49 genes of the six strains had differing nucleotide sequences, but were predicted to have 100% amino acid sequence identity. The ICP4, UL27, UL36, US5 and US8 genes showed the most variability within the six strains of ILTV and the six strains could be distinguished using the nucleotide and/or amino acid sequences of these genes . The UL2All available nucleotide sequences for the ICP4 and UL27 genes of ILTV from the NCBI database were aligned and phylogenetic analyses were performed . The EurTo confirm the close relationship between the Australian origin vaccine strain and strains isolated from backyard flocks in the USA, concatenated nucleotide and amino acid sequences were generated using all available sequences for each of these strains. This included the complete sequences of the UL27, UL32 and UL10 genes from the unique long region, the UL47 and US4 genes from the unique short region, and the complete sequence of the ICP4 gene from the repeat region. Surprisingly, one of the strains isolated from backyard flocks in the USA (25/H/88/BCK) shared 100% amino acid sequence identity  with the concatenated sequence of the Australian origin vaccine. Another strain isolated from backyard flocks in the USA (12/D/02/BCK) differed in only two amino acid residues from the Australian origin vaccine strain . These rA possible mosaic pattern of relationship between the genome sequences of the Australian field strains of ILTV was detected in the phylogenetic analyses of the UL27 and ICP4 genes . In addiTo confirm the mosaic patterns of these relationships and detect the suspected recombination events responsible, we performed additional phylogenetic analyses on the nucleotide sequences of the UL47 and US4 genes . As expeIn order to define recombination crossover points, Bootscan analyses were performed using complete genome alignments of five ILTV strains . Bootscan analyses of the 1874C5 and CSW-1 strains revealed pairs of crossover points in the repeat region, while the 81658 strain had multiple tightly grouped pairs of crossover points in the unique long region . Most ofA history of recombination was not detected in the sequences located in the unique short region of the genome of the eight strains of ILTV for which complete genomic sequence was available, so the sequences of this region were used to investigate the evolutionary history of ILTV. In the resulting trees, all Australian strains of ILTV clustered together and separately from European and USA strains of ILTV . The timin vivo. In this study, we sought to perform broader phylogenetic analyses of ILTV in order to understand the evolution and molecular epidemiology of the virus. We found that the parent strains of Australian origin vaccine and Australian field strains may have been imported into Australia from the USA. Moreover, with the exception of field isolates derived from bird-to-bird passage of commercial vaccines, most field strains of ILTV isolated in Australia and in other geographic areas of the world show evidence of historical recombination events between two distinct viral lineages, represented by the Serva and SA2 strains.Genome wide comparative sequence analyses of closely related strains of ILTV, or of strains from specific geographical regions, have been reported previously The Australian origin SA2 vaccine was produced using an Australian field isolate that induced comparatively smaller pocks on the chorioallantoic membrane of embryonated hen eggs In order to search for an SA2-like strain of ILTV in other geographical areas, we compared the phylogenetic tree inferred from alignments of complete genome sequences with those inferred from alignments for all individual predicted ORFs. The ICP4, UL27, UL36, US5 and US8 genes were found to be sufficiently divergent to allow differentiation between distinct strains of ILTV . ComparaThe European origin Serva vaccine strain was recently registered in Australia and rapidly became widely used by the Australian poultry industry within a relatively short timeframe The Australian field strains V1-99 and CSW-1 and the USA field strain 874C5 shared a distinct sequence segment in the unique long region. This suggests that the Australian field strains and the 1874C5 strain may have shared the same (or very similar) parent strain(s) before recombination, or that these strains may have obtained this distinctive sequence segment from some other strain in independent recombination events.Evidence of historical intra-specific recombination in alphaherpesviruses has been described previously With the exception of the USDAref and 81658 ILTV strains, which each contained three recombination crossover points, all other ILTV recombinants contained a single pair of recombination crossover points between the Serva-like and the SA2-like parental strains, as detected by bootscan analyses. Recombination networks further supported these findings, confirming that recombination events occurred in the unique long and the repeat regions, but not in the unique short region  and 7. TIn conclusion, the origins of Australian strains of ILTV have been determined using complete genomic sequence analyses of multiple strains of ILTV and wider phylogenetic analyses. Moreover, evidence for significant recombination events in most field strains of ILTV was identified by recombination network and bootscan analyses. We found that the Serva-like and SA2-like lineages of ILTV have recombined frequently over the history of ILTV evolution. This, taken together with data from our previous studies Pock purified V1-99 (six passages from isolation) and a laboratory stock of CSW-1 ILTV (approximately twenty passages from isolation) de novo assembled contigs and to produce a consensus sequence using the Serva ILTV genomic sequence (Genbank accession HQ_630064) as reference. Any sequence gaps or ambiguous regions of sequence were confirmed by Sanger sequencing using BDT version 3.1 (Applied Biosystems). The complete genome sequences of the V1-99 and CSW-1 strains of ILTV have been deposited in the NCBI GenBank database under the accession numbers JX646898 and JX646899.Total viral genomic DNA preparation, high-throughput sequencing and genome assembly were performed as previously described Complete genome sequences, nucleotide sequences and amino acid sequences used in this study are summarized in To detect evidence of historical recombination events between ILTV strains, recombination networks were generated using SplitsTree 4 To estimate the time points of divergence between ILTV strains, the Minimum Evolution Table S1ILTV genome and gene sequences used in this study.(DOC)Click here for additional data file."}
+{"text": "A stationary  association between El Ni\u00f1o Southern Oscillation (ENSO), the Indian Ocean Dipole (IOD) and epidemics of cholera in Bangladesh has been widely assumed. However, whether or not elements of the local climate that are relevant for cholera transmission have stationary signatures of the IOD on their dynamics over different time scales is still not clear. Here we report results on the time-varying relationships between the various remote and local environmental drivers and cholera incidence in Bangladesh.We performed a cross wavelet coherency analysis to examine patterns of association between monthly cholera cases in the hospitals in Dhaka and Matlab (1983\u20132008) and indices for both IOD and ENSO. Our results showed that the strength of both the IOD and ENSO associations with cholera hospitalizations changed across time scales during the study period. In Dhaka, 4-year long coherent cycles were observed between cholera and the index of IOD in 1988\u20131997. In Matlab, the effect of ENSO was more dominant while there was no evidence for an IOD effect on cholera hospitalizations.Our results call for the consideration of non-stationary, possibly non-linear, patterns of association between cholera hospitalizations and climatic factors in cholera epidemic early warning systems. Vibrio cholerae, the bacterium that causes the disease, is known to inhabit riverine, estuarine and coastal ecosystems with specific abiotic  and biotic components  V. cholerae has an increased growth rate in aquatic environments with warmer temperatures, particularly when combined with a high pH and blooms of phytoplankton, aquatic plants or algae Cholera remains a major public health problem in many places, including Bangladesh, India, and a number of countries in Africa and South America V. cholerae multiplication It has been reported that the El Ni\u00f1o-Southern Oscillation (ENSO) plays a role in the interannual variation of endemic cholera in Bangladesh The Indian Ocean Dipole (IOD) is another climate mode that arises from ocean-atmosphere interactions that cause interannual climate variability in the tropical Indian Ocean Wavelet analysis is useful for epidemiological time series analyses mainly because of the non-stationarity of associations between the disease dynamics and exposure covariates Dhaka: The ICDDR,B hospital serves a large urban population within the city of Dhaka and provides free treatment for more than 100,000 cases of diarrhea each year. A surveillance system was established at the ICDDR,B in 1979 to systematically sample children and adults with diarrheal illnesses th patient was enrolled in the surveillance system, and since 1996 every 50th patient has been enrolled. Matlab. Matlab is a rural and riverine delta area situated approximately 57 km southeast of Dhaka. Every hospital visit of patients residing within the area covered by the Health and Demographic Surveillance System (HDSS), which consists of 142 villages with populations over 220,000, was registered in the hospital surveillance system The primary outcome for this study was the monthly number of patients with cholera who attended the International Centre for Diarrhoeal Disease Research, Bangladesh  hospitals in Dhaka and Matlab . Dhaka: V. cholerae. The details of the laboratory procedures were described in a previous study V. cholerae of the serogroups O1 or O139 was identified in the stool specimen, regardless of the presence of other pathogens. From the surveillance data that had been collected over a 26-year period (January 1983 to December 2008) for Dhaka and 28-year period (January 1981 to December 2008) for Matlab, we retrieved the date of the hospital visit and the pathogens identified in each stool specimen. From these data, the monthly cholera cases in Dhaka and Matlab were counted separately and used for analysis.For each diarrhea patient of the ICDDR,B hospitals in Dhaka and Matlab, the stool was microbiologically examined to identify common enteric pathogens including www.jamstec.go.jp/frcgc/research/d1/iod/). The DMI values were calculated using the SST data from the HadISST dataset (http://www.metoffice.gov.uk/hadobs/hadisst/). The base period for calculating anomalies was 1958\u20132008. These values were standardized to zero mean and unit standard deviation. The strength of the ENSO was measured by monthly average SSTs in the Ni\u00f1o 3 region  (Nino3) in the Pacific Ocean that we derived from the National Oceanic and Atmospheric Administration (NOAA) Climate Prediction Center data (http://www.cpc.ncep.noaa.gov). We examined the association between DMI and monthly average SST in the northern Bay of Bengal to gain some insight into the causal pathways linking the IOD to the number of cholera cases. Mean monthly SSTs in the Bay of Bengal  were derived from the NOAA Optimum Interpolation Sea Surface Temperature dataset The strength of the IOD was measured by the dipole mode index (DMI), defined as the difference in SST between the western  and eastern  tropical Indian Ocean The daily rainfall and maximum and minimum temperature data for Dhaka and Matlab were obtained from the Bangladesh Meteorological Department. The data for the daily river levels of the Brigonga (Millbarrak in Dhaka) and Danagoda (Matlab Bazaar) rivers were obtained from the records maintained by the Bangladesh Water Development Board. The monthly means for the maximum temperature (\u00b0C) and maximum river level (m), and the total monthly rainfall (mm) were calculated from the daily records. Missing values (17 [5.4%] in Dhaka and 6 [1.9%] in Matlab) for river levels were imputed using the average values of the same month in the other years over the whole time series.Temporal patterns of association in the time series were studied using the continuous wavelet transform 0\u200a=\u200a6 months , a total smoothing window of 31  and parameter W0\u200a=\u200a6 (dimensionless parameter of the Morlet Wavelet). Further details about cross wavelets and software are described in Maraun and Kurths V. cholerae El Tor O1 biotype strain and one for the O139 Bengal strain.We also estimated the cone of influence, where inferences from the wavelet analysis outside the cone of influence are not valid because of the manipulations that were performed to generate the wavelet spectrum in the absence of data for larger period frequencies We did not stratify the analysis by age, because the seasonal patterns were the same and there was no likely reason to expect different cholera-climate associations between the age groups at interannual time scales.The associations between DMI, Nino3 and monthly average temperature, rainfall and SST in the northern Bay of Bengal were also examined by wavelet coherence analysis. All the analyses were performed with R software (version 2.0).The time series for the number of cholera patients per month, by serogroup and biotype, ambient temperature, rainfall and river level during the study period are shown for Dhaka  and MatlThe time series for Dipole Mode Index (DMI), Nino3 and sea surface temperature (SST) during the same period are shown in Four-year long coherent cycles between O1 cholera and DMI were seen in 1988\u20131997 in Dhaka  while thV. cholerae were similar to the result for the El Tor O1 biotype strain alone because the frequency of the O1 biotype was dominant during the study period  in the Bay of Bengal The association between Dipole Mode Index (DMI) and cholera hospitalizations that we found in Dhaka was not observed in Matlab, while a consistent association between Nino3 and cholera hospitalizations was observed only in Matlab. The associations that we found between DMI and Nino3 with cholera are broadly consistent with previous finding There are some limitations in this study. First, less severe cases of cholera are less likely to have been included in the surveillance data; however, this should not pose a threat to the validity of the comparison over time, which was the subject of this study. Second, some cases could have been missed because of limitations in the capacity of the hospitals to receive the patients; particularly, during epidemics of cholera. However, in principle, the hospitals accept all patients who visit the hospital. Thus, the capacity of the hospitals should not be an important limitation of this study. Third, the wavelet analysis explores a periodical synchronicity between two time series, and so has no bearing on mechanisms. Further environmental and microbiological studies are necessary to elucidate the causal pathways of the associations.Because of the serious global consequences of cholera and its sensitivity to climate, the World Health Organization has proposed that an early warning system for cholera epidemics using climatic parameters could be developed Figure S1Monthly time series of cholera hospitalizations by (a) serotype O1 & O139 and (b) bio-type El Tor & Classical for Dhaka (January 1983\u2013December 2008).(TIF)Click here for additional data file.Figure S2Monthly time series of cholera hospitalizations by (a) serotype O1 & O139 and (b) bio-type El Tor & Classical for Matlab (November 1981\u2013December 2008).(TIF)Click here for additional data file.Figure S3Cross wavelet coherence of global and local climatic time series with cholera in Dhaka and Matlab. (A) Dipole mode index (DMI) and cholera in Dhaka; (B) DMI and cholera in Matlab; (C) Nino3 and cholera in Dhaka; (D) Nino3 and cholera in Matlab; (E) Sea surface temperature (SST) in the Bay of Bengal (\u00b0C) and cholera in Dhaka; (F) SST in the Bay of Bengal (\u00b0C) and cholera in Matlab; (G) Rainfall (mm) and cholera in Dhaka; (H) Rainfall (mm) and cholera in Matlab; (I) Temperature (\u00b0C) and cholera in Dhaka; (J) Temperature (\u00b0C) and cholera in Matlab; (K) River level (m) and cholera in Dhaka; (L) River level (m) and cholera in Matlab. Time series span from January 1983 to December 2008.(TIF)Click here for additional data file.Figure S4Cross wavelet coherence of global and local climatic time series with classical biotype and El Tor cholera in Dhaka. (A) Dipole mode index (DMI) and classical cholera; (B) DMI and El Tor cholera; (C) Nino3 and classical cholera; (D) Nino3 and El Tor cholera; (E) Sea surface temperature (SST) in the Bay of Bengal (\u00b0C) and classical cholera; (F) SST in the Bay of Bengal (\u00b0C) and El Tor cholera; (G) Rainfall (mm) and classical cholera; (H) Rainfall (mm) and El Tor cholera; (I) Temperature (\u00b0C) and classical cholera; (J) Temperature (\u00b0C) and El Tor cholera; (K) River level (m) and classical cholera; (L) River level (m) and El Tor cholera. Time series span from January 1983 to December 2008.(TIF)Click here for additional data file.Figure S5Cross wavelet coherence of global and local climatic time series with classical biotype and El Tor cholera in Matlab. (A) Dipole mode index (DMI) and classical cholera; (B) DMI and El Tor cholera; (C) Nino3 and classical cholera; (D) Nino3 and El Tor cholera; (E) Sea surface temperature (SST) in the Bay of Bengal (\u00b0C) and classical cholera; (F) SST in the Bay of Bengal (\u00b0C) and El Tor cholera; (G) Rainfall (mm) and classical cholera; (H) Rainfall (mm) and El Tor cholera; (I) Temperature (\u00b0C) and classical cholera; (J) Temperature (\u00b0C) and El Tor cholera; (K) River level (m) and classical cholera; (L) River level (m) and El Tor cholera. Time series span from November 1981 to December 2008, with the exception of river level which begins in January 1983.(TIF)Click here for additional data file."}
+{"text": "As Breast Cancer and Environment Research Center (BCERC) project leaders, we would like to address what we believe represents inaccuracies and omissions in the recent article by The LIBCSP has been enormously productive, continuing even now, with > 100 scientific publications and $21 million in grant funding using LIBCSP resources. \u201d 16 times, without noting the impressive contributions of the BCERC Community Outreach and Translation Cores (COTC) projects. Advocacy and COTC in the BCERC since 2003 have resulted in extensive and innovative dissemination of knowledge and new ideas (ew ideas . Mutual As noted by"}
+{"text": "Sudden cardiac death (SCD) is responsible for 11% of all deaths and 50% of all cardiovascular deaths. Hypertrophic cardiomyopathy (HCM) is the most common cause of SCD among the young patients. SCD is often the first manifestation of the disease. There are 5 major risk factors for SCD in patients with HCM. However, no single risk factor can be used as a screening test in assessment of SCD. Nowadays new non-invasive risk factors, such as T-wave alternation (TWA), are being studied. They may provide important information on the patient\u2019s susceptibility to life threatening arrhythmias.The study involved 33 hypertensive heart disease (HHD) patients and 22 HCM patients. All patients underwent echocardiography test (ECHO) and 24h Holter monitoring with mTWA evaluation using the modified moving average method. The evaluation involved maximum mTWA figures in 24h (mTWA max), mTWA figures at the heart rate of 100/min (mTWA 100) and at 5:00 am (mTWA 5:00).The common group demonstrated a weak direct correlation between the thickness of ventricular septum (IVSth) and mTWA max, as well as a weak reverse correlation between the left ventricular posterior wall thickness (LVPWth) and mTWA 100. These correlation were revealed primarily in HHD patients who demonstrated correlation between mTWA max and IVSth, between mTWA 5:00 and IVSth, LVPWth, as well as between mTWA 100 and LVPWth. The HCM patients did not demonstrate correlation between mTWA and the thickness of left ventricular wall. The patients with non-obstructive HCM (n=15) demonstrated significantly higher mTWA 100 in comparison to the patients with obstructive HCM (n=5). The presence of higher SCD risk factors in the HCM patients (n=6) did not influenced mTWA figures. The mTWA figures in the HHD and HCM patients differed insignificantly, with the only exception of higher mTWA 5:00 in the HHD in comparison to the HCM group.mTWA figures correlate with the degree of left ventricular hypertrophy, however the revealed correlations are weak. The causes of lower MTWA 100 in patients with more intensive hypertrophy (reverse correlation) as well as in patients with obstructive HCM in comparison with non-obstructive HCM call for additional studies."}
+{"text": "Bordetella pertussis (DTwP). In contrast, similar studies suggest that many African females and males may have their lives saved each year by the nonspecific immunological benefits of Bacillus Calmette-Guerin (BCG) vaccination. From an immunological point of view, we hypothesise that the adverse effects of DTwP vaccine may occur because of the Th2-polarising effect of the aluminium phosphate adjuvant in the vaccine and because intramuscular administration of the vaccine may cause chronic inflammation at the site of injection. However, the Th1-polarising effect of BCG is likely to be beneficial. Sexual dimorphism affecting immune functions and vitamin A supplementation may influence both the deleterious and beneficial nonspecific effects of immunisation.A number of mainly observational studies suggest that many African females below the age of one year die each year from the nonspecific effects of vaccination with diphtheria-tetanus toxoids and killed (whole-cell)  The paper discusses the immunology behind the reported nonspecific effects of DTwP and BCG vaccination: increased childhood mortality rates after DTwP and decreased mortality rates after BCG vaccination given during the course of the WHO recommended vaccine programs implemented in Guinea-Bissau and other low-income countries , 2. BothBordetella pertussis vaccine. A typical DTwP vaccine dose (0.5\u2009mL) from the Serum Institute of India contains diphtheria toxoid (25\u2009Lf), tetanus toxoid (5\u2009Lf), and pertussis toxoid (4\u2009IU), aluminium phosphate (1.5\u2009mg), and a preservative, thiomersal (0.01%). Aluminium phosphate acts primarily as an antigen-adsorbing and Th2-polarizing adjuvant \u03b3 and TNFIn spite of numerous studies, there is still only weak evidence for any effect of micronutrient supplementation on vaccine efficacy (reviewed in ). Howeve The deleterious effect of DTwP vaccination in infant females and the beneficial outcomes of BCG vaccination might reflect nonspecific immune-polarizing and nonintended regulatory effects of vaccines and sex hormones in early childhood. The data from West Africa on the nonspecific effects of DTwP and BCG vaccination in young children discussed here suggest (1) replacement of intramuscular DTwP vaccination with cutaneous vaccination or development of a DTwP vaccine live bacterial carrier such as BCG  which maIn low-income countries with high rates of childhood mortality, the nonspecific effects of routine vaccinations are likely to be of increased importance due to the high disease burden. The nonspecific vaccine effects should therefore be a high-priority research area and be considered in the future planning of immunization programs in these countries to enhance the beneficial impact of immunizations on child survival.The author has no relevant affiliations or financial involvement with any organization of entity with financial interest in or financial conflict with the subject matter discussed in this paper. No writing assistance was utilized in the production of this paper."}
+{"text": "Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A  was associated with the presence of paradoxical heat sensation (p\u200a=\u200a0.03), and transient receptor potential vanilloid 1 1911A>G  with cold hypoalgesia (p\u200a=\u200a0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia  and transient receptor potential vanilloid 1 1103C>G  to cold hypaesthesia (p\u200a=\u200a0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients. Neuropathic pain arises after lesions or diseases of the somatosensory nervous system and involves multiple somatosensory phenomena. In addition to spontaneous pain, these include negative and positive symptoms and signs such as hypaesthesia, hypoalgesia, thermal and mechanical hyperalgesia and allodynia The understanding of the molecular basis of neuropathic pain has been expanded by the cloning and characterization of the transient receptor potential (TRP) family of voltage-gated ion channels. Among these the TRP vanilloid 1 (TRPV1), TRP melastin 8 (TRPM8) and TRP ankyrin 1 (TRPA1) subfamilies have been found to play important roles in transduction and sensitisation in primary afferent somatosensory neurons Beside these physiological functions, TRPs are thought to play an important role in the generation of neuropathic pain, as demonstrated by in vitro and in vivo animal studies and neurophysiological and psychophysical studies in human experimental pain models and pain patients However, the contribution of a genetic variability in TRP channels on pain perception and pain generation in neuropathic pain patients is unknown. In this study we describe the results of an association analysis of polymorphisms in TRPV1, TRPM8 and TRPA1 genes with somatosensory signs of neuropathic pain patients. The aims were (1) to determine the frequencies of TRP variants in a large group of neuropathic pain patients of different aetiology and a cohort of healthy volunteers and (2) to determine the relationship of TRP gene variants and somatosensory function in neuropathic pain patients. Within this study we could demonstrate significant associations between the somatosensory function and TRP gene variants in neuropathic pain patients but no differences in the TRP frequencies compared with healthy volunteers.All subjects gave their written informed consent and the study was approved by the ethics committee of the Medical Faculty of the Christian-Albrechts-University Kiel and subsequently the Ethic Committees of the other participating DFNS centers and performed according to the Declaration of Helsinki.www.neuro.med.tu-muenchen.de/dfns/) were included in the study . The patients suffered from complex regional pain syndrome, postherpetic neuralgia, peripheral nerve injury, trigeminal neuropathy, polyneuropathy, central pain and neuropathies that did not fulfill diagnostic criteria of the above mentioned syndromes as diagnosed by expert physicians. Patient characteristics are listed in A total of 371 patients with chronic neuropathic pain syndromes, all Caucasians, who participated in the German Research Network on Neuropathic Pain  established by the DFNS to determinate somatosensory function and signs of pain Whole genomic DNA was extracted from venous blood samples obtained from patients and volunteers using the Qiagen Gentra Puregene Blood Kit . The final concentration of gDNA was determined spectrophotometrically. Two SNPs in TRPV1, six in TRPM8 and three in TRPA1 genes were identified by literature review in the context of neuropathic pain and selected for detailed association analysis . Except Before statistical analysis the QST values that did not show normal distribution  were transformed logarithmically In order to identify major subpopulations of patients who are characterized by a typical combination of signs, a cluster analysis was performed in those patients only from whom complete QST results were available  and for bi-allelic polymorphisms each subtest and genotype were calculated using analysis of variance (ANOVA). For dominant and recessive models the t-test was used, if applicable. To correct for multiple testing each test was performed using 100,000 permutations.The frequency distribution of all polymorphisms investigated was in Hardy-Weinberg equilibrium. Moreover, after correcting for multiple comparisons, the frequency of all SNPs did not differ significantly between neuropathic pain patients, healthy controls and data from the HapMap project .First, within the group of patients who suffered from paradoxical heat sensation (PHS) heterozygous and homozygous carriers of the TRPA1 710G>A variant were significantly under-represented as compared to neuropathic pain patients without PHS  . Second,Hierarchical cluster analysis detected two main clusters . ClusterZ-scores of all QST tests were stratified to all TRP variants investigated in the entire sample and in both clusters. After correcting for multiple comparisons, two TRPV1 polymorphisms, 1911A>G and 1103C>G, were identified that had a significant relationship with the somatosensory function in cluster 1 .The TRPV1 1911A>G polymorphism was significantly associated with altered heat pain thresholds (HPT). Neuropathic pain patients being heterozygote or with wild type TRPV1 1911G genotype (AA or AG) tended to show heat hyperalgesia whereas TRPV1 1911G homozygotes exhibited significantly higher, i.e. normal heat pain thresholds . Homozygous variant carriers (GG) exhibited cold hypaesthesia compared with heterozygous or wild type carriers Click here for additional data file."}
+{"text": "The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases (IBD) have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of IBD have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn's disease (CD) and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of IBD. The lower gastrointestinal tract of healthy adult humans contains more than 100 trillion bacteria  and the impact of microbiota on these pathologies Figure .+ and CD8+ T lymphocytes, regulatory T cells, neutrophils and macrophages, resembling the pathogenic events in human colitis. Mucosal macrophages may prime the local inflammatory response through both phagocytosis of DSS and activation by bacteria products. The contribution of macrophage polarization phenotype to the development of CAC has been described using this model including the demonstration that Akt2 deficient mice are partly protected from DSS-induced colitis because of a macrophage phenotype shift from M1 to M2 in the colonic mucosa . DSS administered to the drinking water in repeated cycles triggers a state of chronic intestinal inflammation by binding to medium-chain-length fatty acids present in the mouse colon, inducing disruption of colonic epithelial barrier  by cytochrome P450 . DMH is metabolized in liver and its derivatives induce the production of diazonium by gut epithelial cells. The aforementioned metabolite exerts mutagenic effects through oxidative stress and methylation events  initiates acute T cell-mediated, IL-12 driven intestinal inflammation  and develops numerous adenomas. Exposure of Apcmin/+ mice to DSS alone mimics CAC and results in accelerated tumorigenesis  gene in humans are critically involved in familial adenomatous polyposis (FAP) and represent an early genetic aberration in sporadic colorectal cancer  can be adoptively transferred into immunodeficient SCID or RAG1/2\u2212/\u2212 mice, where they traffic to the intestine and induce gut inflammation. Recipient mice repopulated with CD4+CD45RBLo T cells or total CD4+ T lymphocytes do not develop colitis, despite their ability to colonize the host gut. This phenomenon is attributed to the presence of CD25+FoxP3+ regulatory T cells within the CD4+CD45RBLo population  conditions  results in spontaneous colitis which is transmissible to wild-type animals (which express T-bet) upon cross-fostering or co-housing , which harbors 8 genes and 5 micro RNAs and confers protection against H. hepaticus-induced chronic colitis and inflammation-driven colon cancer  activity. Resident Treg produce IL-10 which inhibits Th1 cells and monocyte effector functions associated with inflammation. Suppression of Treg activity thereby unleashes inflammation, leading to a switch in the differentiation program of Ly6Chi monocytes from anti-inflammatory M2 macrophages to inflammatory dendritic cells and M1 macrophages in the colon   microbes or inhibitors of specific microbes and/or their products which \u201cnormalize\u201d the intestinal flora and can improve human health. As the current repertoire of probiotics is limited, further studies to explore the potential of fecal microbiota transplantation (FMT) therapy, the infusion of fecal bacteria from a healthy individual into a recipient patient, for the treatment of intestinal disorders are warranted. FMT has demonstrated tremendous efficacy in treating refractory The microbiome plays an important role in immunity and energy metabolism and will thus be important to determine if the microbial gut ecology may also impact on non-gastrointestinal diseases, including obesity, cancer and neurological disorders.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Early diagnosis of macrophage activations syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) may be challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. However, the diagnostic value of the guidelines for hemophagocytic lymphohistiocytosis (HLH) (1) or sJIA-associated MAS (2) has seldom been examined.To investigate the sensitivity and specificity of diagnostic guidelines for HLH and sJIA-associated MAS in patients with sJIA who developed MAS.The study sample included 155 children with sJIA who had MAS (diagnosed and treated as such by the attending physician) and 2 control groups with potentially \u201cconfusable\u201d conditions, including active sJIA without MAS (n=303) and a systemic febrile infection requiring hospitalization (n=191). Diagnostic guidelines for HLH and sJIA-associated MAS were applied to all MAS and control patients. Because no patient had NK-cell activity and soluble CD25 determination available and bone marrow aspirate was performed in only a few patients, these 3 criteria were excluded from HLH guidelines. HLH criteria were, therefore, met when at least 4 of the 5 remaining variables were present. sJIA-associated MAS criteria were met when at least 2 laboratory criteria or at least 1 laboratory criterion and 1 clinical criterion were present. Sensitivity and specificity of guidelines in discriminating patients with MAS from control patients were assessed.The table shows the comparison of sensitivity and specificity of diagnostic guidelines.The diagnostic guidelines for sJIA-associated MAS revealed strong sensitivity and specificity, whereas HLH guidelines were highly specific, but lacked sensitivity. Sensitivity of HLH was mostly hampered by the excessive stringent threshold for cytopenia and hypofibrinogenemia, and the infrequent occurrence of splenomegaly in patients with MAS."}
+{"text": "Pain is a common problem for patients admitted to the ICU, causing patient discomfort, agitation and accidental self-extubation. For this reason the recognition of pain and its severity is extremely important. Several pain scores and protocols are in use. We aimed to elucidate current practice of pain measurements and treatment in Dutch ICUs.In March 2011, a questionnaire was sent to all Dutch adult ICUs irrespective of the number of ICU beds with active follow-up by telephone calls to optimize the participation rate.A total of 84 ICUs (84/107) returned the survey, representing a response rate of 87%. Most ICUs are community teaching hospitals and nonteaching hospitals (85%) in comparison to academic hospitals (15%). Most ICUs (94%) use a standardized pain score in the group of patients who are capable of verbal communication: the Visual Analogue Scale (57%), Numerical Rating Scale (48%) and Faces Pain Scale (5%) being the most frequently used scores. In the group of patients who are unable to communicate, ICUs less frequently use pain scores (19%), with the Critical-Care Pain Observation Tool (6%) and Behaviour Pain Scale (5%) being used most frequently. Measurement of pain was considered most important for patients with burn wounds (67%), trauma patients (64%), postoperative patients (57%) and those who receive end-of-life care (64%). Barriers to use pain measurements included the patient's inability to communicate (82%), interference with pain assessment due to sedation (79%), hemodynamic instability (64%), insufficient dosages of analgesics (60%) and the unavailability of a standard pain scoring system (51%). In addition, guidelines for management of sedation and analgesics from the Netherlands Association for Intensive Care (NVIC) had been read by only 20% of the respondents. Factors that were mentioned to be useful in contributing to an improvement in pain assessment and effective pain control included adequate analgesic dosage (87%), utilization of protocols and directives (86%), enthusiastic and motivated personnel (81%) and the utilization of standardized pain measurement tools.Most Dutch ICUs measure pain frequently (94%) in patients who are able to communicate. However, in the group of patients who cannot communicate only 19% of the Dutch ICUs use a standardized pain score. This finding applied to both academic and nonacademic ICUs, which suggests that efforts should be put into implementing pain measures in Dutch ICUs."}
+{"text": "Critical transitions between alternative stable states have been shown to occur across an array of complex systems. While our ability to identify abrupt regime shifts in natural ecosystems has improved, detection of potential early-warning signals previous to such shifts is still very limited. Using real monitoring data of a key ecosystem component, we here apply multiple early-warning indicators in order to assess their ability to forewarn a major ecosystem regime shift in the Central Baltic Sea. We show that some indicators and methods can result in clear early-warning signals, while other methods may have limited utility in ecosystem-based management as they show no or weak potential for early-warning. We therefore propose a multiple method approach for early detection of ecosystem regime shifts in monitoring data that may be useful in informing timely management actions in the face of ecosystem change. Transitions between alternative states, i.e., regime shifts, have been shown to occur across an array of complex systems Several early-warning indicators have been proposed to describe the temporal dynamics of complex systems close to a critical transition Pseudocalanus acuspes and Acartia spp., two key indicator species significantly contributing to the reorganization of the Baltic Sea ecosystem  and sprat (Sprattus sprattus) Pseudocalanus acuspes and Acartia spp. serve as suitable indicators for the ecosystem regime shift in the Central Baltic Sea. Furthermore, long-term temporally and spatially resolved monitoring programs Pseudocalanus acuspes and Acartia spp. biomass covering the period 1960\u20132008. Since the primary aim of the study is to investigate and evaluate potential early-warning signals, we chose to focus on and present results on method performance during the time-period immediately preceding and following the regime shift . We used data representing spring as this is the main reproductive season of the copepods We used Pseudocalanus acuspes and Acartia spp. within a 10, 15 and 20-year sliding window, following the approach by Dakos et al. We measured temporal variance  and autocorrelation at lag-1 (AR(1)) in detrended time series of average spring biomass of f\u2032\u2032) as a proxy for statistically significant acceleration in the rate of change (slope) of ecological time series a priori specified degree of smoothing In a second set of methods we applied statistical methods for assessing recent trends in the zooplankton time series. Although not specifically designed for early detection of regime shifts, the idea of using trend analysis as an early-warning signal lies in the possibility of detecting a slight increase in the rate of change (either in an upward or downward trend) in advance of a critical transition in an ecological time series. The approach is based on fitting non-linear Generalized Additive Models (GAM) The third approach was not primarily designed for early detection either, but rather for the identification and detection of regime shift. It is based on the evaluation of statistical time series models including structural breaks and combines several statistical indicators into a so-called \u201cshiftogram\u201d per se but to assess how under the constraints of real ecological time series similar to ours, different approaches may or may not work, and which assumptions and drawbacks may pose the greatest challenges in terms of early-warning detection and applicability to management.The full set of early-warning methods were assessed in terms of (i) the potential for detecting early-warnings signals in the selected indicator time series, (ii) how far in advance early-warning signals could potentially be detected, (iii) associated methodological assumptions and drawbacks influencing early-detection and (iv) applicability to real ecosystem management in terms of data requirements. While the trend analysis and shiftogram approach may quantitatively evaluate the first two criteria , no predefined reference levels exist to objectively assess the performance of our ecological indicators of critical slowing down, nor the possibility to theoretically crash test the methods against a simulated (modeled) spatio-temporal data set Pseudocalanus acuspes  strongly increased two years before the regime shift in 1988  one year ahead of the regime shift  correlation showed p-values exceeding their upper confidence intervals one year in advance of the regime shift for both species . This mate-1980s , may simContrary to temporal indicators of slowing down, spatial approaches for detecting changes in correlation and variance patterns Pseudocalanus acuspes and Acartia spp. prior to the regime shift (f\u2032 (slope) and a positive f\u2032\u2032 (acceleration). As in the previous example, no significant trend or change point was detected when excluding also 1987.The trend analysis me shift . When reme shift , while wme shift , as illuThe trend analysis seems to be highly dependent on the length of time series and the numbers of regression splines used during fitting of the generalized additive models GAMs; . These aPseudocalanus acuspes both the Akaike\u2019s information criterion (AICC) and the p-joint significance test showed a gradual transition towards a local minimum  3\u20134 years before the regime shift  transitions or more gradual changes strongly influence the shape  of the local minimum and hence the degree to which these transitions can be detected sufficiently in advance; a difference illustrated by the abrupt decrease in tia spp.  and the  acuspes . In addiThe versatility of methods for early detection of regime shifts in ecological time series provide an important toolbox for scientists and ecosystem managers. As learned from our example, no \u2018one-size-fits all\u2019 solution to deriving and interpreting spatio-temporal patterns announcing critical transitions exists Hence, we suggest that a multiple method approach may provide a sound scientific basis for detecting and evaluating early-warning signals and thus provide timely advice for immediate management actions in the face of future ecosystem changes Figure S1Map of the Baltic Sea and its location within Northern Europe. The central part of the Baltic Sea encompasses three deep (<70 m) basins important for marine biota, the Bornholm Basin (BB), the Gdansk Deep (GD) and the Gotland Basin (GB); largely corresponding to the International Council for the Exploration of the Sea (ICES) official sub-divisions 25, 25 and 28, respectively (thin lines). Furthermore, these basins are part of a long-term spatially and temporally disaggregated zooplankton monitoring program in the Baltic Sea.(JPG)Click here for additional data file.Figure S2Temporal variance of Pseudocalanus acuspes (circles) and Acartia spp. (triangles) estimated by standard deviations (SD) and the first-order autocorrelation coefficient (AR(1)) of detrended time-series for a sliding window of 10 , 15  and 20  years. Vertical dashed bars mark the timing of the Central Baltic Sea regime shift in the late 1980s.(TIF)Click here for additional data file.Figure S3The degree of spatial correlation for Pseudocalanus acuspes (A) and Acartia spp. (B) estimated as the mean significance  of spatial correlation coefficients derived from a Moran\u2019s I test across 6 (black), 8 (grey) and 10 (black) randomly assigned stations (after 1000 resamples). Vertical dashed bars mark the timing of the Central Baltic Sea regime shift in the late 1980s.(TIF)Click here for additional data file.Figure S4Smoothed indicator time-series of Pseudocalanus acuspes and Acartia spp. with GAM df\u200a=\u200a10  and df\u200a=\u200a20  from 1960\u20131987. Bootstrapped confidence intervals are shown by grey lines. Acceleration in the rate of change (slope) in each year are shown by statistically significant second derivatives (f\u2032\u2032\u2019), where black and white dots represent major downward- and upward trends, respectively.(PPTX)Click here for additional data file.Table S1Test results for recent trends and changes in trends over 3-year periods before the regime shift in 1988 using intersection\u2013union tests. P-values from a \u03c72 goodness-of-fit test indicate whether the GAM fits satisfactory to the entire time-series. Significant negative (\u2212) or positive (+) time trends in the rate of change (f\u2032), as well acceleration (+) or deceleration (\u2212) of the current trend (f\u2032\u2032) are shown. Hence, an increase in a rate of decline is indicated by negative f\u2032 and a positive f\u2032\u2032.(DOC)Click here for additional data file."}
+{"text": "The survival rates for oncology patients admitted to the ICU have improved significantly. The prognostic influence of the pre-admission oncological and treatment history is being questioned, the most significant impact being related to acute physiological status. In this survey, we sought to evaluate the awareness of overall mortality rates in critically ill cancer patients among intensivists in the UK.We surveyed intensive care lead clinicians in December 2011 in order to establish: a profile of the hospital and ICU they work in; their estimate of overall ICU mortality for critically ill cancer patients; the value of six outcome indicators in predicting mortality in two subgroups of oncological candidates for ICU admission; and the local management of acutely deteriorating cancer patients potentially requiring ICU care.The ICU mortality rates estimated by survey respondents differed from those reported in the literature: for solid tumor 21% (SEM 3) versus 10 to 23%, for metastatic solid tumor 38% (SEM 4) versus 23%, hematological malignancy 45% (SEM 3) versus 33 to 43% with allograft transplant 54.8% (SEM 5) versus 39 to 50% and autograft transplant 56% (SEM 5) versus 44%. Regarding the management of cancer patients, there were conflicts reported between teams . Few units had established triage policies for the acutely ill cancer patient (5%) and it was also not common that plans were made prior to the patient's deterioration . Figure The awareness of improved outcome in critically ill cancer patients differs among physicians, and in general estimated mortalities were far higher than those reported in the literature."}
+{"text": "Numerous viruses are responsible for respiratory infections; however, both their distribution and genetic diversity, in a limited area and a population subgroup, have been studied only rarely during a sustained period of time.A 2-year surveillance program of children presenting with acute respiratory infections (ARIs) was carried out to characterize the viral etiology and to assess whether using gene amplification and sequencing could be a reliable approach to monitor virus introduction and spread in a population subgroup.Using multiplex RT-PCR, 15 different respiratory viruses were detected within the 486 nasopharyngeal positive samples collected among 817 children aged <9 years old who presented with ARI during October 2006 to September 2008. A single virus was detected in 373 patients (45.7%), and two to four viruses in 113 patients (13.8%). The most frequent causative viruses were respiratory syncytial virus (RSV) (24.7%), human bocavirus (24.5%), and human rhinovirus (HRV) (15%). RSV was more prevalent in winter and among young infants. Cases of seasonal influenza A and B viruses were reported mainly in January and August. An increase in adenovirus infection was observed during the spring of the second year of the study. Sequence analyses showed multiple introductions of different virus subtypes and identified a high prevalence of the newly defined HRV-C species. A higher viral incidence was observed during the winter of 2008, which was unusually cold.This study supports the usefulness of multiplex RT-PCR for virus detection and co-infection, and for implementation of a molecular monitoring system for endemic and epidemic viral respiratory infections."}
+{"text": "This review provides the available evidence on sexual dysfunctions in India. Most of the studies have concentrated on male sexual dysfunction and hardly a few have voiced the sexual problems in females. Erectile dysfunction (ED), premature ejaculation (PME) and combinations of ED and PME appear to be main dysfunctions reported in males. Dhat syndrome remains an important diagnosis reported in studies from North India. There is a paucity of literature on management issues with an emergent need to conduct systematic studies in this neglected area so that the concerns of these patients can be properly dealt with. Human sexuality is inherently related to some of the social and public health problems in India. These problems may involve contraceptive use, child abuse, sex education, legal issues of homosexuality and AIDS. These health problems have a significant impact on existing health infrastructure and budget. These problems also need to look within the context of poverty, stressful living situations, diverse cultural belief systems, quackery, ignorance and inadequate health services. However, there is little recognition of how these health problems are related to human sexuality and their dysfunctions. There is a need to understand how sexual attitudes, beliefs, and values act and influence these problems. Our cultural perspective can also shape the experience and understanding of these disorders. There isIn this review, our aim is to present sexual dysfunction from the Indian perspective. Available data, based clinical studies from India, are reviewed and important findings highlighted. Our presentation is limited to sexual dysfunction only and paraphilias will be not discussed.et al. (1959). conVerma and his colleagues (1998) analyzedA file review of 178 male patients with sexual dysfunction by Avasthi and his colleagues (2003) revealedGupta and his colleagues (2004) attempteKendurkar and his colleagues (2008) assessedAs compared to male sexual dysfunction, a few Indian studies are available in the area of female sexual dysfunction. This area remains largely unexplored. Agarwal (1977) reportedIn the review by Kulhara and Avasthi (1995), there waKar and Koola (2007) conducteIn the study among 100 consecutive women attending the Department of Pediatrics for the care of non-critical children in a tertiary care teaching hospital, Avasthi and his colleagues (2008), found 17In another cross-sectional survey of 149 married women in a medical outpatient clinic of a tertiary care hospital, Singh and his colleagues (2009), reportedet al. (2005),[et al. (2007).[Studies pertaining to Dhat syndrome, a culture bound syndrome, have mostly defined clinical features. This \u201csemen loss\u201d-related psychological distress has been extensively reviewed by Prakash 2007), and Avas07, and A. (2005), and Dhik. (2007).Wig (1960), coined tBehere and Natraj (1984) and BhatMost studies found erectile dysfunction (22-62%) and premature ejaculation (22-44%) as commonly associated psychosexual dysfunctions, while depressive neurosis (40-42%), anxiety neurosis (21-38%), somatoform/hypochondriasis (32-40%) as the most reported psychiatric disorders in patients diagnosed with Dhat syndrome.Chadda and Ahuja (1990) could not find any abnormality on urine examination except oxaluria (10%) and phosphaturia (6%). On follow-up of these patients, Behere and Natraj (1984) found that majority of the patients recovered (66%), while the rest either improved (22%) or were unchanged (12%).Behere and Natraj (1984) and BhatRegarding management of Dhat syndrome, Wig (1960) suggestePrakash and Meena (2007), providedChadda and Ahuja (1990) advocateThis review highlights the available evidence in the field of psychosexual medicine in India. It is important to mention that all studies were from a hospital setting and none from community. Only a few studies explored female sexual dysfunction. Very few studies spoke about management issues. Dhat syndrome could be an important diagnostic entity to be researched. There is a strong need to perform studies in these areas."}
+{"text": "Studies of spontaneous EEG and visual or somatosensory evoked high frequency oscillations indicate that the abnormal fluctuations of cortical responsivity over time in relation to the migraine attack could be due to abnormal thalamic control. Here we searched for possible structural changes in the thalamus of migraineurs by mean of acquiring diffusion tensor magnetic resonance imaging (MRI). This MRI technique provides quantitative data on water molecular motion, as a marker of tissue structure. Materials & Method \u2013 Seventeen untreated migraine without aura (MO) patients underwent MRI scan (3-Tesla Siemens Gyroscan) during (n=7) and between attacks (n=10) and were compared to a group of 14 healthy volunteers (HV). We examined fractional anisotropy (FA) and mean diffusivity (MD) in the thalamus.Between attacks MO patients had a significantly higher FA and lower MD values in the bilateral thalami when compared to HV (p<0.05). During attacks, all MRI quantitative measurements in migraineurs were similar to those found in HV. In MO patients, FA of the right thalamus was positively correlated with the number of days since the last migraine attack .The higher thalamic FA values noted between attacks in MO patients may be related to a decrease in regional branching and crossing of fibers, which normalizes during an attack. Whether these changes could be considered as the anatomical counterpart of the cyclic functional fluctuations previously observed with the neurophysiology in migraine remains to be determined."}
+{"text": "Sheep chromosome 3 (Oar3) has the largest number of QTLs reported to be significantly associated with resistance to gastro-intestinal nematodes. This study aimed to identify single nucleotide polymorphisms (SNPs) within candidate genes located in sheep chromosome 3 as well as genes involved in major immune pathways. A total of 41 SNPs were identified across 38 candidate genes in a panel of unrelated sheep and genotyped in 713 animals belonging to 22 breeds across Asia, Europe and South America. The variations and evolution of immune pathway genes were assessed in sheep populations across these macro-environmental regions that significantly differ in the diversity and load of pathogens. The mean minor allele frequency (MAF) did not vary between Asian and European sheep reflecting the absence of ascertainment bias. Phylogenetic analysis revealed two major clusters with most of South Asian, South East Asian and South West Asian breeds clustering together while European and South American sheep breeds clustered together distinctly. Analysis of molecular variance revealed strong phylogeographic structure at loci located in immune pathway genes, unlike microsatellite and genome wide SNP markers. To understand the influence of natural selection processes, SNP loci located in chromosome 3 were utilized to reconstruct haplotypes, the diversity of which showed significant deviations from selective neutrality. Reduced Median network of reconstructed haplotypes showed balancing selection in force at these loci. Preliminary association of SNP genotypes with phenotypes recorded 42 days post challenge revealed significant differences (P<0.05) in fecal egg count, body weight change and packed cell volume at two, four and six SNP loci respectively. In conclusion, the present study reports strong phylogeographic structure and balancing selection operating at SNP loci located within immune pathway genes. Further, SNP loci identified in the study were found to have potential for future large scale association studies in naturally exposed sheep populations. Haemonchus contortus, Teledorsagia circumcincta, Trichostrongyles, Nematodirus sp. impose severe constraints on sheep and goat production especially those reared by marginal farmers under low external input system. These parasites incur heavy losses to farmers in terms of body weight loss, direct cost of anthelminthic drugs, loss due to mortality, etc. For example, annual treatment cost for Haemonchus contortus alone had been estimated to be 26 million USD in Kenya, 46 million USD in South Africa and 103 million USD in India Haemonchus contortus, Trichostrongylus colubriformis, Teledorsagia circumcincta and various Nematodirus species. Considerable variation has been reported among sheep breeds on their ability to resist gastro-intestinal nematodes (GIN). For example, indigenous sheep breeds like Red Maasai 2\u200a=\u200a0.149, Avikalin sheep 2\u200a=\u200a0.41, Armidale sheep Assessment of livestock health conditions in developing countries for identification of priority diseases to be targeted for control, revealed helminth infections as one of the most important problems in sheep and goat Exploration of genetic variation either within specific regions of genome or more specifically in candidate genes involved in innate and adaptive immune pathways may help to identify a set of DNA markers significantly associated with parasite resistance characteristics. The former approach in terms of quantitative trait locus (QTL) analysis is a powerful method to understand genotype-phenotype relationship. Several QTL studies on parasite resistance characteristics have been reported in sheep. A quick evaluation of Animal QTL database Haemonchus contortus parasite).One of the important objectives of QTL studies is to identify underlying causative gene polymorphisms associated with the trait. Different QTLs reported in chromosome 3 for parasite resistance characteristics were found to be distributed all over the chromosome with varying overlapping regions. Hence, different candidate genes within chromosome 3 along with genes involved in immune related KEGG pathways (KEGG-Kyoto Encyclopedia of Genes and Genomes) could be important targets for establishing underlying causative variations. It is expected that the potential causative polymorphisms within candidate genes are members of the same overarching KEGG pathway that lead to the phenotypic expression on parasite resistance characteristics in each population. Further, the extent of genetic diversity and population sub-structure at such polymorphic loci are critical for such a genotype-phenotype association study. Population stratification has been demonstrated to result in false positive associations in various species including humans Haemonchus contortus and blood samples were collected from jugular vein under the supervision of qualified veterinarians for extraction of DNA and assessment of blood parameters. 42 days post challenge, animals were dewormed to clear parasites from the gut after the experiment. The experimental challenge in both locations did not involve animals from any endangered or protected species/breeds. Blood sample collection for DNA extraction and genotyping from remaining breeds were performed by local veterinarians in respective countries following good animal practice.All procedures for artificial challenge experiment at different locations in Argentina and Indonesia were approved respectively by the Institutional Committee for Care and Use of Experimental Animals of the National Institute of Agricultural Technology (CICUAE-INTA), Argentina (protocol number 35/2010) and Institutional Research Animal Facility, Bogor Agricultural University, Indonesia following the guidelines described in their institutional manuals. Experimental animals were challenged with infective L3 larvae of in vitro conditions. All animals were maintained together during the entire trial in dry lot or under conditions of minimum additional parasite challenge. Body weight (BW), fecal egg count (FEC) and packed cell volume (PCV) were recorded at 0, 28, 35 and 42 days after artificial infection. 136 animals from Corriedale (66), Pampinta (34), Indonesian Fat Tail (17) and Indonesian Thin Tail breeds of sheep (19) were utilized for artificial challenge at experimental stations located in Argentina and Indonesia respectively.A total of 713 unrelated sheep from 22 different breeds/populations were utilized for diversity analysis in the present study. The sheep breeds/populations were distributed in three macro-environmental geographical locations including Asia (tropics), Europe (temperate) and South America (tropics) with the assumption that level of parasite load and infections vary significantly across these regions http://www.mbio. ncsu.edu/bioedit/bioedit.html). 44 novel SNPs were identified within the candidate genes under study for which competitive allele specific PCR (KASPar) assay based on FRET chemistry were developed for genotyping . Briefly, two forward primers one specific to each allele were designed with the respective proprietary tail sequence complementing the FAM or HEX fluorescence reporting system. A common reverse primer was designed for each genotyping assay. Thermal cycling parameters and recycling conditions were followed as per manufacturer's recommendations and are available on request. Endpoint allele discrimination module incorporated within the BioRad CFX96  was utilized for calling the genotypes based on fluorescent intensity recorded for each of the two alleles. The emission data of all the samples in the plate were plotted in X and Y axis respectively for each allele and the genotypes were called based on distinct clustering. Quality of allele calling was confirmed by comparing the genotypes derived from KASPar assay with the available sequence data on individuals from the panel of unrelated animals. 38 out of 44 assays passed quality control and were subsequently utilized for genotyping large number of animals. Additionally, ten toll like receptor (TLR) genes were selected for in silico mining of SNP variations from sequences available at NCBI-GenBank database. A total of 14 non-synonymous SNPs within coding DNA regions of TLR genes were identified for development of genotyping assays  using SPSS version 13.0. The first three principal components were used to draw the scattergram so as to understand underlying genetic structure and relationship of different breeds in three dimensional geometric space. The extent of population sub-structure was further explored using STRUCTURE with the assumption of different clusters, K\u200a=\u200a1\u201315, 20, 25 and 30. Five replicate runs were performed for each K under admixture model without a priori population information. The number of burn in periods and MCMC repeats used for all the runs were 50000 and 100000 respectively. To identify the optimal \u2018K\u2019, the second order rate of change of L(K) with respect to \u2018K\u2019 was calculated by following the procedure reported elsewhere Basic diversity indices like allele frequency, genotype frequency, expected heterozygosity and test for Hardy Weinberg equilibrium were calculated using PEAS  www.stat.washington.edu/stephens) ST values using ARLEQUIN version 3.1 Thirteen SNP loci within candidate genes involved in different immune related KEGG pathways and located in chromosome 3 were used to reconstruct haplotypes from unphased genotypic data. Reconstruction of haplotypes and estimation of haplotype frequencies were performed using PHASE for Windows, version 2.1 , body weight change (BWC) and packed cell volume change (PCVC) measured 42 days post infective L3 larvae challenge. The data on FEC were subjected to log transformation before applying the program of least squares, LSMLMW A total of 243 sequences were generated by targeted re-sequencing of selected candidate genes  to 0.315 (Hamdani) while the mean expected heterozyosity varied from 0.237 (Pampinta) to 0.315 (Indonesian Thin Tail). Among different geographical regions, mean observed heterozygosity was highest in South West Asian sheep populations (0.309) followed by European populations [0.296] while South East Asian populations had the least mean observed heterozygosity (0.270). This is consistent with the fact that the diversity remains higher around the centre of domestication while decreasing with increasing geographic distance ST  to 0.469 (Pampinta/Mouflon). 21.3% of total genetic variation was found to be due to between breed differences while 77.3% was due to within breed differences. The values are much higher than that reported for European sheep (13.1%) ST values observed could be understood from the fact that the samples were derived from wide geographic locations in the present study . Further, phylogenetic analysis of pair-wise allele sharing distance revealed two major clusters with most of South Asian, South East Asian and South West Asian breeds clustering together while the European and South American sheep breeds clustered together separately  were plotted on a three dimensional scattergram to evaluate the genetic structure of sheep breeds  on 136 animals was used for least squares analysis under a complete fixed effect model. The effect of location of experimental stations  was not found to have significant influence on fecal egg count and packed cell volume while significant effect was observed with respect to body weight change (P<0.01). Although the locations are wide apart geographically, uniform protocol was followed across different experimental stations in terms of age of lambs selected for experiment, deworming and data recording schedule, however some differences did exist in terms of quality of pasture available for grazing, etc. Higher observed body weight change in animals challenged at Aguil Experimental Station (AES), Argentina was due to better growth performance of Pampinta lambs. Higher body weight achieved by Pampinta lambs were due to their genetic differences in growth rate (average pre-weaning weight gain of 295 g/day) and weight gain (average weaning weight of 33.4 kg) as compared to other breeds like Corriedale (218 g/day and 24.6 kg) To evaluate the potential utility of the SNP loci for future association study on a large number of samples, a pilot analysis was performed with the phenotypes generated in four breeds after artificial challenge with infective L3 larvae of In conclusion, the present study reports strong phylogeographic structure in sheep across Asia, Europe and South America and balancing selection operating at SNP loci located within immune pathway genes. Although the present association analysis is preliminary in nature, the SNP loci on chromosome 3 and those within immune pathway genes indicated their potential for future large scale association studies in naturally exposed populations.Figure S1http://www.animalgenome.org/cgi-bin/QTLdb/index).(a\u2013c) QTLs related to gastro-intestinal nematode resistance in sheep (d) Chromosome-wise distribution of QTLs related to parasite resistance traits in sheep and number of SNP loci investigated in the present study (e) Quantitative trait loci (QTL) map of chromosome 3 related to parasite resistance traits in sheep Click here for additional data file.Figure S2Distribution of allele sharing distance (IBS) between pairs of individuals. Distance was plotted separately where pairs were drawn from within the same breed (blue bars) and from across the breeds (red bars).(TIF)Click here for additional data file.Figure S3Bayesian clustering of 713 sheep based on genotype data at (a) 18 non-neutral SNP loci (b) 23 neutral SNP loci under assumption of 2 to 6 clusters without a priori population information. The breed names are given below the box plot and the geographical origin indicated above the box plot with the individuals of different breeds separated by vertical black lines.(TIF)Click here for additional data file.Table S1Details of SNPs identified in silico within TLR genes of sheep.(DOCX)Click here for additional data file.Table S2ST (lower triangle) and allele sharing distance (upper triangle) among different sheep breeds.Pairwise F .(DOCX)Click here for additional data file.Table S3Global F-Statistics among different sheep populations at 41 SNP loci.(DOCX)Click here for additional data file.Table S4Results of Ewens Watterson Neutrality test at different SNP loci in various sheep breeds .(DOCX)Click here for additional data file.Table S5Analysis of molecular variance among different sheep breeds based on (right) genotypes at 18 non-neutral SNP loci and (left) genotypes at 23 neutral SNP loci.(DOCX)Click here for additional data file."}
+{"text": "To the Editor: The severe acute respiratory syndrome (SARS) outbreak of 2002\u201303 and the subsequent implication of bats as reservoir hosts of the causative agent, a coronavirus (CoV), prompted numerous studies of bats and the viruses they harbor. A novel clade 2c betacoronavirus, termed Middle East respiratory syndrome (MERS)\u2013CoV, was recently identified as the causative agent of a severe respiratory disease that is mainly affecting humans on the Arabian Peninsula . Details about the bat sample are available in the RNA-dependent RNA polymerase (RdRp) gene . PCR results were positive for 5 (8%) of the 62 specimens. PCR amplicons for 4 positive specimens yielded alphacoronavirus sequences related to recently described bat alphacoronaviruses from South Africa . During 2011\u20132012, fecal pellets were collected from 62 bats representing 13 different species in the KwaZulu-Natal and Western Cape Provinces of South Africa and stored in RNARdRp fragment generated by the screening PCR to 816 nt, as described . A partial spike gene\u2013based phylogeny using this sequence yielded the same topology as that using the partial RdRp sequence  are urgently needed to elucidate the emergence of MERS-CoV. Such studies should focus on the Arabian Peninsula and Africa.Neoromicia zuluensis bats, and spike gene phylogeny of the 2c betacoronavirus clade.Description of bat sampling, screened bat species, distribution of"}
+{"text": "Verapamil is an off-label first-line drug in prevention of cluster headache (CH) but little is known about the optimal rate of dose escalation. The safety profile of slow dose increment in 80mg intervals has been previously documented. It is possible to achieve the effective dosage earlier with fast escalation, although the safety and tolerability are of concerns.To compare the electrocardiographic abnormalities and other adverse events between fast  and slow titration (by 80mg) of verapamil in CH treatment.Electrocardiograms (ECGs) at baseline and every two weeks in parallel with the increment of the drug were performed in patients attending our clinic. Medical records and ECGs performed in CH patients between 2007 and 2011 were retrospectively reviewed.Of 169 patients, 80 followed the fast and 89 the slow regimen. The slow regimen group differed from the fast regimen group in terms of: higher proportion of chronic CH , duration of verapamil use  and maximum dosage of verapamil achieved . Eighty-three (49%) patients showed ECG changes: bradycardia in 60 (36%), first-degree atrioventricular block (AVB) in 22 (13%), second-degree AVB in 1(1%), third-degree AVB in 2 (1%), junctional rhythm in 7 (4%) and bundle branch block in 3 (2%) patients. The rate of arrhythmias did not differ between two groups. Verapamil was stopped only in second- and third-degree AVB. The rate of drug discontinuation due to arrhythmias or non-ECG adverse events did not differ between groups.The occurrence of verapamil-related serious cardiac arrhythmias was rare in patients adopting fast titration regimen. Our data support the safety and tolerability of rapid escalation of verapamil in patients with CH. Regular ECG assessment is essential throughout the therapy."}
+{"text": "Enzyme-replacement therapy (ERT) with alglucosidase alfa has improved the lifespan of patients with classic infantile Pompe disease, although ERT is not effective in a subset of patients who mount an immune response to the exogenous enzyme. We studied the development of antibodies in response to ERT and its effect on clinical outcomes in 11 patients with classic infantile Pompe disease treated with ERT since 1999 for a median of 4.2 years (range 3 months to 12 years).We determined the endogenous acid alpha-glucosidase expression  and regularly assessed antibody formation in all 11 patients, all of whom developed antibodies. The patients who lacked any endogenous acid alpha-glucosidase production  did not develop a substantially different antibody titer than those who produced an inactive form of the enzyme (n=8). However, the patient\u2019s age at the start of ERT proved to be important: none of the four patients who started ERT before 2 months of age developed titers of more than 1:6,250. Gross motor function and cardiac dimension improved less in patients with high titers and in CRIM-negative patients. The three CRIM-negative patients have died, whereas the eight CRIM-positive patients survived.Antibody formation is common. High antibody titers and a CRIM-negative status are associated with a poorer clinical outcome. Earlier initiation of ERT may prevent the formation of a severe immune response."}
+{"text": "The perceptual inference of the three-dimensional (3D) external world from two-dimensional (2D) retinal input of the left and right eye is a fundamental problem  or changing disparity over time (CDOT) are both binocular inputs that may have improved discrimination performance in this task. However, motion detection and therefore IOVD is relatively insensitive to velocity changes (Gottsdanker, Early motion and disparity processing in the human visual system show tuning characteristics that supplement each other. Motion processing tends to have high temporal but relatively coarse spatial resolution whereas disparity processing has high spatial and relatively limited temporal resolution Tyler, . It has In an influential paper Weiss et al.  demonstrA geometric-statistical model based on motion and disparity constraints provides a flexible computational framework for binocular 3D motion perception that can capture arbitrary 3D trajectories of moving features and objects. For example, motion and disparity information needs to be combined to disambiguate local motion direction of a single line or edge moving in depth (see Figure The observations by Pierce et al.  demonstr"}
+{"text": "Severe hypoglycemia (blood glucose level (BGL) <40 mg/dl) is independently associated with an increased risk of mortality in critically ill patients. The impact of milder hypoglycemia (BGL <70 mg/dl) on outcome is less clear.Prospectively collected data from two observational cohorts in the USA and in the Netherlands and from the prospective GLUCONTROL trial were analyzed. Hospital mortality was the primary endpoint.n = 1,098) and strict glycemic protocol ) and 914 patients who participated in the GLUCONTROL trial  and intensive insulin therapy arm ). The percentage of patients with hypoglycemia varied widely among the different cohorts. Patients with hypoglycemia experienced higher mortality than did those without hypoglycemia within each subgroup , even after stratification by severity of illness or diabetic status. Multivariable logistic regression analysis revealed that hypoglycemia had a greater impact on the mortality of surgical patients than of medical patients. The impact of hypoglycemia on mortality occurred independently of mean glucose level during ICU stay or glycemic variability.We analyzed data from 3,262 patients admitted to Stamford Hospital (ST), 2,063 patients admitted to three institutions in the Netherlands (NL; loose glycemic protocol (L, Even a single episode of mild hypoglycemia was associated with a significantly increased risk of mortality in heterogeneous cohorts of critically ill patients, independently of severity of illness, diabetic status, diagnostic category and glycemic variability."}
+{"text": "The aim of genetic tests performed by Genetic Counseling at Centre of Oncology was to screen for carriers of germline mutations in BRCA1 and 2 genes who are at high risk of developing breast or/and ovarian cancer.Among the patients qualified to genetic tests there are the patients who do not meet the Amsterdam criteria of HBOC syndrome.In Genetic Counseling at Centre of Oncology we find germline mutations in BRCA1 and 2 genes in about 5% of patients. Beginning in January 2003 until now we found mutations in BRCA genes in 247 families. Not all families belong to the group of high risk of developing breast or ovarian cancer. Among them there were 23 families which did not meet pedigree and clinical criteria.Analysis of tumors which were developed by the members of families carrying germline mutations in BRCA1/2 genes revealed mainly breast (415) and ovarian (170) cancers. There were also tumors which were not typical for this mutation. The most frequent not typical tumors in the families with germline BRCA1/2 mutations were: lung cancer (38), intestinal tract tumors (26) \u2013 including stomach cancer, liver cancer (20), pancreas cancer (15) and also hematopoietic tumors \u2013 among them leukemias (17), prostate cancer (14) and other.These findings justify performing genetic tests for germline mutations in BRCA1/2 genes not only for the patients who meet pedigree and clinical criteria typical for HBOC syndrome."}
+{"text": "Normal development of the mammalian embryo requires epigenetic reprogramming of the genome. The level of cytosine methylation of CpG-rich (5meC) regions of the genome is a major epigenetic regulator and active global demethylation of 5meC throughout the genome is reported to occur within the first cell-cycle following fertilization. An enzyme or mechanism capable of catalysing such rapid global demethylation has not been identified. The mouse is a widely used model for studying developmental epigenetics. We have reassessed the evidence for this phenomenon of genome-wide demethylation following fertilisation in the mouse. We found when using conventional methods of immunolocalization that 5meC showed a progressive acid-resistant antigenic masking during zygotic maturation which gave the appearance of demethylation. Changing the unmasking strategy by also performing tryptic digestion revealed a persistence of a methylated state. Analysis of methyl binding domain 1 protein (MBD1) binding confirmed that the genome remained methylated following fertilisation. The maintenance of this methylated state over the first several cell-cycles required the actions of DNA methyltransferase activity. The study shows that any 5meC remodelling that occurs during early development is not explained by a global active loss of 5meC staining during the cleavage stage of development and global loss of methylation following fertilization is not a major component of epigenetic reprogramming in the mouse zygote. The mechanism that is currently considered to best describe 5meC reprogramming should result in an almost complete loss of methylation (<1%) by the time the embryo reaches the blastocyst stage. Analysis of around 1000 CpG islands (CGIs) within ovulated eggs shows that 15% are methylated de novo methylation occurs later, upon epiblast formation (D6.5)The dominant paradigm describing the processes of epigenetic reprogramming in the embryo holds that global active demethylation of 5meC occurs within the first cell-cycle. This demethylation acts preferentially on DNA inherited from the male while passive demethylation of the maternally derived genome occurs over subsequent mitoses Reports of an active process of global 5meC demethylation of the zygotic genome within hours of fertilisation in some species . This re-analysis did not find evidence for extensive active loss of methylation in zygotes or progressive loss due to an absence of maintenance methylation across the first several rounds of cell division. Rather, it was found that the reported loss of methylation immediately after fertilisation was accounted for by changes in the conformation or structure of chromatin that resulted in antigenic masking of 5meC.Mouse zygotes, 2-cell, 4-cell and 8-cell embryos were collected directly from the female reproductive tract from B6CBF1 strain female mice . The embryos were fixed and immunostained with anti-5meC. Zygotes were collected at various times after mating and staged according to the maturation of their pronuclei , is an independent measure of the global levels of CpG methylation. Western blot analysis showed two dominant molecular weight forms of MBD1 present in oocytes and the early stages of development . ImmunolBrief acid-treatment of cells has been the most widely used method of 5meC antigen retrieval reported. Altering the duration and concentration of HCl treatment did not change the pattern of 5meC staining in PN5 zygotes (not shown) showing that the difference between anti-5meC and anti-MBD1 staining was not due to increased acid-sensitive masking of 5meC. To determine whether other forms of masking may have occurred, fixed and acid-treated zygotes were subjected to extensive tryptic digestion. This caused a loss of MBD1 staining from nuclei 1\u20137 and aTo further assess this antigenic masking, condensing chromosomes of the zygote and 2-cell embryo were triple stained for DNA (blue), 5meC (green) and MBD1 (red). Acid-treated chromosomes from the zygote had some segments of undecorated DNA and large segments decorated by MBD1, but were largely devoid of staining by anti-5meC 1. By conIt is reported that further passive demethylation of the embryonic genome occurs during the cell-cycles following fertilisation due to limited maintenance methylation of the newly synthesized DNA Asymmetric anti-5meC staining of the male and female pronucleus after acid-pretreatment has been reported These analyses were all undertaken on embryos from hybrid (B6CBF1) mice. To assess whether the strain of mouse influenced the patterns of anti-5meC staining we also examined staining in an inbred (C57BL/6j) and an outbred (Swiss Quackenbush) strain embryos. Zygotes were collected directly from the reproductive tract fixed and stained for anti-5meC and PI. Hybrid embryos were collected and processed at the same time to act as controls. This analysis showed in acid-treated zygotes there was a similar progressive loss of anti-5meC staining of both PN4 and PN5 pronuclei in all three strains . Hybrid  mice were used in most experiments. In the experiments reported in 2 for the periods indicated in individual experiments. Embryos were treated with the DNA methyltransferases inhibitor N-Phthalyl-L-tryptophan  Embryos were collected from the reproductive tract in Hepes-buffered modified human tubal fluid medium (Hepes-mHTF) Immunofluorescence of zygotes was performed as previously described Unmasking of the 5meC antigen was performed by brief exposure to HCl as previously described Embryos from each treatment were processed at the same time and in parallel for each experimental replicate. All treatments were exposed to the same preparations and dilutions of all reagents including primary and secondary antibodies. Similarly all preparations from an experiment were examined microscopically within the same session, and used identical microscope and camera settings. All image analysis was performed in an identical manner for all embryos within an experiment. All preparations were performed by the same experienced operator throughout the study. Semi-quantitative analysis of staining was independently confirmed by two experienced observers.Western blot analysis on embryo and oocyte extracts was performed as previously described"}
+{"text": "To assess and compare attitudes of general practitioners in different European countries towards screening and early interventions in alcohol use disorders.A total of 2435 general practitioners (GPs) from 9 European countries  were surveyed. The questionnaire included questions on demographic, education and training on alcohol, received by general practitioners, as well as their attitudes towards management of alcohol problems. In addition, the Shortened Alcohol and Alcohol Problems Perception Questionnaire (SAAPPQ) was used.Seventy seven per cent of GPs declared that they placed \u2018somewhat high\u2019 or \u2018very high\u2019 their priority on disease prevention of the general practitioners; 54% reported having received 4 or more hours of education and training on managing alcohol problems, and 43% reported managing seven or more patients for alcohol problems in the previous year. GPs who reported higher levels of alcohol-related CME training were more likely to report regularly asking their patients about alcohol use (chi-square (3)=14.9, p=0.002). Moreover, there was a significant association between experience of alcohol-related CME and the number of patients managed for hazardous drinking (chi-square (5)=83.6, p<0.0005). Busyness (64%) and lack of training (52%) were considered most important barriers and readily available support services (84%) most effective facilitator of early intervention.The recommendations coming from the results of the ODHIN study for improving the delivery of early alcohol intervention and the management of alcohol problems in general practice are: provide better training and infrastructure. The main barriers and facilitators of early interventions did not change throughout last 16 years."}
+{"text": "The human protein encoded by the FOXO1 gene functions as a transcription factor of insulin signaling key genes. Human uncoupling proteins 3 (UCP3) are mitochondrial proteins that are involved in the control of energy metabolism and the pathophysiology of obesity. In this study we investigated the role of genetic variation in the FOXO1 and UCP3 gene in susceptibility to non-alcoholic fatty liver disease (NAFLD) and relevant metabolic traits.We genotyped nine single nucleotide polymorphisms (SNPs) for association analyses in children . Body mass index (BMI), waist and hip circumference, blood pressure, fasting blood glucose (FBG), insulin (FIN), lipid profiles were measured and performed B-ultrasound examination in all the subjects.In the NAFLD group, FOXO1A and UCP3 allele were significantly more frequent in both association studies. There was a significant difference in the overall distribution of the genotype frequencies , (FOXO1 rs2721068), and there was a significant difference  in the distribution of the haplotype , might be good NAFLD markers.In conclusion, our study suggests a effect of UCP3 haplotype on NAFLD development and relevant intermediate phenotypes which predispose for NAFLD."}
+{"text": "Patients with atrial fibrillation (Afib) routinely undergo a transesophageal echocardiogram (TEE) for evaluation of the left atrial appendage (LAA) to rule out thrombus prior to undergoing cardioversion or pulmonary vein isolation (PVI). Cardiac MRI (CMR) is now increasingly used for evaluation of these patients for defining pulmonary vein anatomy prior to PVI.We hypothesized that 2D and 3D non-contrast and contrast CMR is as effective as TEE in evaluating for LAA thrombus while providing simultaneous comprehensive non-invasive evaluation of the pulmonary vein anatomy within a single exam.Afib Pts  underwent TEE and non-contrast and contrast CMR prior to undergoing an initial PVI procedure. CMR was performed on 1.5T GE scanner and two blinded CMR experts analyzed the images. The CMR images were analyzed under two categories: 1) the 2D non-contrast cine images showing LAA in 2 chamber and orthogonal views 2) 3D atrial contrast source-images acquired during pulmonary vein angiogram. CMR variables evaluated were the presence or absence of LAA thrombus, quality of images and the results were compared with the results of TEE in a blinded fashion.In 62% of pts (n=65) the CMR and TEE studies were performed on the same day, in 37 % of patients (n=39) the mean interval between the two studies was 7 days and in the remaining 6 patients the mean interval was 3+1months. All pts (n=110) were analyzed for the evaluation of LAA thrombus (avg time: 35 min). All (100%) of patients were in Afib and in all (100%) the images were of diagnostic quality (good correlation between the two CMR observers with only one grade difference when in disagreement). Thrombus was absent in 108 of 110 pts on TEE and CMR and present on 2 TEE and CMR images (100% concordance). In 9 cases the 2D CMR images were indeterminate where 3D contrast images were most helpful in the final rule out of LAA thrombus.CMR offers a comparable and equally specific alternative to TEE for the complete non-invasive evaluation of LAA thrombus in patients with Afib without the obligate need for sedation, radiation or nephrotoxicity. In one single examination a CMR exam can provide LAA anatomy, rule out thrombus and display the pulmonary veins in patients undergoing a PVI procedure."}
+{"text": "Despite the availability of an effective vaccine, Hepatitis B virus (HBV) infection still remains a foremost health problem. Undoubtedly, finding the key routes of hepatitis transmission from the point of prevention in every country, specifically in endemic regions, is of high priority. Such efforts are especially important given that many infected patients with hepatitis are asymptomatic 2]. Iran. Iran2].HBV is transmitted through both vertical and horizontal routes. Although vertical routes have both been very common in Turkey and Iran, nowadays the horizontal routes are much more important . In otheOther studies recommend the extension of HBV vaccinations in infant and high risk group, screening during pregnancy, and implementing additional strategies Such as adding the injection of hepatitis B immunoglobulin (HBIG) to the routine vaccination in neonates of mother HBs Ag positive, extension of vaccination in adults 13]14][[14][13][[[14][13]"}
+{"text": "Cross-priming serves to activate cytotoxic T lymphocytes for immune defense against viruses and tumors and plays an important role in vaccinations. Only certain dendritic cell (DC) subsets can cross-present. Several cell surface markers have been described that more or less specifically and sensitively characterize these subsets. The cell-biological mechanism(s) why a DC subset can cross-present are less clear. Theoretically, the task of cross-presentation can be divided into several mechanistic steps: (1) Antigen uptake by various endocytosis mechanisms, (2) Intracellular antigen routing into distinct organelles including the crossing of organelle membranes, (3) Antigen processing into peptides, (4) Peptide loading onto MHC molecules, and (5) Transport of these complexes to the cell surfaces for presentation to T cells. Each of these steps is dependent on numerous parameters, not only the DC subtype, but also the nature of the antigen or the presence of further signals that impact DC function or signify the presence of danger or infection.This research topic contains 10 articles by leading experts in the field of antigen presentation that cover our current knowledge on the molecular mechanisms underlying cross-presentation (Chopin et al.,"}
+{"text": "The results section of the published article  state thThe above definition contains an error and should instead be written as follows: 46,XY.ish der(15)tmat."}
+{"text": "FRB), length (FRL), and root area index (RAI) were significantly lower for spruce than for beech in mixed stands. Vertical profiles of fine root attributes adjusted to one unit of basal area (BA) exhibited partial root system stratification when central beech is growing with spruce competitors. In this constellation, beech was able to raise its specific root length (SRL) and therefore soil exploration efficiency in the subsoil, while increasing root biomass partitioning into deeper soil layers. According to relative values of fine root attributes (rFRA), asymmetric below-ground competition was observed favoring beech over spruce, in particular when central beech trees are admixed with spruce competitors. We conclude that beech fine rooting is facilitated in the presence of spruce by lowering competitive pressure compared to intraspecific competition whereas the competitive pressure for spruce is increased by beech admixture. Our findings underline the need of spatially differentiated approaches to assess interspecific competition below ground. Single-tree approaches and simulations of below-ground competition are required to focus rather on microsites populated by tree specimens as the basic spatial study area.Scientists are currently debating the effects of mixing tree species for the complementary resource acquisition in forest ecosystems. In four unmanaged old-growth spruce-beech forests in strict nature reserves in southern Sweden and northern Germany we assessed forest structure and fine rooting profiles and traits (\u22642 mm) by fine root sampling and the analysis of fine root morphology and biomass. These studies were conducted in selected tree groups with four different interspecific competition perspectives: (1) spruce as a central tree, (2) spruce as competitor, (3) beech as a central tree, and (4) beech as competitor. Mean values of life fine root attributes like biomass ( Fagus sylvatica L.) and Norway spruce [Picea abies (L.) Karst], Pretzsch and Sch\u00fctze  show evidence of species interaction and its effects on tree performance and stability. Several studies in managed mature beech-spruce mixtures in Germany and Austria found indications for vertical root system stratification  Karst.] or oak  expand its distribution range northwards  finding evidence for vertical root system stratification in the unmanaged spruce-beech forests, (2) quantifying effects of spruce-beech competition in different mixture constellations on fine root structural traits, and (3) evaluating the competitive status of both species below ground considering different levels of interspecific competitive pressure.Our present study includes a temperate near-natural forest within the high montane zone of the Harz Nationalpark (Northern Germany) with climate and site conditions comparable to the hemi-boreal forests of our other two study sites in Southern Sweden (see Table Picea abies (L.) Karst.] and European beech (Fagus sylvatica L.) are located in the boreo-nemoral zone  covered with moraine sediments whereas at the Harz site both metamorphic \u201cHornfels\u201d and sedimentary \u201cGrauwacke\u201d sandstones prevail, partly covered by loess (eolic silt sediment). All sites have comparably low amounts of fine-textured soil and are riddled with boulders. Soil traits of all three sites are comparable with a moderate to thick accumulation of organic material 5\u201312 cm; the humus type is moder to raw humus  or raw humus (Siggaboda) with a high C/N ratio. Fine soil material is dominated by silt (40\u201365%) and sand (18\u201352%); the clay proportion is relatively low (8\u201317%) and the texture can be classified as sandy silt or silty sand, respectively. The soil type is a Haplic Podzol BGR,  with a hdbh), tree heights, and basal area (BA) .All three mixed stands are dominated by spruce with higher mean values of stem density, diameter at breast height (A) Table . The SweForest stand structures were recorded in a 1 ha square core plot (100 \u00d7 100 m) in the center of the semi-natural forest representing a typical section of the old-growth stand. We subdivided the plot using a 20 m-grid  of 7 cm and larger in winter 2004 at Siggaboda and in spring 2005 at the other sites. For each tree, species, cardinal location coordinates of the stem using above mentioned equipment and dbh with a girth tape were recorded. Subsequently, a tagging system  was used for temporarily (between 2004 and 2007) marking and numbering each measured tree.Within the entire 1 ha core plot, we assessed each tree with a A) spruce as the central tree, (B) spruce as competitors, (C) beech as the central tree, and (D) beech as competitors. This design was completed by monospecies groups with comparable intraspecific competitive status  that was only used as a reference for analyses of mixed species representation .We studied fine root structure of mature trees focusing on tree groups with one central tree with its mostly four\u2013five competitors . Therefore, beech-spruce tree groups representing four different types of interspecific competitive situations were selected:  until the solid bedrock layer was reached. The maximum mineral soil depth sampled varied from 20 to about 40 cm. Various studies revealed that the maximum of fine roots is found in the top soil layers  and vitality . We applied morphological criteria for the identification of dead root material: dead root parts exhibits a dark discoloration of the central cylinder and a decreased flexibility of root segments . The reported measurements allowed the calculation of specific root length  and specific root surface area (SRA)  from the ratio of fine root length (FRL) and root biomass, and fine root surface area and rooting biomass, respectively.All recorded root fragments were then dried for 48 h at 40\u00b0C and weighed in order to measure living fine root biomass , and thus variable species abundance above-ground :The data was included in a relational database running on the open source database system PostgreSQL and analyzed with the software package Statistica 9  and SAS JMP 9 (SAS Institute Inc. 2010). Differences between mean root traits were assessed either by the Kolmogorov-Smirnov-two-sample test, or by the Kruskal-Wallis H test when more than two samples or groups were compared. We used the respective tree BA per hectare of either spruce or beech as a reference unit for the comparison of fine root attributes (FRA are the life fine root attributes in terms of FRB (g m\u22122), FRL (m m\u22122), and RAI (cm2 m\u22122) of a central tree (CT) or n competitors (COMP), respectively. BA (m2 ha\u22121) is the BA of either spruce or beech, and FRAad are fine root attributes adjusted to the same BA (1 m2 ha\u22121) of either one central tree or of n competitors .where CT) or competitor (COMP) constellations of spruce and beech were further assessed by calculating relative fine root attributes  in mixed groups with either CT or COMP constellations to those of pure stand groups (Equation 3). This enables the assessment of under- (<1) or overrepresentation (>1) of beech and spruce below ground growing in different mixed stand constellations under interspecific competition.The fine root representation of either central tree  attained higher adjusted fine root abundance  along the vertical rooting profile than the competitors  exhibited significantly higher fine root abundance in both the humus layer and deeper soil layers compared to beech competitors (COMP). This was not the case for spruce with a quite equal allocation of fine root proportion along the profile for both CT and COMP constellations. A spatial separation of the fine roots of spruce and beech was visible for the deeper soil horizons (10\u201340 cm) when growing with beech as the central tree  and spruce as competitors  resulting in high beech and low spruce fine root quantities. This partially vertical stratification was mainly due to high plasticity of beech fine rooting as a central tree. No stratification was visible in the organic layer and top soil where both species reached their maximum abundances.For both spruce and beech, central trees (SRL and specific fine root surface area (SRA) attained values for mixed beech (CT and COMP) of SRL 12.7 \u00b1 5.5 m g\u22121 and of SRA 367.3 \u00b1 125.9 cm2 g\u22121 compared to mixed spruce of SRL 6.6 \u00b1 3.8 m g\u22121 and of SRA 253.6 \u00b1 108.1 cm2 g-1 . However, total SRL and SRA differences between CT and COMP constellations within both species were not significant.Total means of specific SRL and SRA support the idea of higher plasticity of beech fine rooting . For spruce in contrast, we did not find such changes between central spruce trees (CT) and its competitors (COMP) rooting behavior. However, significant higher SRL and SRA values of CT constellations in the humus layer  and the top soil  points to higher competitive investments for rooting space sequestration in the upper soil horizons of single central spruce trees (CT), whereas single beech trees (CT) invested more in deeper soil horizons with less competitive abundance of spruce roots. Comparing beech and spruce as interspecific competitors (COMP), one can observe quite similar vertical rooting behavior , beside the above mentioned fact that the overall level of beech is much higher than that of spruce.The vertical profiles of g Figure . WhereasrFRA, cf. Equation 3) in mixed CT and COMP constellations  and COMP  constellations on interspecific tree species representation compared to the intraspecific one (Table rFRA). Two major findings were derived: (1) spruce is underrepresented in fine root abundance in mixed stands (mean rFRA < 1) whereas beech is overrepresented (mean rFRA > 1); (2) both beech overrepresentation and spruce underrepresentation address CT constellations with beech as the central tree (B). This indicates that beech rooting was favoured by an asymmetric interspecific competition of both species when several spruce competitors grew together with a single beech tree. But this was not the case for CT constellations with central spruce and beech competitors where we found a quite symmetric interspecific competition. Combining results from the existing mixtures (means of A + D) of central spruce (CT) and competing beech (COMP) or vice versa (means of B + C) one can assess fine root representation effects of the mixtures compared to either beech or spruce pure groups. It turned out that due to the low fine root representation of spruce no existing mixture reaches the high fine root representation of pure beech. However, both mixture constellations  lead to higher fine root representation compared to the pure spruce plots.For the analyses of fine root representation  of the mixed stand plots  in Sweden  is related to the remarkably low tree abundance above ground  compared to the Swedish plots. The positive relationship between tree dimension (BA) and soil exploration (FRB) on microsite and tree level has been demonstrated by Bolte and Villanueva  of central beech and competing spruce in deeper soil horizons  and mixed beech (12.7 m g\u22121) lie within the lower part of the range for spruce and beech (d < 2 mm) of 4.5\u201326 and 5.7\u201331.5 m g\u22121, respectively, reported by the extensive meta-analyses of Ostonen et al.  are similar to those reported for mixed spruce by Bolte and Villanueva  of beech does not mean that resource exploitation is more efficient compared to spruce  increased SRL in deeper soil layers. This indicates additional soil exploration activities at low carbon costs in soil depths from 20 cm downwards fitting well to the findings of changed root system partitioning favouring deeper soil horizons for increasing complementary resource exploitation and \u201cunderground niche separation\u201d  adjusted to the same unit of above ground performance (1 m2 BA per hectare) with adjusted values for monospecies plots  is in line with other studies reporting an over-proportional reduction of fine root abundance in beech mixtures with spruce  surrounding a single beech tree (CT) have a low fine root representation possibly reflecting intensive above ground competition between central beech and spruce competitors leading to increased biomass partitioning toward aboveground tree compartments. Beech fine root representation on the other hand is favored by interspecific competition with spruce. The found morphological belowground plasticity (variation of rooting depth in CT constellation and of SRL/SRA) reflects the high crown plasticity (Dieler and Pretzsch, The relative fine root representation is a measure to compare mixed species abundance (SRL and with this soil exploration efficiency in the subsoils while increasing root biomass partitioning toward deeper soil layers. Moreover, asymmetric below-ground competition was observed favoring beech toward spruce in a mixed constellation with central beech. We conclude that beech fine rooting is facilitated in the presence of spruce by lowering competitive pressure compared to intraspecific competition whereas the competitive pressure for spruce is increased by beech admixture. This is most obvious when central beech trees are admixed with spruce competitors. Our findings underline the need of spatially differentiated approaches to assess interspecific competition below ground. Since tree competition is a process that affects tree at an individual scale, stand scale analyses should be complemented by single tree approaches, above and below ground. In line with the recent development of crown competition assessments and stand simulation methods (e.g., Pretzsch et al., The results of the presented study exhibited an only partially vertical root system stratification in the subsoil in the three spruce-beech old-growth stands and depended on specific mixture constellation: beech central tree with spruce competitors. In this mixture constellation, beech was able to raise The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Headache diagnostic software (HDS), developed by Headache center, Neurology Clinic in Belgrade integrates a diagnostic expert system able to suggest the correct ICHD-II diagnosis once all clinical characteristics of a patient\u2019s headache have been collected.Purpose The aim of this pilot study was to test its diagnostic accuracy, the usefulness and applicability in the diagnosis of primary headache disorders and medication overuse headache (MOH).Forty patients with clinical diagnosis of migraine, tension type headache (TTH), cluster headache and MOH with an Internet access agreed to fill the web-based headache diary 4-6 weeks after their first consultation in Headache center. This diagnostic diary is developed exclusively based on the ICHD-II criteria, and represents the core of HDS. We analyzed the level of agreement between diagnosis given after clinical interview and obtained by HDS as well as patients\u2019 level of compliance.Patients\u2019 understanding of the diary proved highly satisfactory which was followed by good compliance (77.5%). Number of patients with one headache diagnosis was 22; 9 patients received 2 or 3 different diagnosis. All patients with a clinical diagnosis of migraine (21) had at least one migraine attack recognized by HDS; episodic TTH was less frequent diagnosed using standard clinical interview than by DHS. In all MOH (4) and cluster headache patients (3) there was complete concordance between clinical and software generated diagnosis.Web-based HDS can be considered as advanced, user-friendly, useful and reliable diagnostic tool in headache center."}
+{"text": "Mycobacterium tuberculosis (MTB) strains is a worrisome trend seen during recent years. Rapid detection of MDR strains is very important to restrict their spread in the population. Gold standard methods for drug susceptibility testing (DST) of MTB are either costly or very slow. Nitrate reductase assay (NRA) is one of the methods for rapid detection of resistance. This technique is based on the capacity of M. tuberculosis to reduce nitrate to nitrite. The WHO recommends that the NRA be used as direct test on smear-positive sputum specimen or as an indirect test on Mycobacterium tuberculosis isolates grown from conventional solid cultures. We evaluated the performance of NRA as rapid, reliable & inexpensive method for drug-susceptibility testing of Mycobacterium tuberculosis against first line antitubercular drugs, Rifampicin (RIF) and Isoniazid (INH).Increase in multi-drug resistant (MDR) M. tuberculosis isolated from sputum samples of pulmonary tuberculosis patients were subjected to NRA and absolute concentration method for comparison.80 strains of Out of 80 isolates, 12 strains were resistant to INH & 11 strains were resistant to RIF and 9 strains are resistant to both INH & RIF constituting MDR strains. Sensitivities and specificities were 99%, 98% for RIF and 99%, and 100% for INH by NRA as compared to Absolute Concentration. However median time of obtaining results was shorter using NRA (9-10 days) compared to Absolute Concentration (30-40 days).Mycobacterium tuberculosis.We conclude that NRA has the potential to be a useful tool for rapid DST of"}
+{"text": "The complete funding information is: \"This study was supported by Clinical Translational Science Institute (CTSI)(1UL1RR029893) seed fund to PL, Northwestern Memorial Hospital Dixon Translational Research Fund and Marsha Rivkin Center For Ovarian Cancer Research Award to JJW, and predoctoral fellowships from NYU CTSI TL1 (1UL1RR029893) and NYU Molecular Oncology and Immunology Training grant (T32 CA009161) to GD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\""}
+{"text": "Selecting the treatment of choice for multilevel cervical myelopathy remains a controversial issue. The most important factor in choosing a treatment method for patients with cervical myelopathy is the sagittal curvature and the site of compressive pathology.A total of 20 cases were available for the last 4 years with acceptable follow-up (f/u) of at least one year after surgery. Clinical examinations were obtained before surgery, 3 months post-surgery and at f/u. Evaluating the operative results performed by analyzing the recovery rate using the Japanese Orthopaedic Association (JOA) scoring system.Analysis were conducted on a total 20 patients undergoing surgery via anterior approach (9 patients), posterior approach with fixation (3 patients), and anterior. Posterior approach (8 patients). Two patients underwent surgery with hybrid decompression fixation technique. There were two patients who had decreased level of the JOA score which need posterior decompression. One patient had early onset post of infection in posterior approach.Our strategy base on naderi algorithm were effective and the follow up showed stable clinical results which depended on the completely removal of the possible causes of the pathology.Cervical spine, Multilevel, Myelopathy"}
+{"text": "To the Editor: Mediterranean spotted fever (MSF) is endemic in Italy, where it is a reportable disease. From 1992 to 1998, the Italian Ministry of Health was notified of approximately 8,500 cases of human rickettsioses presumed to be MSF. MSF occurs more commonly in some central (Lazio) and southern  regions  for ompA gene and restriction analysis under conditions previously described by Roux et al.  and aligned sequence data with homologous sequences of reference strains of the spotted fever group rickettsiae retrieved from the GenBank database. Sequence analysis showed 100% similarity with the homologous sequence of Israeli spotted fever Rickettsia reference strain ISTT CDC1 (GenBank accession no. U43797). The Israeli spotted fever Rickettsia belongs to the R. conorii complex .Molecular analysis of spotted fever group"}
+{"text": "Global evaluation of influenza vaccination in children indicates that current recommendations are not followed. Most children at high risk for influenza-related complications do not receive the vaccine, and increased efforts are needed to protect them. Furthermore, immunizing healthy infants 6\u201323 months of age and their close contacts should be strongly encouraged. Vaccinations are recommended for children with recurrent acute otitis media or recurrent respiratory tract infections and possibly for healthy daycare and school-age children because of the potential socioeconomic implications of influenza. Issues that need to be addressed include educating physicians and parents concerning influenza-related illness and complications, cost-effectiveness and safety of licensed vaccines, adequate vaccine supply, and availability of intranasal products. The most important of these obstacles are lack of understanding of the risks for complications and lack of knowledge of efficacy (Seven main obstacles to complying with recommendations for vaccination in children exist: 1) lack of understanding of the risk for influenza complications in children; 2) lack of knowledge of annual immunization\u2019s efficacy in primary prevention; 3) parents\u2019 negative reaction to parenteral vaccine administration (\u201cNot another shot!\u201d); 4) need for two priming doses in children <9 years old followed by annual administration; 5) fear of limited protection in younger and high-risk children; A number of studies of adult (particularly elderly) populations have shown that knowing risk factors for influenza complications, favorable perceptions of the vaccine, and clinician recommendations are the main variables predicting the administration of influenza vaccination  and require annual administration to maintain protection  were randomized to receive the vaccine (n = 67) or no vaccination (n = 66). During a 6-month period, 24 vaccine recipients (35.8%) experienced 32 episodes of AOM, and 42 control participants (63.6%) experienced 64 episodes. The overall efficacy of vaccination in preventing AOM was 43.7%  . Recurrent AOM is common in infants and children, and its possible sequelae make prevention desirable (= 0.002)  (13). Mo>6 episodes per year if >3 years; >8 episodes per year if <3 years) were randomized to receive the intranasal virosomal influenza vaccine (n = 64 with 176 household contacts) or a control placebo (n = 63 with 173 household contacts). During the influenza season, vaccinated children had fewer respiratory infections or febrile respiratory illnesses, received fewer prescribed antimicrobial and antipyretic drugs, and missed fewer school days than the controls (A second group of children who could be considered for influenza vaccine are those with recurrent episodes of respiratory tract infections (RRTIs). A large number of children without any immunologic problems experience multiple episodes of RRTIs during the first years of life; although these generally have a benign prognosis, they can cause substantial medical and socioeconomic problems  in 555 school-aged children in Russia demonstrated that both were efficacious in preventing school absenteeism by reducing the number of missed school days by 47% to 56% compared to missed school days in unvaccinated children . AlThe socioeconomic importance of influenza in childhood is confirmed by economic analyses showing that vaccinating healthy preschool and school-age children can lead to health and economic benefits during epidemic and pandemic periods , and the central role of children in disseminating the infection in households and communities. The issues that need to be addressed include educating physicians and parents about the illness caused by influenza, the cost-effectiveness and safety of licensed vaccines, adequate vaccine supplies, and the availability of intranasal products. Improved compliance associated with nasal administration should increase the use of influenza vaccination. Only a heightened and regular demand for influenza vaccine will result in sufficient vaccine supplies at all times (not just on a year-to-year basis) and place us in a better position to detect a novel pandemic influenza virus strain."}
+{"text": "The recent article by Prud'homme et al  suggestsThe above examples clearly illustrate the role of neuropilin-1 in tumor progression in systemic malignancies and the urgent need to identify further inhibitors of neuropilin-1 expression."}
+{"text": "Critically ill patients with inadequate lid closure are susceptible to developing exposure keratopathy. Protective measures can prevent this and reduce the risk of subsequent microbial keratitis and irreversible visual loss. Of two published surveys ,2, one wA team of researchers telephoned all general ICUs and other specialty critical care units in England caring for sedated, ventilated patients and asked a supervising nurse questions from a questionnaire piloted earlier in London.Two hundred and seventeen out of 267 ICUs (81%) participated. One hundred and thirty out of 217 (60%) ICUs had an eye care protocol. Sixty-six per cent of units with protocols assessed lid closure compared with 65% of those without. Geliperm application was the most common protective therapy , followed by Lacrilube . Most ICUs used a combination of methods. The total estimated incidence of ocular complications in the last year was 502. The most recent complications witnessed included corneal ulceration (23 cases), microbial keratitis (11) and chemosis (23). Cases of severe visual loss were caused by anterior ischaemic optic neuropathy following prone positioning (two cases) and microbial keratitis in a patient's only functioning eye.There is a need for protocols that encourage proper eyelid position assessment, effective protection of the ocular surface and referral to ophthalmologists in the event of any complications or any loss of corneal clarity."}
+{"text": "Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based \u201cconformational selection\u201d of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected residue clusters may be a rather general functional requirement encoded across molecular chaperones. The obtained insights may be useful in guiding discovery of allosteric Hsp90 inhibitors targeting protein interfaces with co-chaperones and protein binding clients. The molecular chaperone Hsp90 (90 kDa heat-shock protein) is required for managing conformational development, stability and function of proteins in the cellular environment E coli homologue, HtpG Structural and biochemical studies have established Hsp90 as an ATP-dependent system that operates as a homodimer in a functional cycle associated with the ATP binding and hydrolysis Modern biophysical approaches including X-ray crystallography, electron microscopy and small-angle X-ray scattering (SAXS) have provided a more detailed characterization of the Hsp90 conformational states during progression through the ATPase cycle Computational approaches have been instrumental in revealing the atomic details of the inter-domain communication pathways which may regulate the conformational equilibrium of the molecular chaperone. We have recently reported the first computational study of the Hsp90 allosteric binding with an atomic level analysis of the conformational motions and the inter-domain communication pathways in the full-length yeast Hsp90 dimer in the apo form and complexes with ATP and ADP Mechanistic and thermodynamic models of allosteric communication have become widely accepted and broadly applied to analyze mechanisms of allosteric regulation in proteins and biological networks Structure-functional studies of Hsp90 regulation have proposed a number of functional motifs that may contribute to the regulation of Hsp90 activity, including ATP hydrolysis and allosteric interactions. Nevertheless, molecular mechanisms that control the relationship between conformational diversity and biological functions of Hsp90 lack a detailed quantitative characterization. In this work, we integrated molecular dynamics (MD) simulations and modeling of the principal collective motions with the energy landscape models and structure-functional analyses of regulatory interactions to characterize functional dynamics of the Hsp90 molecular chaperones and formulate a unifying theoretical framework that may adequately describe and rationalize molecular principles of Hsp90 dynamics and function.We begin by providing a road-map through the manuscript and formulating main questions, computational experiments conducted and hypotheses tested. In the present work, we integrated all-atom MD simulations with modeling of principal correlated motions, the energy landscape analysis and structure-functional characterization of regulatory interactions to investigate functional dynamics and mechanisms of the Hsp90 molecular chaperones. The following specific objectives were pursued in this study: (a) to quantify molecular mechanisms by which functional dynamics and allosteric motions of Hsp90 may be connected with the probabilistic nature of the underlying energy landscape; (b) to identify and characterize functional hotspots shared by the Hsp90 chaperones that could coordinate functional dynamics and \u201cconformational selection\u201d of the functional states. We proposed that conformational dynamics and functional motions of Hsp90 may be described using the energy landscape models and principles of \u201cconformational selection\u201d (or \u201cpopulation-shift\u201d) between preexisting conformational ensembles In the first section, we discussed the results of MD simulations performed for all structural forms of Hsp90. A comparative analysis of the conformational ensembles highlighted fundamental aspects of Hsp90 dynamics that may be exploited by the chaperone to accommodate functional requirements during the ATPase cycle. In the second section we characterized functional dynamics and principal collective motions of the molecular chaperone. This analysis demonstrated that a central evolutionary conserved characteristic of Hsp90 dynamics is the presence of long-range inter-domain motions that enable allosteric signaling. We concluded that allosteric interactions may provide a mechanism for structural adaptation of Hsp90 by shifting the dynamic equilibrium between the ensembles of functional states. A switch-based conformational change is a hallmark of complex biomolecular systems that function via allosteric signaling and are often regulated by a relatively small number of functional hot spots , , The crystal structures of the full-length Hsp90 dimer from three different species revealed a similar domain architecture, yet significant differences in the global conformational flexibility and the relative domain orientation Figure 1Figure S1) that may serve as stabilizing \u201chandlers\u201d in assisting the central \u201cstrap\u201d of hydrophobic residues (residues 755\u2013765) to ensure structural integrity of the M-domain and CTD  of MD trajectories. The structural distribution of the protein mobility and the cross-correlation maps of protein residue fluctuations were computed along the dominant principal component (PC) modes. This analysis identified the shapes of the low frequency modes and the protein regions subjected to correlated and/or anti-correlated motions along the selected low frequency modes.Sstructural mapping of the HtpG mobility projected along the low frequency modes revealed a heterogeneous and diffuse network of structurally stable regions distributed across all domains of the extended HtpG form , the catalytic loop in the M-domain (residues 332\u2013342) and the adjacent H10 helix (residues 343\u2013366) are among functional regions that become protected upon ATP binding The full-length mammalian Grp94 in complex with either ATP or ADP has a semi-open, V-shaped conformation of the dimer , , , The ATP-bound yeast Hsp90 is characterized by structurally constrained conformation, stabilized by a dense network of both intra-monomer and inter-monomer interactions , , , 8These findings are in accordance with insights by Wolynes and coworkers Within the energy landscape framework, long-range cooperativity of allosteric interactions during allosteric transitions may favor a combination of the population-shift and induced-fit mechanisms Allosteric signaling is often enabled by a relatively small number of evolutionary conserved and sparsely connected regulatory hotspots. In this section, we describe a computational approach to identify and characterize a network of conserved functional motifs responsible for regulation of Hsp90 dynamics. We propose that functional motifs coordinating functional dynamics and collective motions of the Hsp90 chaperone may serve as central regulators of Hsp90 activity. Structurally rigid and conformationally flexible residues may often occupy proximal positions to the hinge sites, since the regions of high and low structural stabilities could participate in binding sites We focus on the low-frequency functional motions represented by the normalized mean square fluctuation (NMSF) of the Hsp90 chaperone residues, along the two lowest frequency modes. These profiles can reflect salient features of the intrinsic protein dynamics , , According to this analysis, the NMSF profiles along the two slowest modes of HtpG motions confirmed the presence of anti-correlated motions between the NTD and CTD in the open apo-HtpG form , 10. TheInterestingly, this charged linker in Grp94 (residues 287\u2013327) was deleted in the protein construct and replaced by four glycine residues in the crystal structures In the framework of the energy landscape model, this inter-domain region may facilitate cooperative interactions and efficient allosteric communication networks in HtpG. The alterations in this region observed in Grp94 may introduce a degree of inter-domain frustration that would detrimentally affect allosteric interaction networks. These findings could rationalize several important biochemical experiments REILQD-342 in HtpG . When Hsp90 dimer forms an initial complex with two Cdc37 molecules Figure S2). According to our mechanistic model, the binding sites of these motifs may recognize the \u201cincoming\u201d co-chaperone molecules, and the Cdc37 dimer would then bind the two linker regions. The regulatory elements of these motifs may then \u201cpass\u201d the binding signal information via allosteric communication pathways and trigger switching of the thermodynamic equilibrium towards a more open and flexible ADP-bound state of Hsp90 suitable for recognition of protein kinase clients.Hence, allosterically regulated conformational equilibrium of Hsp90 and co-chaperone binding are closely associated and may be modulated via the stochastic nature of the underlying energy landscape. Based on our findings and agreement with structure-functional experiments , IV-539 containing a pivotal switch point Ile-538 in HtpG  emerged as a central element of the CTD regulatory motif involved in coordinating the inter-domain communications. The evidence of an efficient molecular communication between NTD and CTD regions at the interface is of special importance given a rapidly growing interest in developing novel and specific Hsp90 inhibitors targeting allosteric C-terminal nucleotide binding site Hence, we identified universal functional motifs shared by the Hsp90 chaperones in different species that could play a universal role in coordinating functional dynamics and principal collective motions of Hsp90. These motifs may also serve as central functional regulators of Hsp90 activity, including control of ATP hydrolysis, the inter-domain communications and protein client binding. We observed that recognition sites may correspond to the conformationally mobile regions along slow modes of principal motions. Moreover, the recognition sites are often strategically positioned close to the regulatory anchor motifs containing catalytic and/or hinge residues. According to our results, functional coupling of structurally stable and conformationally mobile elements in the regulatory motifs is what may enable allosteric signaling and recognition of co-chaperones and protein clients. The central result of this study is that a small number of functional motifs may be utilized by the chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, co-chaperone binding and protein client recognition. Mutations, drug targeting, and probing protein binding in these regions would allow furthering pinpointing specific residues responsible for various functions including protein binding.It becomes more apparent now that functional dynamics of Hsp90 is closely associated with the ability of the molecular chaperone to bind and control activity of numerous protein clients. During client binding, the Hsp90 chaperone can adopt equilibrium between structurally different states that is maintained even after substrate loading In this work, we identified and characterized evolutionary and functionally conserved elements of the Hsp90 chaperone that may serve as key regulators of collective motions and hubs of long-range communication networks. We propose that functional clusters corresponding to stable regions in principal collective motions define minimally frustrated anchor sites (\u201chot spots\u201d). These minimally frustrated residue clusters with optimized local interactions may be critical for regulation of allosteric signalling between distant protein regions. The proximal recognition sites (\u201csoft spots\u201d) may be functionally coupled to the anchoring regulatory residues and form networks of communicating interaction clusters. These \u201csoft spots\u201d may be formed by locally frustrated residues, whose interaction networks are energetically optimized and prone to dynamic modulation by mutations or protein client binding. Hence, allosteric signaling may involve a dynamic coupling between structurally rigid  and plastic  clusters of residues. A switch in state at a soft cluster upon protein client binding can shift the thermodynamic balance and activate a specific network of allosterically coupled residues. This model is consistent with the central role of regulatory nodes as \u201cdiscrete breathers\u201d or independent dynamic segments in allosteric signaling Overall, the proposed mechanistic picture of Hsp90 function is consistent with studies showing that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected groups of residues, suggesting that rapid transmission of allosteric signals through a small network of distantly connected residue clusters may be a universal requirement encoded in the molecular chaperones and possibly other macromolecular assemblies. Our analysis has also confirmed that Hsp90 homologues sharing the same fold architecture may exhibit similar dynamical characteristics, including conservation of principal collective motions. The results support a mechanistic hypothesis according to which that the interaction networks regulating collective motions of the Hsp90 chaperone may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based \u201cconformational selection\u201d of Hsp90 functional states is likely to be readily modulated by co-chaperones and protein binding partners.Targeting allosteric binding sites and interrupting protein client binding with Hsp90 can produce a broad-spectrum antitumor activity and a low risk of drug resistance due to a combinatorial blockade of multiple signaling pathways. While there has been a steady progress in structural studies of the Hsp90-NTD complexes with small molecules, much less is known about the molecular basis of allosteric Hsp90 binding with co-chaperones and protein clients. A second nucleotide-binding domain has been reported to exist in the C-terminus of Hsp90, and specific inhibitors to this domain are represented by novobiocin and the related coumarin antibiotics The results of our study could guide design of experiments for probing allosteric binding of celastrol by introducing mutations in the communicating residues from the regulatory and recognition motifs of Hsp90. Integration of computational and experimental approaches may thus facilitate experimentally-guided mapping of allosteric binding states and help to specify whether Hsp90 or its co-chaperone Cdc37 is the primary target for binding of celastrol. Recent evidence suggests that Hsp90 interacts and stabilizes a growing list of protein kinases, and Cdc37 serves as the key co-chaperone for a large portion of the yeast kinome +) and chloride (Cl\u2212) counter-ions were added to achieve charge neutrality in MD simulations at physiological concentration of 0.15 mol/L. All Na+ and Cl\u2212 ions were placed at least 8 \u00c5 away from any protein atoms and from each other. The system was subjected to initial minimization for 20,000 steps (40 ps) keeping protein backbone fixed which was followed by 20,000 steps (40 ps) of minimization without any constraints. Equilibration was done in steps by gradually increasing the system temperature in steps of 20 K starting from 10 K until 310 K and at each step 15000 steps (30 ps) equilibration was run keeping a restraint of 10 Kcal mol\u22121 \u00c5\u22122 on protein alpha carbons (C\u03b1). Thereafter the system was equilibrated for 150,000 steps (300 ps) at 310 K (NVT) and then for further 150,000 steps (300 ps) at 310 K using Langevin piston (NPT) to achieve uniform pressure. Finally the restrains were removed and the system was equilibrated for 500,000 steps (1 ns) to prepare the system for simulation. An NPT simulation was run on the equilibrated structure for 20 ns keeping the temp at 310 K and pressure at 1 bar using Langevin piston coupling algorithm. The integration time step of the simulations was set to 2.0 fs, the SHAKE algorithm was used to constrain the lengths of all chemical bonds involving hydrogen atoms at their equilibrium values and the water geometry was restrained rigid by using the SETTLE algorithm. Nonbonded van der Waals interactions were treated by using a switching function at 10 \u00c5 and reaching zero at a distance of 12 \u00c5. The particle-mesh Ewald algorithm (PME) as implied in NAMD was used to handle long range electrostatic forces.MD simulations of the Hsp90 structures (each of 20 ns duration) were performed for a closed ATP-bound conformation of yeast Hsp90  (PDB ID 2CG9) \u03b1 atoms) i and j was calculated for each of the 20 ns MD simulation trajectories: snapshots from trajectories were taken every 200 ps, overall translation and rotation were removed, and only C\u03b1 was kept for analysis.Protein flexibility was analyzed by combining the results of MD simulations with the principal component analysis of conformational ensembles To obtain collective motion coordinates that represent the overall dynamics of each trajectory, PCA was performed, in which the covariance matrix Figure S1Time-Dependent History of High Occupancy Salt Bridges. Thermal fluctuations of the salt bridges in Grp94 (A) and yeast Hsp90 (B). (A) The depicted high occupancy hydrogen bond interactions in the M-domain and CTD of Grp94 are Glu564-Lys530 (in blue), Asp573-Lys493 (in red), and Glu548-Arg660 (in green). (B) The depicted high occupancy hydrogen bond interactions in yeast Hsp90 are Glu165-Arg174 , Glu355-Lys335 , and Asp506-Lys426 .(TIF)Click here for additional data file.Figure S2Allosteric Coupling of the Regulatory and Recognition Sites in the Hsp90 Chaperone. The coordinated involvement of the inter-domain charged linker, the catalytic functional loop from the M-domain and the projecting recognition loops are shown in blue spheres (only main chain is shown). The ADP-bound Hsp90 crystal structure (PDB ID 2IOP) was used for clarity of illustration. The protein structure is shown in ribbons colored according to secondary structures.(TIF)Click here for additional data file."}
+{"text": "Elevated intracranial pressure (ICP) episodes are associated with poor outcome and should be prevented. We developed models to predict these episodes 30 minutes in advance, and to predict long-term neurological outcome by using dynamic characteristics of continuous ICP and mean arterial pressure (MAP) monitoring.The Brain-IT  dataset Predictions of elevated ICP episodes Figure  were extDynamic data in continuous MAP and ICP monitoring allows prediction of elevated ICP. Adding information of the first 24 hours of ICP and MAP to known risk factors allows accurate prediction of neurological outcome at 6 months."}
+{"text": "Whereas the use of discrete pitch intervals is characteristic of most musical traditions, the size of the intervals and the way in which they are used is culturally specific. Here we examine the hypothesis that these differences arise because of a link between the tonal characteristics of a culture's music and its speech. We tested this idea by comparing pitch intervals in the traditional music of three tone language cultures  and three non-tone language cultures  with pitch intervals between voiced speech segments. Changes in pitch direction occur more frequently and pitch intervals are larger in the music of tone compared to non-tone language cultures. More frequent changes in pitch direction and larger pitch intervals are also apparent in the speech of tone compared to non-tone language cultures. These observations suggest that the different tonal preferences apparent in music across cultures are closely related to the differences in the tonal characteristics of voiced speech. Tonal differences between traditional Eastern and Western music are readily heard. Explanations often refer to the use of different scales The use of pitch in speech varies greatly among languages. The most obvious example is the broad division of languages into \u201ctone\u201d and \u201cnon-tone\u201d groups Based on these differences, we asked how, if at all, differences in the use of pitch in the traditional music of tone and non-tone language speaking cultures compares with the use of pitch in speech. To address this question, we compiled databases of speech and music from several tone and non-tone language cultures. The analysis focused on two aspects of pitch dynamics: the frequency of changes in pitch direction , and the size of the pitch intervals used. These aspects were chosen because they differentiate tone and non-tone language speech and play a central role in the structure of musical melodies U\u200a=\u200a9843.5, P<0.001; U\u200a=\u200a2317, P<0.001; t\u200a=\u200a-11.4, P<0.001), whereas intervals equal to or larger than a major second occur more often . The only exception in this overall pattern is major thirds (400 cents), which are more frequent in the music of non-tone language cultures (7.7% vs. 2.3%). t\u200a=\u200a\u22125.6, P<0.001), whereas larger intervals occur more often .  and three that use non-tone languages . The patterns apparent in music parallel those in speech. Thus the music of tone language cultures changes pitch direction more frequently and employs larger melodic intervals. Similarly, the speech of tone language cultures changes pitch direction more frequently and employs larger prosodic intervals. Presumably tone language speech exhibits these characteristics because the lexical meaning of each syllable in a tone language is tonally determined The only exception to this pattern is the use of major thirds. Despite the greater frequency of larger prosodic intervals (\u2265200 cents) in the speech of tone compared to non-tone languages, there are fewer melodic major thirds (400 cents) in the music of tone language cultures see . A possiIn sum, co-variation of tonal characteristics in the music and speech of the tone and non-tone language speaking cultures we examined indicates an intimate relationship between these two modes of social communication, providing a way of explaining at least some aesthetic preferences in biological terms.Monophonic folk melodies from tone and non-tone language speaking cultures, all of which could be either played on an instrument or sung, were obtained from scores and MIDI format files obtained principally from National University of Singapore and the Singapore National Library Board. The tone language database comprised 50 traditional Mandarin, 20 traditional Thai, and 20 traditional Vietnamese melodies. The non-tone language database comprised 50 traditional American, 20 traditional French, and 20 traditional German melodies. To mitigate cross-cultural contamination by modern media, all compositions pre-dated 1900, often by hundreds of years.Tone and non-tone speech samples were acquired by recording monologues read by native speakers of each of the 6 relevant languages . Each speaker read 5 emotionally neutral monologues translated into the appropriate language . Prior tThe analysis of music focused on melodic slope reversals, and melodic interval size. Melodic slope reversals were defined as any change in the direction of the pitch contour of a melody. For each melody, the number of local minima and maxima was tabulated and divided by the total number of notes; this value was multiplied by 100 to give the incidence of melodic slope reversals per 100 notes. Melodic interval size was defined as the pitch difference (in cents) between adjacent notes see . The analysis of speech focused on two aspects of pitch dynamics analogous to those examined in music: prosodic slope reversals, and prosodic interval size. Prosodic slope reversals were defined as any change in the direction of the simplified pitch contour of a speech recording Click here for additional data file.Figure S2Music analysis. (A) Musical notation of the traditional American melody \u201cHome on the range\u201d. (B) The same melody reformatted for analysis. Notes are represented by black bars with open circles marking their beginnings and endings. The length of each bar is proportional to the duration of the note. Local maxima (max) and minima (min) indicate slope reversals in the melodic pitch contour; melodic interval size (i) is the vertical distance between successive notes. Dashed lines have been added to aid visualization of the melodic pitch contour.(TIF)Click here for additional data file.Figure S3Speech analysis. (A) Recording of the sentence \u201cI applied for a job that would give me a good work experience\u201d spoken in American English (B) Fundamental frequency (F0) of the recording in (A) over time . (C) F0s in Panel (B) segmented into syllables with simplified contours. Syllables are represented by black bars with open circles marking their beginnings and endings. (D) Output of the Prosogram analysis. Local maxima (max) and minima (min) indicate slope reversals in the prosodic pitch contour; prosodic interval size (i) is the vertical distance between successive syllables. Dashed lines have been added to aid visualization of the prosodic pitch contour.(TIF)Click here for additional data file.Figure S4Interval size in the music and speech of tone and non-tone language speaking cultures sorted into descending and ascending. (A) The distributions of descending (left panel) and ascending (right panel) melodic interval sizes per melody in the tone (red) and non-tone (blue) language music databases. Unisons (0 cents) are shown in both panels. (B) The distributions of descending (left panel) and ascending (right panel) prosodic interval sizes per speaker in the tone (red) and non-tone (blue) language speech databases. The left panel inset shows the percentages of large (\u2265200 cents) vs. small (<200 cents) descending prosodic intervals . The right panel inset shows the percentages of small (<200 cents) vs. large (\u2265200 cents) ascending prosodic intervals .(TIF)Click here for additional data file.Figure S5Slope reversals in the music and speech of tone and non-tone language speaking cultures sorted by the individual languages examined. (A) Box plot showing the distribution of the number of melodic slope reversals per melody  in the Mandarin, Thai, and Vietnamese melodies (red), and in the English, French, and German melodies (blue). Horizontal yellow lines indicate medians; colored boxes specify inter-quartile ranges and dashed lines the ranges without outliers. (B) Box plot of the number of prosodic slope reversals per speaker  in the Mandarin, Thai, and Vietnamese speech (red) and English, French, and German speech (blue). Format is the same as in (A). Crosses indicate outliers (defined as greater/lesser than 1.5x the inter-quartile range). See (TIF)Click here for additional data file.Figure S6Interval size in the music and speech of tone and non-tone language speaking cultures sorted by the individual languages examined. (A) The distribution of absolute melodic interval sizes per melody in Mandarin, Thai, and Vietnamese melodies (red), and in the English, French, and German melodies (blue). (B) The distributions of absolute prosodic interval sizes per speaker in the Mandarin, Thai, and Vietnamese speakers (red), and the English, French, and German speakers (blue). See (TIF)Click here for additional data file.Figure S7Comparison of melodic intervals arising from pentatonic vs. heptatonic scale structure. (A) Illustration of heptatonic and pentatonic scales on piano keyboards . The pattern within a single octave repeats in each octave. (B) Histogram of the percentages of all possible intervals \u2264 500 cents arising from analysis of the scales in (A). Red bars represent pentatonic scale percentages, and blue bars heptatonic scale percentages.(TIF)Click here for additional data file.Table S1Statistics comparing the number of slope reversals in tone and non-tone language music and speech databases for each possible pair of the cultures examined. (A) Statistics for melodic slope reversals in music. (B) Statistics for prosodic slope reversals in speech; n1 and n2 refer to the sample sizes of group 1 and group 2. (DOC)Click here for additional data file.Table S2Statistics for the comparisons of interval size distributions in the tone and non-tone language music and speech databases for each possible pair of the cultures examined. (A) Statistics for melodic interval size distributions. (B) Statistics for prosodic interval size distributions; n1 and n2 refer to the sample sizes of groups 1 and 2. (DOC)Click here for additional data file.Text S1Supporting Methods and Results. This file gives an overview of the methods and results used in this manuscript.(DOC)Click here for additional data file."}
+{"text": "In patients with diabetes mellitus, coronary artery disease (CAD) is a major cause of mortality and results in substantial morbidity. Non-invasive detection of CAD in diabetic patients is challenged by silent ischemia and microvascular disease. Pharmacological stress CMR perfusion imaging (CMRPI) may identify evidence of flow limiting CAD at high resolution and tissue contrast. We therefore sought to test the hypothesis that stress CMRPI can provide robust prognostication to identify diabetic patients at high risk for major adverse cardiac events (MACE).Stress CMRPI was performed on 138 consecutive patients with diabetes  referred for assessment of ischemia. Rest and vasodilator stress CMRPI were performed each using a bolus of 0.1mmol/Kg of gadolinium, followed by late gadolinium enhancement (LGE) and cine imaging. Myocardial ischemia was defined by the presence of a stress induced perfusion defect, reversible at rest, in the absence of LGE in the same territory. At a median follow up of 21 months (IQR 30 months), 21 MACE (15%) had occurred (14 cardiac deaths and 7 AMIs).By univariable analysis, the presence of myocardial ischemia by CMRPI portended to 3-fold increase in MACE hazards . The absence of myocardial ischemia and LGE by CMRPI indicated a low annual rate of cardiac death (0.9%, Figure Stress CMRPI provides robust prognostication for major cardiac events in patients with diabetes. While a CMR study negative in both myocardial ischemia and LGE indentifies diabetic patients with lower event rates for MACE, the presence of myocardial ischemia by CMRPI indentifies a subgroup of diabetic patients at high risk for cardiac events."}
+{"text": "Xenotropic murine leukemia virus-related virus (XMRV) infects different human cells in vitro. In this study the pathogenic effect of XMRV in lymphoid tissue was investigated by infection of human tonsil histocultures.Human tonsils were obtained from healthy donors, dissected into small blocks and cultured on top of gelfoams. Tissue blocks were left uninfected or infected with an XMRV stock obtained from a 22Rv1 cell culture supernatant in the presence or the absence of AZT or Raltegravir. Viral infection was evaluated by PCR at different times in the cells migrating out the tissue and at day 14 in tissue cells. In addition, tissue cells were immunophenotyped and the expression of XMRV envelope protein was analyzed by western blot.Cells migrating out the tissue and tissue cells were positive for XMRV and both AZT and Raltegravir blocked the detection of viral DNA. Despite the presence of XMRV DNA, tissue lysates exhibited undetectable expression of XMRV env proteins by WB. XMRV infection did not modify the percentage of CD3 , CD4 (47 vs 48), CD8 (20 vs 19), or CD19 cells (29 vs 27) neither the naive/memory cell ratio, nor immune activation markers, as evaluated by the expression of HLA-DR and CD38.XMRV could specifically infect human lymphoid tissue cells although this process does not culminate in an explicit productive infection. This infection did not result in changes of T or B cells nor in immune activation, suggesting that lymphoid tissue could latently support XMRV infection."}
+{"text": "Diversity of immunoglobulins and the T cell antigen receptors is achieved via the recombination activating gene (RAG)-mediated rearrangement of variable (V), diversity (D) and joining (J) gene segments, and this underpins the efficient recognition of a seemingly limitless array of antigens. Analysis of V(D)J recombination activity is typically performed using extrachromosomal recombination substrates that are recovered from transfected cells and selected using bacterial transformation. We have developed a two-colour fluorescence-based system that simplifies detection of both deletion and inversion joining events mediated by RAG proteins.This system employs two fluorescent reporter genes that differentially mark unrearranged substrates and those that have undergone RAG-mediated deletion or inversion events. The recombination products bear the hallmarks of true V(D)J recombination and activity can be detected using fluorescence microscopy or flow cytometry. Recombination events can be detected without the need for cytotoxic selection of recombination products and the system allows analysis of recombination activity using substrates integrated into the genome.This system will be useful in the analysis and exploitation of the V(D)J recombination machinery and suggests that similar approaches could be used to replace expression of one gene with another during lymphocyte development. The antigen receptor loci of B and T lymphocytes exhibit a unique mechanism of control amongst the genes of multicellular organisms. The production of functional immunoglobulin (Ig) and T cell receptor (TCR) genes is accomplished through a tightly regulated process of recombination. Variable (V), diversity (D) and joining (J) gene segments of antigen receptor loci are assembled into a functional coding unit by a series of site-specific recombination events mediated by the products of recombination activating gene (RAG)1 and RAG2 [Escherichia coli [Assays of V(D)J recombination have relied extensively upon the transfection of extrachromosomal plasmid substrates into RAG-expressing cell lines and the recovery of these plasmids in hia coli -6. Many hia coli -5. This hia coli -9, or rehia coli -12. Furthia coli . Here, wDiscosoma and enhanced green fluorescent protein (EGFP). The system was designed such that unrearranged substrates would express the DsRed gene, whereas substrates that had undergone RAG-mediated recombination would replace DsRed expression with EGFP expression. In one construct, the EGFP open reading frame was placed on the opposite strand to DsRed and the RSS motifs arranged such that the segment containing DsRed and EGFP would be inverted by RAG-mediated recombination J recombination can occur either by deletion of the DNA between RSS motifs or by inversion of the intervening segment Figure . We geneThe inversion and deletion constructs were stably transfected into two cell lines representing different developmental stages of the B cell lineage. The cell line 300-19P is a pre-B cell line, expresses RAG1 and RAG2 and is known to catalyse V(D)J recombination, whereas WEHI231 is a B cell line in which RAG gene expression has been silenced and is therefore unable perform V(D)J recombination. The expression of RAG1 and RAG2 in these two cell lines was confirmed using reverse transcription polymerase chain reaction (RT-PCR) Figure . Pools oThese transfectants were then analysed for expression of the DsRed and EGFP reporter genes at the mRNA level. RT-PCR analysis established that expression of the EGFP gene was restricted to the RAG-expressing cell line and that EGFP transcripts could be detected in cells transfected with both the inversion and deletion construct Figure . A largeOur aim was to identify V(D)J recombination at the single cell level. We therefore analysed expression of the DsRed and EGFP molecules by fluorescence. Fluorescence microscopy of the stably transfected RAG negative WEHI231 and RAG positive 300-19P cells indicated that expression of EGFP was restricted to the 300-19P cells. Furthermore, EGFP expression was clearly detectable in both the deletion and inversion transfectants Figure . ExpressThe process of V(D)J recombination has evolved to generate a repertoire of antigen receptors. Large repertoires are generated by both combinatorial diversity and by the imprecise nature of the recombination process whereby the location of the double strand break is not fixed and nucleotides can be added or deleted from the free DNA end, generating extensive diversity in complementarity determining region (CDR)3 of the antigen receptor -16. Clonin situ in the absence of selection. Previously, assays of V(D)J activity have relied heavily upon extrachromosomal recombination substrates that are transiently transfected into cells before recovery and transformation into E. coli [In the system described here, the use of the twin fluorescent protein system distinguishes individual cells that have recombined a V(D)J recombination substrate from those which carry the substrate in a configuration representing germline gene segments. The ability to assay the absence of recombination is important when testing the effects of mutations or local chromatin environment on the recombination process. Importantly, the twin fluorescent protein system allows recombination to be detected  E. coli -6. Chrom E. coli ,18 and fcis-acting sequences (RSS12 + RSS23) need to be provided to ensure correct expression of the exogenous gene (unpublished results). The ability to switch gene expression from one gene to another by harnessing endogenous recombinase activity may have practical applications in the B and T cell lineage analogous to the use of the Cre/Lox system or other exogenous recombinases [Interestingly, the twin fluorescent protein system also indicates that V(D)J recombination could be used to control the expression of exogenous genes. Just 67 bp of mbinases .The inversion and deletion plasmids  for selection.Murine B cell lineage cell lines (300-19P and WEHI231) were maintained in RPMI medium supplemented with 10% foetal calf serum and 50 \u03bcM 2-mercaptoethanol. The recombination substrates were transfected into pre-B (300-19P) and B (WEHI231) cell lines by electroporation. Approximately 20 \u03bcg of linearised DNA were electroporated  into 10DNA and RNA were isolated from 10 ml aliquots of culture using Genelute kits  as per the manufacturers' protocols. The optical density was measured at 260 nm and the concentration of the nucleic acid calculated; 500 ng of genomic DNA was used as template in a PCR reaction. Recombination events were detected by PCR using appropriate primers  using the FL1 channel of a FACS Calibur flow cytometer . The mean fluorescence intensity of EGFP expression was compared between transfected and non-transfected cells and the data expressed as a fold increase in fluorescence with non-transfected cells assigned an arbitrary value of 1.The authors declare that they have no competing interests.GPC designed the overall strategy, GPC and GBS designed the constructs, GBS performed the experiments, EADW assisted with flow cytometry and GPC and GBS wrote the paper."}
+{"text": "MyoG and Myf6) than the genes encoding myogenic determination factors (Myf5 and MyoD). Additionally, the functional divergence within the myogenic determination factors or differentiation factors was also under positive selection pressure. The positive selection sites were more frequently detected from MyoG and MyoD than Myf6 and Myf5, respectively. Amino acid residues under positive selection were identified mainly in their transcription activation domains and on the surface of protein three-dimensional structures. These data suggest that the functional gain and divergence of myogenic regulatory factors were driven by distinct positive selection of their transcription activation domains, whereas the function of the DNA binding domains was conserved in evolution. Our study evaluated the mechanism of functional divergence of the transcriptional regulation factors within a family, whereby the functions of their transcription activation domains diverged under positive selection during evolution.The functional divergence of transcriptional factors is critical in the evolution of transcriptional regulation. However, the mechanism of functional divergence among these factors remains unclear. Here, we performed an evolutionary analysis for positive selection in members of the myogenic regulatory factor (MRF) gene family of vertebrates. We selected 153 complete vertebrate MRF nucleotide sequences from our analyses, which revealed substantial evidence of positive selection. Here, we show that sites under positive selection were more frequently detected and identified from the genes encoding the myogenic differentiation factors ( Recent studies in evolutionary genetics have provided several lines of evidence supporting the role of positive selection in the evolution of many genes. These studies have suggested that positive genetic selection is also the major evolutionary force in addition to neutral mutations and random genetic drift MyoD), myogenic factor 5 (Myf5), myogenin (MyoG), and Myf6 (MRF4) genes. All MRFs share a conserved basic helix-loop-helix (bHLH) domain that is required for DNA binding and dimerization with other proteins, such as E protein. All four MRFs are characterized by their capacity to convert a variety of cell lines into myocytes and to activate muscle-specific gene expression Myf5 and MyoD are myogenic determination factors and contribute to myoblast determination, which is activated in proliferating myoblasts before overt differentiation. In contrast, MyoG and Myf6 are myogenic differentiation factors that contribute to the differentiation of myoblasts and act downstream of Myf5 and MyoD, though Myf6 partly acts at both the determination and differentiation levels Myf5 and MyoD have redundant functions in myoblast determination and can compensate for the functional loss of each other, Myf5 plays a more critical role during the early determination of epaxial muscle, whereas MyoD is more critical for hypaxial muscle determination Myogenesis involves two major temporally ordered steps. First, myogenic progenitor cells (myoblasts) originate from mesenchymal precursor cells, and second, these cells then terminally differentiate into mature muscle fibers Myf5, MyoD, MyoG, and Myf6 genes were duplicated from a single invertebrate gene Caenorhabditis elegansAnthocidaris crassispinaDrosophila melanogasterCiona intestinalis, it gives rise two different transcripts of MRFs (MDFa and MDFb) as a result of alternative splicing. Moreover, in cephalochordates, the amphioxus have two MRF genes: BMD1 and BMD2MyoD in ascidians suggest that the regulation pattern of multiple MyoD genes has evolved under selective pressure before the MRF genes were duplicated into multiple copies Myf5 and MyoD genes were then duplicated from one of these two lineages, whereas MyoG and Myf6 were duplicated from the other lineage during vertebrate evolution. Therefore, the functional redundancy between Myf5 and MyoD as well as between MyoG and Myf6 might be due to their common genetic origin Genome duplication is believed to be a major genetic event that occurs during the evolution of a gene family from a single gene to multiple gene copies The mechanisms underlying the evolution of the MRF gene family during their duplication remain unclear. In particular, the evolutionary forces affecting the functional divergence of the four MRFs genes have not been fully elucidated. In this study, we investigated the mechanisms underlying the evolution of the four MRF genes with particular emphasis on the selective pressures imposed on the branches and sites of MRFs during vertebrate evolution. Our study provides several lines of evidence for the role of positive selection in the functional divergence of transcription factors.Myf5 and MyoD), but not in the myogenic differentiation factors (Myf6 and MyoG)  . Two amiand MyoD .Nucleotide mutations in coding sequences are important for the evolution of gene functions. The likelihood ratio (LR) tests of site models in the CODEML program of phylogenetic inference by maximum likelihood (PAML4) Typically, the relatively short period of positive selection is usually followed by long periods of continuous negative selection MyoG lineage  and myogenic differentiation factors (MyoG/Myf6) play distinct roles in myogenesis. The functional divergence between these factors was estimated using the DIVERGE 2.0 program Myf5/MyoD and MyoG/Myf6 branches, which was significantly greater than 0 (p<0.01). Thus, the functional divergence between Myf5/MyoD and MyoG/Myf6 was significant. Twenty-nine residues have a stringent threshold of a posterior ratio higher than eight. Most of these sites were located in the BASIC, MYF5 domains and C-terminus, which might be critical for the functional divergence between the myogenic determination factors (Myf5 and MyoD) and myogenic differentiation factors (Myf6 and MyoG) (Myf5/MyoD lineage (branch a in MyoG/Myf6 lineage (branch b in The myogenic determination factors (nd MyoG) . The rolnd MyoG) . Using tMyoD coding sequences  tree of 53 vertebrate equences  was geneequences . No siteequences . Using aequences . These rMyoD and MyoG, no branch or site under positive selection was identified in the vertebrate Myf5 gene  analysis, a total of 55 positive selection sites during the divergence of MRFs were identified using the site and branch-site models of PAML4. We plotted the genetic location of positively selected sites onto the protein secondary structure and three-dimensional structure . PositivdN) and synonymous (dS) substitution rates  were transcribed by a single MRF gene, which was different than lower invertebrates, whereby a single MRF ortholog was transcribed Ciona intestinalisMyf5 and MyoD evolved from one of these lineages, whereas MyoG and Myf6 (MRF4) evolved from another lineage Myf6 and MyoG (Myf5 and MyoD) and the myogenic differentiation factors (MyoG and Myf6). In addition, two amino acid regions (SXXTSPXSNCSDGM and SSLDCLSXIVXRIT) might be critical in the functional gain of the myogenic determination role in Myf5 and MyoD  and differentiation factors (Myf6 and MyoG) was driven by positive selection. Positive selection sites responsible for this divergent process were identified from the BASIC, MYF5 domains and C-terminus  was also under positive selective pressure. The evolution processes of MyoD in all vertebrates are driven by positive selection on the BASIC and MYF5 domains  also diverged under positive selection. The positive selection on the BASIC and C-terminus were identified in the bird MyoG lineage and the teleost MyoG lineage . The MRF sequences were aligned by the program MUSCLE or ClustalW, and all gaps were eliminated by manual edition  and synonymous (dS) substitution rates were calculated by the Nei-Gojobrotri (Jues-Cantor) method as implemented in the MEGA5.0 program to measure the pairwise sequence distances of the three domains among different MRFs The CODEML program in the PAML4 Three-dimensional structures of the proteins were predicted using the worldwide web following the methods of a case study using the Phyre server Myf5/MyoD) and myogenic differentiation factors (MyoG/Myf6). The Type I functional divergence was measured as the coefficient of functional divergence, \u03b8 (ranging from 0\u20131), which was calculated by model-free estimation (MFE) and maximum-likelihood estimation (MLE) under a two-state model. The value of \u03b8 represents the functional divergence The DIVERGE 2.0 program Table S1Likelihood Ratio Tests for the positive selection on all MRF genes.(XLS)Click here for additional data file.Table S2Likelihood Ratio Tests for the positive selection on each of the MRFs.(XLS)Click here for additional data file.File S1Alignment results for the 153 vertebrate MRF coding sequences.(NEXUS)Click here for additional data file.File S2Alignment results for the 53 vertebrate MyoD coding sequences.(NEXUS)Click here for additional data file.File S3Alignment results for the 43 vertebrate MyoG coding sequences.(NEXUS)Click here for additional data file.File S4Alignment results for the 19 mammalian MyoG coding sequences.(NEXUS)Click here for additional data file."}
+{"text": "Dear Editor,The increasing incidence of aspergillosis emphasizes to improve the diagnostic tools. AspergilA standard isolate of Aspergillus fumigatus PTCC5009 was grown in potato dextrose broth. DNA extraction of Aspergillus fumigatus, Fusarium oxysporum PTCC5115 and Aspergillus flavus PTCC5004 as control species were done according to established methods.[4] BloodThe alignment of the three DNA sequences was performed with the program Gene Works , Selection of the primer sequences was based on a close check for sequences with matching homologies in current DNA databases (Gen Bank). By using a nested PCR technique, two pairs of o primers  derived from sequences of the A. fumigatus 18s rRNA gene (GenBank No.) were chosen for PCR assays. For eachThe two mentioned primers with the highest sensitivity and species specificity of Aspergillus which amplified a fragment of 404 bp, were followed by AFU5S and AFU5AS which produced an internal fragment of 335 bp. These primer-binding sites are located in the 3' part of the 18S rRNA gene and in variable region V7-V9 (AFU7AS) or V8-V9 (AFU5AS), with no sequence overlap between the primers used in the first and second PCRs to reduce contamination problems. Comparison of clinical characteristics of the patients, and their PCR results showed that IA negative patients had an age>25, WBC count>3000 while positive patients had an age<30 and WBC count=1000-2000.Our results showed that out of 30 BMT patients, six patients had positive nested PCR results (20%). So detection of Aspergillus DNA from blood is possible and helpful in diagnosis of IA and can assist in distinguishing this disease from others . Most of"}
+{"text": "We surveyed intensivists to evaluate their stated use of systemic steroids in the ICU. The efficacy of steroids in septic shock and ARDS remains uncertain and clinicians' perceptions of competing indications and contraindications may jeopardize future randomized controlled trials (RCT). Knowledge of current practice will inform the design of future RCTs addressing the efficacy of systemic steroids in septic shock and ARDS.We designed and conducted a self-administered survey of intensivists practicing in academic settings with expertise in ARDS clinical research. We generated questionnaire items in focus group sessions with content experts and refined them through a standardized process of clinical sensibility, pilot and intra-rater reliability testing. Respondents used a four-point scale to grade how frequently they would administer systemic steroids in a 14 different clinical situations and reported their opinions of 16 near absolute indications or contraindications for systemic steroids. Local research staff distributed the survey to all intensivists practicing in the 11 centres (Canada and USA) with most patients enrolled in the OSCILLATE trial.In total, 103 of 125 potential respondents returned completed surveys (response rate 82%). A majority of respondents 'almost always' prescribe systemic steroids in the setting of recent systemic steroid use and low blood pressure (93%), significant bronchospasm in a mechanically ventilated patient (93%) and vasopressor refractory septic shock (52%). A majority of respondents would 'almost never' prescribe steroids in severe community-acquired pneumonia (81%), ALI (76%) and ARDS (65%). One-half (50%) would 'almost never' prescribe steroids for severe ARDS (50%). The near absolute indications selected by a majority of respondents were 'known adrenal insufficiency' (99%) and 'suspicion of cryptogenic organizing pneumonia' (89%). The only near absolute contraindication selected by a majority of respondents was 'systemic fungal infection' (52%).Certain clinical conditions may prompt intensivists to almost always prescribe systemic steroids and reduce equipoise for future placebo-controlled trials. Moreover, this survey shows that in selected academic centres a majority of intensivists do not prescribe corticosteroids for pneumonia, ALI and ARDS."}
+{"text": "Objective. The aim of this study was to identify patients with Parkinson's disease who showed loss or decrease of nocturnal blood pressure fall (nondipper patients) as a marker of autonomic dysfunction. Presence or absence of orthostatic hypotension was considered to investigate whether alterations in circadian blood pressure pattern are associated with posture-related dysregulation of blood pressure. Methods. 40 patients with Parkinson's disease underwent 24-hour blood pressure monitoring. 21 patients were diagnosed with arterial hypertension and received anti-hypertensive drugs. Nondipper patients were defined as having nocturnal decrease of mean systolic and diastolic blood pressure less than 10%. Presence or absence of orthostatic hypotension was determined by Schellong's test. Results. We identified 35 nondipper patients (88%). Nondipping was detected in 20 patients with orthostatic hypotension (95%) and in 15 patients without orthostatic hypotension (79%). 18 patients with hypertensive and 22 patients with normal blood pressure values were detected. Conclusions. In conclusion 24-hour blood pressure monitoring showed a high prevalence of nondipping in 40 patients with Parkinson's disease with and without orthostatic hypotension independent of coexisting arterial hypertension and antihypertensive treatment. 24-hour blood pressure monitoring may be useful to identify non-dipping as a marker of autonomic dysfunction in patients with Parkinson's disease. Parkinson's disease is a multisystem degeneration . Beside Involvement of the autonomic nervous system (ANS) occurs in the early stages of the disease . Cardiovascular dysautonomia, especially orthostatic hypotension, is frequently reported in Parkinson's disease .Involvement of peripheral components of the ANS can be demonstrated by MIBG scintigraphy.MIBG scintigraphy shows reduced cardiac uptake of MIBG (meta-[123I]iodobenzylguanidine) representing loss of postganglionic myocardial sympathetic nerve fibers in patients with Parkinson's disease and autonomic failure . HoweverFurther effects of autonomic cardiovascular dysfunction are demonstrated in earlier studies such as baroreceptor reflex dysfunction, alterations in circadian blood pressure regulation, and supine hypertension \u201315. FindAmbulatory blood pressure monitoring is frequently used in the diagnosis and therapy monitoring of arterial hypertension and allows an evaluation of the circadian blood pressure evaluation , 18.The aim of this study was to identify patients with Parkinson's disease who showed loss or decrease of nocturnal blood pressure fall (non dipper patients) as a potential marker of autonomic dysfunction.Presence or absence of orthostatic hypotension was considered to investigate whether alterations in circadian blood pressure pattern are associated with posture-related dysregulation of blood pressure.40 patients with Parkinson's disease underwent ambulatory 24-hour blood pressure monitoring. Parkinson's Disease was diagnosed according to the criteria of the United Kingdom Parkinson's disease Society Brain Bank . None ha20 of the patients were male, 20 were female; they were aged 41 to 82 years ; disease duration (Parkinson's disease) was 1 to 152 months (mean disease duration 49 months) . 21 patiLong-term blood pressure measurements were performed with \u201cMobilograph,\u201d an oscillometric recorder . Patients were asked to maintain their normal physical activity. Nondipper patients were defined as having nocturnal decrease of mean systolic and diastolic blood pressure less than 10%. Presence or absence of orthostatic hypotension was determined by Schellong's test ; orthostatic hypotension was defined as a minimum decrease in systolic and/or diastolic blood pressure of 20\u2009mmHg or 10\u2009mmHg, respectively, on standing at the third minute .Results are presented as mean values (\u00b1 standard deviation (SD)). A correlation analysis was performed between the presence of loss of nocturnal blood pressure fall and disease duration, age and presence of arterial hypertension/use of antihypertensive medication.Ambulatory blood pressure was recorded without interruption in all patients with a mean measurement period of 23 hours . The average number of measurements obtained during the 24-hour recording was 88% (\u00b1 11). Results of the mean diurnal arterial pressure showed 18 patients with hypertensive blood pressure values and 22 patients with normal blood pressure. Beside the 21 patients who were already diagnosed with arterial hypertension 6 patients showed hypertensive blood pressure values in ambulatory blood pressure recording; thus a total of 27 patients (68%) had arterial hypertension .We identified 35 non dipper patients (88%) among 40 examined patients with Parkinson's disease; 25 patients (63%) showed nocturnal increase of blood pressure . CorrelaAutonomic test results showed 21 patients with orthostatic hypotension. Loss of nocturnal blood pressure fall was detected in 20 patients with orthostatic hypotension (95%); this was also detected in 15 patients without orthostatic hypotension (79%). We found 11 patients with supine hypertension who were non dipper (100%) and 24 patients without supine hypertension who were non dipper (83%) .We investigated ambulatory blood pressure monitorings in patients with Parkinson's disease to evaluate the circadian blood pressure profile, especially the presence or absence of loss of nocturnal blood pressure fall (non dipper). Results of earlier studies show a variable percentage of non dipper patients , mainly Our results show that most of our examined patients with Parkinson's disease were non dipper (88%); this was even found in 79% of the patients without orthostatic hypotension. In conclusion, ambulatory blood pressure monitoring could be useful to detect autonomic dysfunction even in the early stages of Parkinson's disease when orthostatic hypotension is not present. \u03b1-adrenergic receptors due to sympathetic denervation in patients with Parkinson's disease may contribute to supine hypertension during the night due to exaggerated vasoconstriction [The alterations in the circadian blood pressure profile may be caused by impairment of the autonomic regulatory mechanisms, possibly through postural dysregulation of blood pressure as mentioned in earlier reports . This dytriction , 23, 24.Presence or absence of arterial hypertension was additionally investigated in our patients  to evaluate a possible association with loss of nocturnal blood pressure fall; there was no correlation between the presence of non-dipping and the presence of arterial hypertension or use of antihypertensive medication. 27 patients were additionally diagnosed with arterial hypertension or had hypertensive blood pressure values in ambulatory blood pressure recording (68%). 24-hour blood pressure monitoring should be performed in patients with Parkinson's disease and coexisting arterial hypertension, who are treated with antihypertensive medication. For prevention of an increased prevalence of end-organ damage we propose treatment of nocturnal hypertension in patients with Parkinson's disease. Treatment with antihypertensive drugs in patients with orthostatic hypotension may be complicated by worsening of the postural blood pressure fall in the upright position in these patients and thus may cause syncopes or cerebral ischemia. Consequently, vasoactive drugs should be used carefully in patients with Parkinson's disease and autonomic dysfunction. Alternatively sleeping in a 12\u00b0 head-up tilt position may be helpful . Concerning an increased cardio\u2014and cerebrovascular risk in patients with nondipping, Corn\u00e9lissen et al. showed that\u2014compared with dipping\u2014abnormal chronobiological end points such as reduced circadian standard deviation of heart rate or elevated pulse pressure are more useful to discriminate between patients who are at a higher risk and who are not . HoweverIn conclusion 24-hour ambulatory blood pressure monitoring showed a high prevalence of non-dipping in 40 patients with Parkinson's disease with and without orthostatic hypotension independent of the coexisting arterial hypertension, and antihypertensive treatment. Our data strengthens the role of ambulatory blood pressure recording for detection of non-dipping not only in patients with orthostatic hypotension, but also in patients without orthostatic hypotension. Beside other autonomic tests  24-hour blood pressure monitoring may be helpful to support the detection of autonomic dysfunction in patients with Parkinson's disease even in the early stages of the disease."}
+{"text": "There is an error in the legend for Figure 3. The legend refers to figures 3a, 3b and 3c, which is not correct. Figure legend 3 should read:Figure 3: The figures display the mean % BOLD signal change for each of the 3 tasks  for each delay  in the ROI. The graphs show: the medial temporal cortex (V5), the supramarginal gyrus (SMG), and superior parietal lobe (SPL), the cerebellum (CBM), primary visual cortex (V1), the frontal eye fields (FEF), supplementary eye fields (mid SEF), and dorsolateral prefrontal cortex (DLPFC). The centre of mass for the regions of interest used in the analysis are highlighted within a template brain on either side of the % signal change graph for all figures and brain coordinates are presented using the Montreal Neurological Institute (MNI). T values and significance corrected cluster level P values are also displayed for each ROI."}
+{"text": "Pancoast syndrome (Pancoast\u2019s syndrome) is characterized by a malignant neoplasm of the superior sulcus of the lung (lung cancer) with destructive lesions of the thoracic inlet and involvement of the brachial plexus and cervical sympathetic nerves (stellate ganglion) which causes Horner syndrome .Following trimodality treatment for (SSTs), the 5-year survival rate has significantly improved. The objective of this study was mortality and morbitity and quality of life after the resection of superior sulcus tumours following neoadjuvant chemoradiation.Between Januar 2002 and December 2012 ; 55 consecutive patients were treated with primary radiotherapy followed by surgery or with primary excision and subsequent radiotherapy in the absence of an initial histological diagnosis.In total, 55 patients participated in this study (45 men and 10 women). The median age was 60 years (range 40\u201373), median radiation dose 45 Gy (range 40\u201360) and median follow-up 50 months (range 4\u2013101). The mortality of patients given the combined treatment was 8.6% (one death due to pulmonary embolism and one death due to myocard ischemia), and the five year survival rate was 20.6% for all patients and 37% for those who underwent complete resection without N2 disease.Stage III lung cancer, classified as Pancoast tumour according to strict, consistent criteria, is best treated by primary radiotherapy; combined treatment should be used only for patients with potentially resectable cancer without N2 disease and/or malignant invasion of the first rib."}
+{"text": "Despite the increasing public health burden associated with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD), the molecular mechanisms responsible for the pathogenesis of these diseases remain unclear. The goal of this study was to comprehensively profile the lung small RNA transcriptome via next-generation sequencing, and elucidate microRNAs that might contribute to COPD and ILD pathogenesis.n = 150) or ILD (n = 149), and from normal lung tissue (n = 65). 319 lung tissue samples were sequenced via multiplexing on the Illumina HiSeq 2000 (10 samples/lane) and 45 samples were sequenced on the Illumina GAIIx (one sample per lane). Reads were trimmed using the FASTX toolkit and aligned to hg19 using Bowtie. Reads mapping to a microRNA locus were grouped into those with the canonical seed and those with an alternative seed due to variation in the 5' start position (isomiRs). Negative binomial generalized linear models were used to identify microRNAs and isomiRs differentially expressed between phenotypes. The large RNA from a subset of these samples was also sequenced using the Illumina GAIIx (one sample per lane). A network was generated by identifying all microRNA-mRNA pairs that were significantly anti-correlated  <0.05) and had a predicted microRNA-binding site in the mRNA 3'UTR (TargetScan 6.0).As part of the Lung Genomics Research Consortium, we sequenced the small RNA in lung tissue samples from subjects with COPD (n = 72). 2,133 genes in the network (65%) were predicted to be regulated by at least one differentially expressed isomiR. Both the canonical form and three isomiRs of miR-338-3p were significantly downregulated in ILD. Predicted targets of the canonical form of miR-338-3p were enriched in extracellular matrix genes while the predicted targets of a miR-338-3p isomiR were enriched in the Wnt signaling pathway (P<0.001), suggesting different roles for multiple forms of this microRNA in ILD.An average of 26.3 million and 7.1 million reads were sequenced per sample using the singleplex and multiplex protocols, respectively. An average of 73% of reads per sample aligned to the human genome with one or fewer mismatches at 10 or fewer locations. 287 novel microRNA precursors were predicted using the miRDeep algorithm. One of these candidates was validated by quantitative RT-PCR and found to be expressed across a range of human tissues. The expression of 309 canonical microRNAs was significantly different between patients with disease and controls (FDR <0.05). In addition, we found that 242 isomiRs from 159 different microRNA loci were also differentially expressed (FDR <0.05). We developed a network of microRNA-mRNA interactions by integrating small RNA and large RNA sequencing data generated on the same samples (Our results demonstrate the power of deep sequencing to reveal additional complexity in the microRNA transcriptome, such as novel microRNAs and isomiRs. The disease-related patterns of microRNA expression can provide insights into the molecular pathogenesis of chronic lung diseases and novel targets for therapy."}
+{"text": "O. rufipogon as a reference in the characterization. Results indicated relatively rich genetic diversity (He = 0.63-0.65) in Italian rice varieties. Further analyses revealed a close genetic relationship of the Italian traditional varieties with those from northern China, which provides strong genetic evidence for tracing the possible origin of early established rice varieties in Italy. These findings have significant implications for the rice breeding programs, in which appropriate germplasm can be selected from a given region and utilized for transferring unique genetic traits based on its genetic diversity and evolutionary relationships.The characterization of genetic divergence and relationships of a set of germplasm is essential for its efficient applications in crop breeding and understanding of the origin/evolution of crop varieties from a given geographical region. As the largest rice producing country in Europe, Italy holds rice germplasm with abundant genetic diversity. Although Italian rice varieties and the traditional ones in particular have played important roles in rice production and breeding, knowledge concerning the origin and evolution of Italian traditional varieties is still limited. To solve the puzzle of Italian rice origin, we characterized genetic divergence and relationships of 348 rice varieties from Italy and Asia based on the polymorphisms of microsatellite fingerprints. We also included common wild rice  Oryza sativa L., referred to as rice hereafter) is the third largest cereal crop of the world, and provides staple foods and nutrition for nearly one half of the global population [Asian cultivated rice  and 1.6 million tons of total grain production. Nearly all rice varieties grown in Italy are japonica ecotype [Italy is the largest rice production country in Europe, with about 250,000 hectares of cultivation area , although no written document about these is available. The earliest rice cultivation documented in Italy can be traced back to 1468 in the wetlands of Tuscany, near Pisa [Magnaporthe oryzae). To guarantee the continued rice cultivation that was seriously threatened by this fungal disease, new varieties were introduced from China and Japan at the beginning of 19th century. These varieties were characterized by their high yielding and resistance to rice blast. As a consequence, five Italian rice varieties were cultivated in Italy in 1872: Ostiglia, Bertone, Novarese, Francone, and Giapponese. Because of the recrudescence of blast attacks that created a new crisis for Italian rice cultivation, more rice varieties were imported from Asian countries including China, India, and Japan in 1880, which led to a substantial increase in the number of Italian rice varieties in the subsequent years. A milestone of Italian rice cultivation in history was the presence of a set of varieties grouped under the general name of \u201cChinese Originario\u201d with high yield and strong resistance to blast [The first official documentation of rice introduction to Italy is related to the Spanish Presence in the Kingdom of Naples because of the ties between the Aragon family (The Kings of Naples) and the Sforza family (Dukes of Milan) in the second half of 15 century . Rice maear Pisa . At thatRice production in Italy fluctuated significantly, depending essentially on the national and international varieties used. A number of successful varieties  were bred in 1926 through the systematic selection from \u201cChinese Originario\u201d or, in a few cases, improved from old American varieties. This illustrates the importance of rice improvement in Italy relying on the introduction of alien germplasm from other countries. A number of recent studies have systematically characterized the existing Italian rice germplasm for its genetic diversity , agronomOryza rufipogon Griff.) accessions were also used as a reference. The primary objectives of this study were to (i) estimate the general genetic diversity of different historical groups of Italian rice germplasm in comparison with that from other sources; (ii) determine genetic divergence of Italian rice germplasm from that of Asian rice germplasm; and (iii) trace the possible origin of Italian rice varieties based on genetic data. The answer of these questions will facilitate the continued genetic improvement of Italian rice for the sustainable rice production in the region.To solve the \u201cpuzzles\u201d of Italian rice origin, we characterized a large set of rice germplasm from extensive sources, based on the polymorphisms of microsatellite (SSR) fingerprints at 24 loci across the rice genome. The set of germplasm is represented by 183 Italian rice varieties, including nearly all traditional and modern varieties currently available in Italy, and 165 rice varieties from Asia. In addition, ten common wild rice (Oryza sativa) from Italy and Asian countries were included in this study  represented the modern Italian varieties that were improved under local genetic breeding programs. The third group  included the modern Italian varieties improved under genetic breeding with rice germplasm from North America. These rice varieties covered the entire range of Italian rice cultivation regions and represented nearly all rice germplasm currently available in Italy (http://www.enterisi.it/ris_schede.jsp).A total of 348 rice varieties (is study . InformaO. rufipogon) from Guangdong and Hunan Province of southern China (Wild) were also included as a reference group  the Chinese group that included varieties from different Provinces of this country (encoded as China); (2) the East Asian group included varieties from Japan and South Korea (E Asia); (3) the South Asian group included varieties from India and Sri Lanka (S Asia); and (4) the Southeast Asian group comprised of varieties from different countries in southeastern Asia (SE Asia), including Cambodia, Indonesia, Laos . In addice group . Seeds of sampled rice varieties and wild accessions were germinated in an incubator at the temperature of ~25\u00b0C. The total genomic DNA was extracted from about 1g fresh leaf tissues for each seedling, separately, at about the three-leaf stage 10 days after seed germination. The extraction followed a modified cetyltrimethyl ammonium bromide (CTAB) protocol described by . http://www.gramene.org). All the forward primers were labeled by one of the following fluorophore: FAM (blue), ROX (red), or JOE (green) . Twenty-four SSR primer pairs distributed on the two arms of each of the 12 rice chromosomes were selected for analyses from The RiceGenes Database (2+), 0.2mM each of dNTPs, 0.2\u03bcM each of SSR primers, 20 ng of genomic DNA and 0.3U of Taq polymerase . The reaction procedure was programmed as following: a denaturation period of 4 min at 94\u00b0C followed by 28 cycles of 30 s at 94\u00b0C, 30 s at 55\u00b0C and 40 s at 72\u00b0C, and then 7 min at 72\u00b0C for the final extension.The polymerase chain reaction (PCR) was performed in the \u201c2720 Thermal Cycler\u201d . Reactions were carried out in a volume of 10 \u03bcL mixture, containing 1\u00d7buffer  and internal lane size standard (GeneScan\u2122 -500 LIZ) for fragment separation after denaturing at 94\u00b0C for 5 min and then cooled at 4\u00b0C. The SSR fragments were separated on a capillary electrophoresis genotyper, ABI 3130xl . The separated SSR fragments were scored as genotypic data using the software Genemapper ver. 3.7 .P); (2) the effective number of alleles per locus (Ne); (3) the observed heterozygosity (Ho); (4) Nei\u2019s unbiased genetic diversity (He) [I). In addition, the number of private alleles per rice group (Npa) was also calculated to estimate the uniqueness of each group. To determine genetic relationships among cultivated rice groups (see definition in sampling of rice germplasm) from various regions, the values of Nei\u2019s unbiased genetic similarity [The genotypic data matrix from all rice varieties and wild accessions generated by the 24 SSR primer pairs was analyzed to estimate the level of genetic diversity. The following five diversity parameters were calculated: (1) the percentage of polymorphic loci (ty (He) ; and (5)milarity  were calmilarity .To illustrate the relationships of different rice groups, an UPGMA dendrogram was constructed based on the unbiased genetic similarity , using tRice germplasm included in this study with different origins presented a relatively high level of overall genetic diversity, although with a considerable degree of variation among rice groups . A totalThe Nei\u2019s unbiased genetic similarity  was calcFor estimate genetic relationships of rice varieties from Italy (three groups) and Asia (four groups), a dendrogram  was consindica and japonica rice varieties as shown in previous studies. The NJ tree did not suggest an obvious variation pattern of the rice varieties from different regions either. However, the Italian traditional rice varieties categorized in Italy-1 , a neighbor joining (NJ) tree was constructed based on the genetic distance of all the individual rice varieties using wild rice as an out-group . In geneindica and japonica) of rice varieties in different regions, which was considered for dividing the whole group into subgroups. The newly divided Asian regions included different Provinces of China, Southeast Asia, East Asia, and South Asia  with Chinese and East Asian varieties as groups. Given the abundant genetic diversity in Italian traditional rice varieties  as a reference, to estimate its genetic variation and relatedness. The total number of alleles (442) detected in these varieties was unexpectedly high, compared with those detected in a previous study where 172 Italian rice varieties and 47 introduced foreign varieties were analysed using 24 SSR loci [O. rufipogon that had a much higher Ho value . We analyzed a large set of rice germplasm including 183 varieties representing nearly all Italian rice germplasm, 165 varieties from Asia, and ten accessions of wild rice  in Italian rice varieties (three groups) is comparable to that (0.59) reported in a previous study on the temporal trends of variation in Italian germplasm [The level of genetic diversity  and locally improved modern  rice varieties share a close affinity, and showed their close linkage with rice varieties from China and East Asia. This finding reveals that the Italian rice varieties produced based on germplasm from similar sources  remain much closer genetic relationships than those with germplasm from different sources such as North American . In addition, Italian rice germplasm as a whole showed a relatively distant genetic affinity with that from South Asia and Southeast Asia, where varieties, it makeindica and japonica differentiation as suggested by other studies [Notably, the Italian traditional and locally improved rice varieties have a close genetic affinity with Chinese and East Asian varieties. When alien germplasm was introduced from North America and used as breeding materials for hybridization, the genetic relationship between Italy-3 and Chinese/East Asian rice varieties became loose due to mixture of North America rice germplasm. Obviously, the evolution and divergence of Italian rice germplasm depend essentially on the introduced exotic rice varieties from different geographical sources and the breeding methods. The NJ tree based on genetic relatedness of individual rice varieties did not show particular groupings of these varieties associated with either  studies ,25, or g studies ,18. HoweUnderstanding genetic relationships of the current Italian rice germplasm has its important implications in rice breeding, through properly selecting and introducing exotic germplasm into Italian rice varieties . The intindica and japonica rice varieties [Our results generally indicated a close relationship of Italian traditional and locally bred modern varieties to Chinese varieties as a whole group. However, China is a large country with the extensive cultivation of diverse types of arieties ,23,24. IOur results based on genetic similarity analysis of Italian traditional varieties  with Chinese rice germplasm represented by different Provinces evidently indicated their close genetic affinity to that from northern rice cultivation regions . These rAlthough the tales such as Marco Polo\u2019s contribution to the introduction of rice from China to Italy may never be fully confirmed, results from this study provide solid genetic evidence to confirm the close linkage between Italian and Chinese rice varieties. Rice varieties from northern China may provide genetically most accessible and useful germplasm for Italian rice breeding because of their close genetic relatedness and abundant genetic diversity, even though rice varieties from other regions in Asia can also provide unique and especially valuable germplasm that has not been represented in the Italian rice gene pool. As the largest rice production country in Europe, Italy holds important and diverse rice germplasm, which guarantees the sustainable rice production and breeding in Italy and neighboring countries. Knowledge concerning the genetic diversity, origin, and evolutionary relationships of Italian rice has important implications for its effective breeding by selecting proper exotic rice germplasm. The early introduced rice varieties such as \u201cChinese originario\u201d have played an important role in Italian rice production and breeding programs. However, the origin and evolutionary relationships of these early introduced varieties have not been properly documented. Results based on SSR fingerprints of a large set of rice germplasm from Italy and Asia in this study demonstrate a close genetic relationship between Italian and Chinese rice varieties, suggesting the possible origin of Italian traditional rice from northern China. Although the conclusion on Chinese origin of Italian traditional rice still needs supports from further studies, this finding has significant implications for Italian rice improvement by including appropriate exotic germplasm in its breeding programs.Figure S1A Neighbor-Joining (NJ) tree showing individual-based genetic relationships of 348 rice varieties analyzed in this study (see Table 1 and Table S1 for detail information), using wild rice as an out-group (root). The yellow-color highlighted entries indicate the Italian traditional varieties, and the green-color highlighted entries indicate Chinese varieties. The NJ tree was constructed based on the \u201cdistance methods\u201d installed in the software PAUP ver. 4.0 [ver. 4.0 .(PDF)Click here for additional data file.Table S1Rice germplasm included in the analysis. Accession numbers and indica (i) or japonica (j) characteristics are indicated in the parentheses following the name of a rice variety. IBS = Institute of Biodiversity Sciences of Fudan University; AAV = Shanghai Agricultural Gene Center; ENR-CRR = Ente Nazionale Risi-Centro Ricerca sul Riso; RNV = Registro Nazionale Variet\u00e0 2013.(DOC)Click here for additional data file."}
+{"text": "Associations between clinical outcome and patient characteristics, such as tumour gene expression, and inherited variation (single nucleotide polymorphisms) can be difficult to reproduce between ovarian cancer cohorts. Sources of variation include the size and composition of patient cohorts and treatment, which has varied over time and can vary between countries. We have undertaken a review of treatment in patients recruited to the Australian Ovarian Cancer Study (AOCS) to determine the primary treatment patterns and levels of consistency across the cohort. Australian clinical practice guidelines for the management of women with epithelial ovarian cancer were published in 2004  and AOCSAOCS collected fresh tissue, blood, epidemiological/dietary questionnaires and clinical follow-up data for women aged 18-79 diagnosed with invasive (n=1476) and borderline (n=352) cancer, and material and data are available for research, by application. Clinical data was collected through a national research nurse network at pre-specified intervals: at diagnosis, completion of primary treatment and then at 6-monthly intervals. At the end of Feb 2011 primary treatment data was complete on 99% of eligible cases and the median follow-up time was 5.1 years.Most patients with invasive cancer underwent surgery prior to chemotherapy  and a small proportion had an interval debulk  or other procedure (<10%). The vast majority of women with advanced stage cancer (FIGO stage II-IV) received chemotherapy  and of these, over 99% (1110/1116) received a platin-based regimen. The most common regimens were carboplatin/paclitaxel (77%) and carboplatin alone (9%), most women (86%) received 6-8 cycles and 95% of women who received adjuvant chemotherapy began treatment within 6 weeks of surgery.In conclusion, the majority of women in AOCS were treated according to national guidelines, enabling the selection of cases with uniform treatment for projects investigating associations of genomic and genetic features with clinical outcome."}
+{"text": "Number of studies indicates on possible role of toxic substances in development of heart malformations during cardiogenesis. The aim of our research is studying of toxic element barium content in different biosubstrates of children with CHD.29 patients  boys and 12  girls), aged from 14 days to 17 years (medium age: 26 month\u00b12 month) old with CHD were examined by the spectral analysis of toxic element barium in intraoperative (23) and autopsy (6) biopsies of endocardium (22), myocardium (26), pericardium (7), aorta (10), skin (8), subcutaneous fat (8), intercostal muscles (24), fascia (2), kidneys (5), brain (2) and hair (9) by methods of the atomic emission spectrometry in the inductively coupled plasma and atomic absorption spectrometry with electrothermal atomization.A comparative analysis of barium level in different biosubstrates demonstrated it\u2019s highest content (\u0447\u0438\u0441\u043b\u0430) in muscle tissue . Whereas in other tissues the concentration was decreased or absent. Barium content exceeded toxic level in heart tissues of 72.4% of patients. The excess degree of barium content depended on biopsy topics, namely, in aorta coarctation place, valve atresia place, septal defect its level was in two, ten or more times higher than in normal heart area or great vessel area. Dependence between the barium excess degree content in the heart tissue and severity of malformation or its combinations was also established: children with exceeding level of barium in the heart tissues had significantly more (p <0.05) of combined complex CHD.Barium affinity to the myocardium, blood vessels smooth muscles and striated skeletal muscles was confirmed. Spectrum of barium content depends on the type and severity of the defect and biopsy point. Received data indicate on possible role of barium in cardiogenesis malformation, that needs deeper investigation."}
+{"text": "To study the association between house dust endotoxin levels and respiratory symptoms and allergen sensitizations in children from the urban areas (Guangzhou) and rural areas (Conghua) of Guangdong province, China.20-FEV1) and allergen skin reactions were analysed by logistic regression.Three hundred and seventeen children aged 13-14 years  with self-reported respiratory symptoms and 537 healthy children were selected from 854 school-children according to their response to ISAAC standardized questionnaire. These children attended the school infirmary again to complete a detailed questionnaire and medical examinations including skin prick test (SPT) to 8 common aeroallergens, lung function test, histamine bronchial provocation test and peripheral blood eosinophil counts. House dust samples were collected from living room and mattresses of 156 of these children with the agreement of their parents . The content of endotoxin in house dust was quantified using an endpoint chromogenic kinetic limulus amoebocyte lysate test. Associations between levels of house dust allergens and endotoxin and the provocation dose producing a 20% fall in forced expiratory volume in one second , and a negative association (p<0.01) between endotoxin levels and the wheal sizes of skin response to Dermatophagoides pteronyssinus (Der. p) and Dermatophagoides farinae (Der. f).The prevalence of wheeze symptom, asthma, nasal symptoms and allergic rhinitis in the children of Guangzhou were significantly higher  than the children of Conghua . Endotoxin concentrations in dust samples in homes of Conghua were significantly higher  than those of Guangzhou . Logistic regression analyses showed a positive association between endotoxin levels and PDThese findings suggest that exposure to higher levels of house dust endotoxin might contribute to the lower risk of allergic sensitization in children."}
+{"text": "Our objective was to evaluate if the implementation of a multifaceted intervention program for quality improvement in ICUs of nonacademic hospitals would decrease mortality and the catheter-related bloodstream infection rate (CRBSI).\u00ae); (6) 3-day workshop to share the coordinating institution quality improvement practices with directors and ICU coordinators from the 17 participant institutions; (7) 3-day nursing visits from the coordinating hospital to perform advice on care practice; (8) basic life support courses, 56 vacancies per hospital, and fundamentals of critical care support, 30 vacancies; and (9) implementation of a web-based system to collect ICU and hospital mortality, SAPS3, standardized-mortality ratio (SMR) and CRBSI after June 2011. We assessed variation of SMR and CRBSI on time using weighted linear regression, and variation of mortality on time using generalized-estimating equations.A clinical practice improvement program involving 17 Brazilian ICUs of nonacademic public hospitals located far from major economic centers under coordination of a not-for-profit private hospital with the support of Brazilian Ministry of Health. We implemented the following interventions: (1) hospital visits to assess the facilities, human resources and processes; (2) workshop with hospital directors and ICU coordinators to elaborate improvement proposals based on the initial visit findings; (3) multidisciplinary videoconference lectures every 3 weeks about critical care medicine assistance and quality issues; (4) website containing project educational material, videoconference recordings, and an evidence-based practice course; (5) subscription of an electronic clinical information resource for all participating hospitals (UpToDateThe results are presented in Table A multifaceted intervention program applied to a network of ICUs in nonacademic public hospitals reduced mortality."}
+{"text": "The aim of the study was to evaluate the effect of cumulative dose of glucocorticoids during 3 years on bone mineral density (BMD) and bone turnover (BMT) measurement in children suffering from inflammatory bowel disease (IBD).In cohort of 64 children with IBD (54 children with Crohn disease and 10 with Ulcerative colitis) we measured bone mineral density at the time of diagnosis and two times during follow-up. Bone turnover /osteocalcin (OC) and C-terminal telopeptide of type I collagen (CTx)/ was measured using ELISA same time as BMD. All patient were treated by glucocorticoids with average of cumulative dose 4,46g. The obtained results were analyzed using correlation analysis.\u00b1 SD). There was no change during the treatment . The level of CTX and osteocalcin paradoxically increased, but there was no statistical significance.At the time of diagnosis we observed the total body BMD Z-score \u20131,7 (mean In our study we didn\u2019t find correlation between BMD, cumulative dose of glucocorticoids, CTX and osteocalcin during period of 3 years. Insignificant increase of bone markers was established. According to our results we can speculate that bone status impairment of bone mass is independent in children with IBD on treatment with glucocorticoids regarding to inflammation itself."}
+{"text": "Population fluctuations are often driven by an interplay between intrinsic population processes and extrinsic environmental forcing. To investigate this interplay, we analyzed fluctuations in coastal phytoplankton concentration in relation to the tidal cycle. Time series of chlorophyll fluorescence, suspended particulate matter (SPM), salinity and temperature were obtained from an automated measuring platform in the southern North Sea, covering 9 years of data at a resolution of 12 to 30 minutes. Wavelet analysis showed that chlorophyll fluctuations were dominated by periodicities of 6 hours 12 min, 12 hours 25 min, 24 hours and 15 days, which correspond to the typical periodicities of tidal current speeds, the semidiurnal tidal cycle, the day-night cycle, and the spring-neap tidal cycle, respectively. During most of the year, chlorophyll and SPM fluctuated in phase with tidal current speed, indicative of alternating periods of sinking and vertical mixing of algal cells and SPM driven by the tidal cycle. Spring blooms slowly built up over several spring-neap tidal cycles, and subsequently expanded in late spring when a strong decline of the SPM concentration during neap tide enabled a temporary \u201cescape\u201d of the chlorophyll concentration from the tidal mixing regime. Our results demonstrate that the tidal cycle is a major determinant of phytoplankton fluctuations at several different time scales. These findings imply that high-resolution monitoring programs are essential to capture the natural variability of phytoplankton in coastal waters. What drives fluctuations in population abundances? In the 1920s the famous zoologist Charles Elton argued that population fluctuations of many birds and mammals are most likely due to climatic fluctuations This interplay between intrinsic population processes and external forcing is exemplified by the plankton of freshwater and marine ecosystems. Theory and experiments have shown that plankton communities can display striking fluctuations, and even chaos, under constant conditions without external forcing Environmental forcing by the tidal cycle is an important driver of phytoplankton variability in coastal waters We hypothesize that these different sources of phytoplankton variability can be distinguished by investigating the time scales of phytoplankton fluctuations. For instance, phytoplankton fluctuations with a periodicity of 6 hours 12 min indicate an alternation between entrainment of sinking phytoplankton into the surface layer during high tidal current speeds and settlement of sinking phytoplankton during tidal slacks. A periodicity of 12 hours 25 min indicates changes in phytoplankton concentration due to horizontal transport of different water masses. A 24 hour periodicity would signal environmental forcing by the day-night cycle , which would be very different from the 24 hour 50 min periodicity of a mixed semidiurnal tide. At longer time scales, the spring-neap cycle and apogee-perigee cycle generate variation in the intensity of tidal mixing that could affect phytoplankton populations.Furthermore, we hypothesize that the impact of environmental forcing on phytoplankton population dynamics will depend on the relative magnitude of intrinsic population growth versus environmental forcing. For instance, settling and resuspension of phytoplankton in shallow coastal waters depends on the vertical mixing intensity generated by wind action and tidal motion To investigate these hypotheses, we analyze phytoplankton fluctuations in a high-resolution time series obtained from an automated mooring station in the coastal North Sea. The mooring measured chlorophyll fluorescence, suspended particulate matter (SPM), nitrate, salinity, temperature and irradiance at a high temporal resolution for a period of nine years. Earlier analysis of the first year of this time series showed that the phytoplankton spring bloom was initiated by an improved light availability in spring, due to a combination of enhanced solar radiation and reduced SPM concentrations We analyzed data of mooring station Warp, located in the coastal waters of the southern North Sea near the Thames Estuary . The maihttp://www.cefas.defra.gov.uk. More information on the methodology and application of SmartBuoys can be found in Kr\u00f6ger et al. At the mooring station an automated measuring platform, called a \u2018SmartBuoy\u2019, has been deployed from 30 November 2000 onwards, as part of the United Kingdom\u2019s eutrophication monitoring program in situ Seapoint fluorometer measurements versus extracted chlorophyll concentrations in the water samples had a R2 of 0.86 when averaged over all monthly samples. Although chlorophyll fluorescence is a very convenient measurement technique, it is known that the fluorescence signal can be quenched when cells are exposed to high light Chlorophyll fluorescence was measured with a Seapoint fluorometer (Seapoint Inc.). Fluorescence data were calibrated against chlorophyll concentrations in water samples taken during monthly service visits to the mooring stations. Chlorophyll concentrations were measured by filtering known sample volumes through glass fiber filters  in triplicate. Pigments were immediately extracted in 90% buffered acetone and refrigerated prior to analysis. A Turner Designs Model 10AU filter fluorometer was used to measure the fluorescence of extracted chlorophyll and phaeopigment before and after acidification as described by Tett in situ Seapoint turbidity measurements versus SPM concentrations in the water samples had a R2 of 0.72 when averaged over all monthly samples.Optical backscatter was measured with a Seapoint turbidity meter (Seapoint Inc.), and converted to SPM concentration using calibration against monthly water samples. SPM concentrations in the samples were measured by filtering known sample volumes through pre-weighed 0.4 \u00b5m polycarbonate filters and subsequent rinsing with 2\u00d750 mL ultrapure water. Filters were then dried in a desiccator at room temperature and weighed until filter weight remained constant. Calibration curves of The concentration of total oxidisable nitrogen (hereafter referred to as nitrate) was measured with a NAS-3X nutrient analyzer (EnviroTech). Salinity and temperature were measured using an FSI CT sensor . Salinity measurements were calibrated using a Guildline 8400B salinometer, which had been standardized with IAPSO standard seawater. Downwelling PAR was measured at 1 and 2 m depth using two LiCor (LI-192) underwater quantum sensors (LiCor Biosciences).The SmartBuoy measurements went through a Quality Assurance protocol within the SmartBuoy Data Management System, checking all data manually for possible sensor malfunction and biofouling. For instance, fluorescence measurements directly before each monthly service were compared with those directly after monthly service to identify signatures of biofouling. Data that looked suspect were flagged and not used in the analyses.Phytoplankton species composition at the mooring station was determined on an approximately monthly basis. Water samples (150 mL) taken at 1 m depth were preserved with 2.5 mL acidified Lugol\u2019s solution, and analyzed by inverted microscope after 12 hours of settling in a 25-mL glass chamber Tidal data were obtained from a tide gauge at the nearby coastal station Sheerness . Inspect\u00b5mol quanta m\u22122 s\u22121), to remove possible effects of non-photochemical quenching of chlorophyll fluorescence. We analyzed the hourly averaged and daily averaged time series separately to investigate variability at different time scales.Because the sampling interval of the automated measurements varied between instruments and between years, we calculated hourly averages to obtain a more uniform dataset. We also calculated daily averages of all variables, where the chlorophyll data were confined to measurements made in the dark  to reduce the effect of small-scale variability caused by e.g. measurement noise, intermittent turbulence or local patchiness. We used these small intervals for the moving average filter to avoid smoothing out relevant periodicities of the tidal cycle. Third, we calculated the rates of change from the difference between the data values at time t and time t-\u0394t, where \u0394t represents a single time step of one hour or one day. Because we had log-transformed the data, this procedure effectively resulted in a time series of the relative rates of change (\u2018relative growth rates\u2019) of the measured variables, since.We analyzed the rates of change of the data instead of their concentrations, because concentrations are the result of growth and decay processes during the preceding period whereas instantaneous rates of changes better reflect the conditions at the time of measurement.We used wavelet analysis We applied wavelet coherence, an extension of wavelet analysis, to investigate the \u2018coherence\u2019 of two time series http://www.pol.ac.uk/home/research/waveletcoherence/).The statistical significance of periodicities revealed by wavelet analysis was tested by comparing the wavelet power spectrum of our time series against the 95% confidence level of wavelet power spectra generated by red noise, using an autoregressive AR1 model with the same autocorrelation coefficient as our time series Our time series contained several data gaps. Small gaps of at most one data point were filled by linear interpolation. Larger gaps could not be filled by interpolation without affecting the results. Therefore, we calculated separate wavelet power spectra for all subsets of the time series with a sufficient number of consecutive data points. Wavelet analysis can accurately detect periodicities up to \u223c25% of the length of a time series Phaeocystis). Most abundant were chain-forming diatoms , and benthic diatoms .Time series of water level, chlorophyll, SPM, nitrate, light intensity, temperature and salinity all displayed strong variability at several different time scales , S8, S9.Light intensity (PAR) at 1 m depth followed the expected seasonal pattern, but with distinct daily and biweekly variation . High liWe first analyzed the tidal data measured at station Sheerness . In lineThe spring-neap cycle is clearly visible in the time series of the tidal range . Close iWavelet analysis of the hourly-averaged chlorophyll concentration of the year 2007 reveals significant periodicities of 6 hours 12 min and 12 hours 25 min during most of the year, and an additional 24-hour periodicity in late spring and summer only . LikewisComparison with the tidal data reveals that chlorophyll concentrations consistently peaked a few hours before high tide and a few hours before low tide . The timTaking the absolute value  transforms the 12 hour 25 min periodicity of the water level to a 6 hour 12 min periodicity in tidal current speed. Indeed, the rate of change in chlorophyll concentration seems to fluctuate in phase with tidal current speed .This phase relationship can be tested by wavelet coherence analysis, which displays the coherence (colors) and phase angles (arrows) between two fluctuating time series. Bold black lines delineate areas of significant coherence. Arrows pointing to the right indicate in-phase fluctuations. This confirms that the rate of change in chlorophyll concentration fluctuated in phase with tidal current speed at a significant 6-hour periodicity . In otheIn Wavelet coherence analysis shows that the chlorophyll concentration fluctuated in phase with the tidal range  and SPM This sequence of events, where a strong decline of the SPM concentration in late April or early May was accompanied by a large spring bloom, was also observed in the years 2001, 2003, 2004 and 2008 , S8, S9.\u22123 of chlorophyll should contribute 100 mg m\u22123 of SPM. In view of the measured concentrations of chlorophyll and SPM in our time series, this implies that phytoplankton comprised less than 5% of the SPM concentration throughout the entire year, except during the spring bloom when phytoplankton increased to \u223c20% of total SPM. However, during the spring bloom the phytoplankton dynamics diverged from the SPM dynamics, as the decline in SPM concentration was accompanied by a rise in chlorophyll concentration. For these reasons, the in-phase fluctuations of chlorophyll and SPM cannot be explained by the assumption that SPM consisted mostly of phytoplankton particles.Our results show that short-term fluctuations of coastal phytoplankton were dominated by periodicities of 6 hours 12 min, 12 hours 25 min, and to a lesser extent 24 hours, reflecting the typical periodicities in tidal current speed, horizontal displacement of tidal waters, and the day-night cycle, respectively. Likewise, SPM also fluctuated at 6-hour and 12-hour periodicities, in phase with the chlorophyll fluctuations. One possible explanation for the in-phase fluctuations of chlorophyll and SPM could be that SPM is largely composed of phytoplankton. We therefore estimated the relative contribution of phytoplankton to SPM. Assuming a phytoplankton biomass to carbon ratio of 2.5 Cylindrotheca, Paralia, Plagiogrammopsis), which combine a benthic and pelagic life style as they commonly settle on the sediment during weak mixing but are resuspended during intense tidal mixing Instead, we hypothesize that the 6-hour periodicity and in-phase dynamics of chlorophyll and SPM are explained by alternating sinking and vertical mixing of phytoplankton and SPM driven by the tidal cycle. Phytoplankton and SPM both have a particulate nature. Hence, surface concentrations of phytoplankton and SPM will decrease simultaneously due to sedimentation during weak turbulent mixing . Conversely, phytoplankton and SPM will increase simultaneously by resuspension during periods of intense tidal mixing generated by the high current speeds between each high and low tide. This explanation is supported by the in-phase fluctuations of the chlorophyll dynamics and tidal current speed . In fact\u22121\u22121Sinking rates of single diatom cells range from near zero to 10 m dSalinity, nitrate and temperature are not subject to sedimentation and resuspension by tidal mixing. Indeed, salinity, nitrate and temperature showed only minor 6-hour periodicity, but fluctuated predominantly at a periodicity of 12 hours 25 min. This periodicity matches the typical time scale of horizontal displacement of water masses moving back and forth by tidal motion. Horizontal transport of different water masses is further confirmed by the observation that salinity fluctuated in phase with water level, while nitrate fluctuated in anti-phase with water level at a 12-hour 25-min periodicity . This reAn additional process contributing to the 12 hour 25 min periodicity might be the vertical excursions of the SmartBuoy, which moved up and down with the water level. This could be particularly relevant in waters with strong vertical gradients of the chlorophyll and SPM concentrations in the upper meters of the water column, where the measurements are made. At station Warp, however, the upper meters of the water column are well mixed . TherefoIn summer, we also found a 24-hour periodicity in chlorophyll fluorescence, but not in SPM. The 24-hour periodicity was less pronounced than the periodicities at 6 hours 12 min and 12 hours 25 min. Wavelet analysis indicates that this 24-hour periodicity is independent of the tidal periodicity, because the peak of the global power spectrum was located at 24 hours sharp rather than at 24 hours 50 min. This day-night cycle is probably caused by non-photochemical quenching of the fluorescence signal during sunny days. Alternatively, this day-night cycle might reflect diurnal variation in convective mixing driven by thermal micro-stratification during the daytime and surface cooling at night. Van Haren et al. Superimposed upon the 6-, 12- and 24-hour periodicities the chlorophyll concentration also fluctuated at a significant 15-day periodicity, in phase with the spring-neap tidal cycle. A possible explanation for the 15-day periodicity in phytoplankton abundance is that the spring-neap cycle modulated the nutrient supply. This mechanism was described by Sharples et al. 2. Hence, the chlorophyll and SPM fluctuations observed at the time scale of the spring-neap cycle will probably not represent small-scale processes restricted to the local neighborhood of station Warp, but may integrate sedimentation and resuspension over a large area. The 15-day periodicity of the SPM concentration confirms recent spectral analyses of remote sensing data of the North Sea, which indicated spring-neap variations in SPM in the East Anglia plume and Rhine plume Instead, the in-phase fluctuations of both chlorophyll and SPM with the tidal range suggest that a large fraction of the phytoplankton and SPM sinks to the sediment or deeper water layers during calm conditions at neap tide, while they are resuspended by strong tidal mixing during spring tide. Station Warp is part of a large shallow outer estuary of more than 100 kmEarlier analysis indicated that the spring bloom at our coastal mooring site is triggered by improved light conditions due to a combination of enhanced solar radiation and reduced SPM concentrations in spring What caused the conspicuous decline of the SPM concentration in mid spring? It might be induced by a strong reduction in tidal range, weakening tidal mixing and thereby enhancing sedimentation of SPM. For instance, the strong SPM decline in early May 2007 occurred when spring tide coincided with apogee of the moon, resulting in a weak spring tide . LikewisThe phytoplankton spring bloom resulted in rapid depletion of inorganic nutrients, which was followed by lower phytoplankton concentrations during the remainder of the summer. This classic pattern was also observed in the earlier study of Weston et al. Prorocentrum micans and Peridinium trochoideum) aggregated near the water surface during slack water, while they became homogeneously distributed when tidal mixing intensified. Conversely, large pelagic diatoms (Coscinodiscus spp.) relied on enhanced turbulent mixing during ebb and flood currents to prevent sinking from the photic zone. In view of these studies, it seems quite plausible that the 6-hour periodicity in chlorophyll concentration observed in our tidal system may also be accompanied by a concomitant 6-hour periodicity in phytoplankton species composition, due to species-specific differences in vertical dispersal by the tidal cycle.Temporal variation in turbulent mixing may result in temporal variation in the phytoplankton community. For instance, Huisman et al. According to the intermediate disturbance hypothesis, biodiversity will be highest in ecosystems exposed to intermediate frequencies of environmental forcing The superposition of several periodic fluctuations in chlorophyll concentration and phytoplankton species composition are a challenge for the design of marine monitoring strategies. Measurements taken at fixed time intervals that are not commensurate with the natural frequencies of the tidal cycle may introduce structural biases in monitoring data. For instance, the semidiurnal tidal cycle takes slightly longer than 12 hours. Hence, if measurements are taken, say, once every day at noon, this may erroneously suggest large changes in phytoplankton concentration over a period of several days, while these data simply represent different phases of the semidiurnal tidal cycle. Likewise, the spring-neap cycle takes slightly longer than 14 days. Hence, if a water body is sampled once every two weeks, then the data may erroneously suggest large changes in phytoplankton concentration and phytoplankton species composition over a period of several months, while these data actually reflect different phases of the spring-neap cycle. To avoid such structural biases, the temporal resolution of the measurements should be sufficiently refined to capture the periodicities in the system. In practice, this implies that chlorophyll concentrations should be measured at minimum time intervals of \u223c1 hour to capture the semidiurnal tidal cycle. Alternatively, if resources are limited, one might consider measuring less frequently but always at the same moments with respect to both the semidiurnal and spring-neap tidal cycle. In those marine ecosystems where the tidal cycle is a key determinant of chlorophyll variability, it will be difficult to make sense of phytoplankton data obtained from low-frequency sampling programs ignoring the tidal periodicities.Our results show that careful investigation of the time scales of population fluctuations in relation to environmental forcing can reveal much information on the underlying processes. We found that phytoplankton fluctuations in the southern North Sea reflect different oscillatory modes of the tidal cycle, including variation in tidal current speeds (6 hours 12 min), horizontal water motion (12 hours 25 min) and the spring-neap tidal cycle (15 days). A weaker 24-hour periodicity was also observed. During most of the year, chlorophyll and SPM concentrations fluctuated in phase with the tidal cyle, indicative of alternating periods of sedimentation and resuspension. However, phytoplankton escaped from the spring-neap tidal cycle in spring, when a strong decline in SPM concentration led to improved light conditions. Hence, fluctuations of coastal phytoplankton were strongly driven by external forcing, but intrinsic population processes took over when growth rates were high during the spring bloom. Our findings illustrate that high-resolution monitoring is required to capture this natural variability, which is considered an essential first step for the reliable detection and prediction of the long-term response of coastal phytoplankton to changing environmental conditions.Figure S1Contour plots of water density. The contour plots are based on CTD profiles taken during service visits to the Smartbuoy from August 2004 to July 2006.(TIF)Click here for additional data file.Figure S2Time series measured in 2001. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S3Time series measured in 2002. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S4Time series measured in 2003. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S5Time series measured in 2004. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S6Time series measured in 2005. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S7Time series measured in 2006. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S8Time series measured in 2008. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S9Time series measured in 2009. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S10Coherence between fluctuations in light attenuation and SPM on a daily time scale. (A) Time series of the light attenuation coefficient Kd (pink line) and SPM concentration (black line) using daily averaged data of spring 2005. Kd is calculated from PAR measurements at 1 m and 2 m depth. (B) Wavelet coherence spectrum of the two time series in panel A. Color coding indicates the coherence of the two time series. Arrows indicate the phase angle between fluctuations of the two time series. See the legend of (TIF)Click here for additional data file.Figure S11Coherence between fluctuations in water level, salinity and nitrate on an hourly time scale. (A) Time series of water level (red line) and salinity (blue line) on an hourly time scale during 8 days in winter 2007. (B) Wavelet coherence spectrum of the two time series in panel A. Color coding indicates the coherence of the two time series. Arrows indicate the phase angle between fluctuations of the two time series. See the legend of (TIF)Click here for additional data file.Figure S12Coherence between fluctuations in nitrate concentration, tidal range and salinity on a daily time scale. (A) Time series of nitrate concentration (thick purple line) and tidal range (thin blue line) on a daily time scale during spring of 2007. (B) Wavelet coherence spectrum of the two time series in panel A. Color coding indicates the coherence of the two time series. Arrows indicate the phase angle between fluctuations of the two time series. See the legend of (TIF)Click here for additional data file."}
+{"text": "The aim of the present study was to evaluate the long term follow-up of patients enrolled in the Italian Registry of cryopirin associated periodic sindrome (CAPS).The Italian CAPS Registry started in 2004 and has currently enrolled 29 patients: 16 with Chronic Infantile Neurologic Cutaneous Articular Syndrome (CINCAs), 8 with Muckles Welles syndrome (MWS) and 5 with Familial Cold Urticaria (FCU). 16 patients were treated with Anakinra (IL-1 receptor antagonist) at 1 mg/kg/day. The Child Health Questionnaire (CHQ-PF 50) was used to assess the health related quality of life.Rapid clinical and laboratory improvement was observed in all patients, but six patients who declined treatment and experienced progressive course of the disease. All the treated patients maintained persistent remission; 5 patients required an increase of the dosage to 300 mg per day. No adverse effects were recorded except injection site reactions.Until today, 8 of the 16 patients initially treated with Anakinra have subsequently switched to Canakinumab  at the initial dose of 150 mg every 8 weeks.IL-1 inhibition seems to be crucial in modifying the natural history of CAPS. Long-term follow up of patients treated with Anakinra established its efficacy and tolerability. The same evaluation will be done for Canakinumab, that appears to be equally effective but whose side effects still need to be evaluated. The bimonthly administration of Canakinumab may be certainly useful, especially in pediatric population, however its long half-life implies a tight surveilance in case of infections."}
+{"text": "The objective of this study was to systematically review the medical literature for the prevalence of waterpipe tobacco use among the general and specific populations.We electronically searched MEDLINE, EMBASE, and the ISI the Web of Science. We selected studies using a two-stage duplicate and independent screening process. We included cohort studies and cross sectional studies assessing the prevalence of use of waterpipe in either the general population or a specific population of interest. Two reviewers used a standardized and pilot tested form to collect data from each eligible study using a duplicate and independent screening process. We stratified the data analysis by country and by age group. The study was not restricted to a specific context.Of a total of 38 studies, only 4 were national surveys; the rest assessed specific populations. The highest prevalence of current waterpipe smoking was among school students across countries: the United States, especially among Arab Americans (12%-15%) the Arabic Gulf region (9%-16%), Estonia (21%), and Lebanon (25%). Similarly, the prevalence of current waterpipe smoking among university students was high in the Arabic Gulf region (6%), the United Kingdom (8%), the United States (10%), Syria (15%), Lebanon (28%), and Pakistan (33%). The prevalence of current waterpipe smoking among adults was the following: Pakistan (6%), Arabic Gulf region (4%-12%), Australia (11% in Arab speaking adults), Syria (9%-12%), and Lebanon (15%). Group waterpipe smoking was high in Lebanon (5%), and Egypt (11%-15%). In Lebanon, 5%-6% pregnant women reported smoking waterpipe during pregnancy. The studies were all cross-sectional and varied by how they reported waterpipe smoking.While very few national surveys have been conducted, the prevalence of waterpipe smoking appears to be alarmingly high among school students and university students in Middle Eastern countries and among groups of Middle Eastern descent in Western countries. Tobacco smoking using waterpipe - also known as narguileh, hookah and shisha - is traditional to region of the Middle East Figure 1]. The . The 1].A recent systematic review found that waterpipe tobacco smoking was significantly associated with lung cancer, respiratory illness, low birth weight and periodontal disease . An assoRecent studies have reported relatively high prevalence rates of waterpipe tobacco smoking in Middle Eastern countries, but alsoThe primary objective of our study was to systematically review the medical literature for the prevalence of waterpipe tobacco use among the general population as well as specific populations. A secondary objective was to identify the factors associated with waterpipe tobacco use.No protocol for this review has been published.Inclusion criteria were:\u2022 Cohort studies and cross sectional studies\u2022 Assessment of the prevalence of use of waterpipe for the purpose of tobacco smoking.\u2022 The target population is either the general population or a specific population of interest such as high school students, university students, and pregnant women.\u2022 Prevalence of waterpipe smoking reported separately from the prevalence of other forms of smokingExclusion criteria were:\u2022 Convenience sampling\u2022 Sampling methodology did not clearly lead to a representative sample of the target population .\u2022 No measure of prevalenceWe electronically searched the following databases in June 2008, MEDLINE (1950 onwards), EMBASE (1980 onwards), and ISI the Web of Science using no language restrictions. The search strategy was based on related systematic review, a reviewTwo reviewers independently screened the title and abstract of identified citations for potential eligibility. They then used a standardized and pilot-tested form to independently screen the full texts of citations judged potentially eligible by at least one reviewer. They resolved disagreements by discussion or using an arbitrator.Two reviewers used a standardized and pilot-tested form to independently abstract data and resolved disagreements by discussion or using an arbitrator. Abstracted data related to the following:\u2022 Study methodology: sampling frame, sampling method, recruitment method, and administration method\u2022 Methodological quality: sample size calculation, validity of tool, pilot testing, and response rate\u2022 Population: country, target population, setting (location and time period), and numbers sampled, participated, and analyzed\u2022 Results including prevalence results  of waterpipe only smoking, waterpipe smoking (regardless of other tobacco products use), cigarette smoking, and factors significantly associated with waterpipe smoking.We calculated the kappa statistic to evaluate the agreement in assessing full texts for eligibility. We stratified data analysis by country and age group. We present the results by the region of the world.Figure The studies varied by whether they reported the prevalence of waterpipe only smokers (n = 5), all waterpipe smokers (n = 37) , and by the types of measure of waterpipe smoking: ever smoker (n = 16), current smoker (n = 34), and regular smoker (n = 3). Five studies reported on group waterpipe smoking while 35 studies reported on individual smoking.Ten studies reported sample size calculation. The instruments used to measure waterpipe use were: self developed instrument with no validation reported (n = 15); self developed instrument based on previously validated instruments, with no validation of the new instrument reported (n = 7); self developed validated instrument (n = 1); previously developed instrument with no validation reported (n = 1); previously validated instrument that measured \"forms of smoked tobacco products other than cigarettes\" which the authors assumed to be waterpipe smoking (n = 1) and not reported (n = 13). Fifteen studies reported pilot testing the measurement instrument. Twenty-nine studies reported response rate that varied from 18% to 62% for online administered surveys, 46% to 100% for paper-based surveys, and 70% for telephone survey.Additional file two studies of intermediate and secondary school students in Lebanon reported 25% current and 65%-66% ever waterpipe smoking ,,46-48 th%-15%,,46Our findings are consistent with national surveys conducted by the WHO and the Global Youth Tobacco Survey (GYTS) in a number of countries  and the type(s) of measure of waterpipe smoking .The authors declare that they have no competing interests.EAA contributed to drafting the protocol, designing the search strategy, developing the forms, screening, data abstraction, data analysis, and drafting of the manuscript. SKG contributed to data abstraction, data analysis, and drafting of the manuscript. RO and SA contributed to data abstraction. PAJ and RH contributed to screening. JI contributed to drafting the protocol and designing the search strategy. All authors revised the article critically for important intellectual content and approved its final version. All authors had full access to all of the data  in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. EAA is the guarantor. All authors read and approved the final draft.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/244/prepubElectronic search strategies. Provides the detailed search strategies used in the systematic reviewClick here for fileExcluded studies. Provides a list of excluded studies and the reason for their exclusionClick here for fileTables describing the characteristics of included studies measuring waterpipe smoking prevalence by world region. Provides tables describing the characteristics of included studies measuring waterpipe smoking prevalence by world regionClick here for fileResults of the Global Youth Tobacco Survey (GYTS) and World Health Organization (WHO) surveys. Provides the prevalence of waterpipe smoking in the GYTS and WHO surveysClick here for file"}
+{"text": "Superficial siderosis (SS) is a rare disease which affects people in all ages and both sexes, but three times more in men. Pathological etiology is deposition of hemosiderin (a product of the breakdown of blood) in leptomeninges, subpial layer, ependymal surface and other parts of central nervous system (CNS) and typically leads to neurological dysfunction and progressive irreversible signs and symptoms. We present a 33-year-old man with complete deafness in left ear, partial hearing loss in right ear, gait imbalance, bilateral frontotemporal throbbing headache and anosmia resulted from superficial siderosis. His familial history was noncontributory.Neurological examination revealed a good alert patient with no evidence of cognitive impairment, horizontal nystagmus in both eyes with normal saccade and pursuit, normal force and tone of muscle with decreased light touch and pin prink with stocks and gloves pattern, severe dysmetria and moderate dysdiadochokinesia, generalized hyperreflexia, bilateral equivocal plantar reflexes, and ataxic gait with impossibility to perform tandem gait.Audiogram showed bilateral, high-frequency sensorineural hearing loss especially in left side.Magnetic resonance imaging (MRI) findings are shown in 2 It was first described in 1908 by Hamill; but with no access to modern technology and MRI, the only diagnostic way was biopsy.2 Using the results of 270 reported cases of SS in articles from 1908 to 2006 revealed different causes for this disease;2 some of the most frequent ones are Idiopathic (35%), head or neck trauma (13%), AVM (9%), current CNS tumor (15%), previously resected CNS tumor (6%), post CNS surgery (non-tumor) (7%), amyloid angiopathy (3%), brachial plexus injury (6%), and other cause of subarachnoid hemorrhage (6%).5 The probable cause in the presented case was recurrent head trauma in his childhood.Superficial siderosis (SS) is a rare disease affects people in all ages and both sexes but three times more in men.4 and as the result of these depositions and central nervous system involvement; there are progressive, irreversible clinical manifestations of the disease; the most common one is sensorineural hearing loss which over a period of 1 to 12 years progresses to total deafness.2 In our case, hearing loss and loss of sense of smell began at the age of 20 and over 13 years developed to complete deafness and anosmia. The second most common sign is gait imbalance and ataxia which was also in our case a remarkable, slowly progressive problem.After breaking down of erythrocytes or red blood cells exiting in CSF and CNS, hemoglobin and iron-containing heme are released in CSF and in response to this upsurge in heme levels, Bergmann glia and microglia cells produce heme oxygenase-I enzyme which breaks down free heme into biliverdin, carbon monoxide and iron. The deposition of iron in cerebral tissue is the main pathology of superficial siderosis2 The largest review of the literature to date, reported that patients presented with bilateral SNHL (95%), ataxia (88%), and pyramidal tract signs (46%);6 cerebellar dysarthria is common and nystagmus may be present.7 But, sensory symptoms or a sensory level are uncommon.8Using the result of 270 reported cases of SS, the most common features of the disease are hearing loss (81%), ataxia (81%), myelopathy (53%), urinary problems (14%), headache (14%), anosmia (14%), diplopia (4%), bowel problems (3%), and cranial nerve palsies (2%).2 and optic or trigeminal neuropathy9 also are uncommon but have been reported. In approximately one third of the cases in an earlier literature review,2 severe recurrent headaches which were indicative for symptomatic subarachnoid hemorrhage were reported; but was infrequent in recent large studies.10Extraocular nerve palsies11The first step for early detection of SS is via MRI which shows iron depositions in affected tissues as a hypointense band, and characteristic rim of intensity appearing on the cerebellum, with no enhancement These signal loss areas in T2-weighted scans are pathognomonic for the disease, but hyperintense rime is also rarely seen.11 Iron or copper chelators and steroids are other treatments but with little success.12 In one study, using oral deferiprone (a lipid-soluble iron chelator with ability to cross the blood-brain barrier) at a dose of 30 mg/kg per day has been caused reduction of hemosiderin deposition in MRI;13 and the usage of trientine also has been reported to reduce iron concentration in CSF.14There is no successful or specific treatment for SS. With early detection of source of bleeding, the surgery may be helpful.In conclusion, according to our literature review, SS with CNS involvement is a rare disorder which formed because of the deposition of hemosiderin in leptomeninges, subpial layer, ependymal surface and other parts of CNS and leads to neurological dysfunction and progressive irreversible signs and symptoms. In our case, hearing loss and loss of sense of smell began at age of 20 and over 13 years developed to complete deafness and anosmia. There is no successful or specific treatment for SS but Iron or copper chelators and steroids are some treatments with little success."}
+{"text": "Identification of the genetic differences between the two lesions may assist in identifying genes that promote the invasive phenotype. To annotate these alterations we analysed 21 breast tumours containing synchronous areas of DCIS and IDC. Tumour cells were microdissected from FFPE tissue and analysed by 300K Molecular Inversion Probe (MIP) copy number arrays. Matched IDC and DCIS showed highly similar copy number profiles (average of 83% of the genome shared). Four regions of loss  and four regions of gain  were recurrently affected in IDC but not in the matching DCIS. CCND1 and MYC showed increased amplitude of gain in IDC. One region of loss (17p11.2) was specific to DCIS. Our data shows that DCIS is an advanced pre-invasive tumour with genetic instability and continues to evolve in parallel with co-existing IDC. In the IDC-specific regions of genomic alteration we have identified novel loci as well as genes with previous links to breast cancer progression.Ductal carcinoma"}
+{"text": "Methods. A secondary school having girl students in the age group of 12\u201315 years studying in sixth to ninth standard was selected. Serum ferritin concentration was estimated by ELISA. For assessing the cognitive function mathematics score, one multi-component test for memory, attention and verbal learning and Intelligent Quotient scores of the students were used. Results. Scholastic Performance, IQ and Scores of Mental balance, Attention & Concentration, Verbal Memory and Recognition were decreased in iron deficient girls, both anemic and non anemic as compared to the non iron deficient girls.Iron deficiency anemia is most common nutritional deficiency disorder in India and remains a formidable health challenge. Girls in the period of later school age and early adolescence are prone to develop iron deficiency. Iron deficiency leads to many non-hematological disturbances which include growth and development, depressed immune function in infants; reduces physical work capacity; decreases the cognitive function in both infants and adolescents. Present study was done to know the prevalence of iron deficiency in both the anemic and non anemic school going adolescent girls, to assess the effect of iron deficiency on cognitive functions in anemic iron deficient and non-anemic iron deficient school girls in a village school situated in central India.  Iron deficiency is the third greatest global health risk after obesity and unsafe sex . Anemia Iron deficiency has both physiologic and pathologic causes. Physiologic causes relate to the greater iron demands during periods of growth and development whereas pathologic causes refer to iron losses secondary to a chronic medical condition. In general, iron deficiency results when iron demands by the body are not met by iron absorption. Thus, iron deficiency can result from inadequate intake, impaired absorption, increased requirements, and chronic blood loss.More than half of the world's undernourished population lives in India  and halfIron deficiency is a systemic condition which has many non ematological consequences, which occurs in relation to its severity, like decreased physical work capacity , decreasIn present study, effort has been made to assess the effect of iron deficiency on cognitive functions in anemic iron deficient and in nonanemic iron deficient school going adolescent girls in a village school.The present study was carried out in the Department of Pathology, MGIMS, Sevagram, India from July 2007 to September 2009. Approval was obtained from the Institutional Ethics Committee for the study.A secondary school in the neighborhood, having girl students in the age group of 12\u221215 years studying in sixth to ninth standard was selected. Necessary permission was taken from the school authority and girls were explained in detail about the study in the school assembly. Participation in the screening programme was voluntary. An explanatory letter and consent form was given to all the girls. Written consent was obtained from parents or guardian for participation in the screening as all participants were minor. Participants completed a questionnaire asking for significant family, medical and menstrual history, parent education, and their dietary habits.Screening for anemia and iron deficiency was done by (1) complete blood count: done by automatic cell counter, that is, Coulter for hemoglobin concentration. (2) estimation of serum ferritin concentration was done by ELISA. For this recommended protocol by the kit used was followed. Established age adjusted values for hemoglobin and serum ferritin were used.Group I\u2014participants who were anemic (Hb < 12\u2009gm%) and iron deficient (serum ferritin less than 12\u2009\u03bcg/L).Group II\u2014participants who were nonanemic (Hb \u2265 12\u2009gm%) and iron deficient (serum ferritin less than 12\u2009\u03bcg/L).Group III\u2014participants who were nonanemic (Hb \u2265 12\u2009gm%) and noniron deficient (serum ferritin levels of 12\u2009\u03bcg/L or more).The participants after screening were divided into three groups.After dividing the participants into three groups, that is, anemic iron deficient (group I), nonanemic iron deficient (group II), and nonanemic noniron deficient (group III), for assessing the cognitive function mathematics score, one multicomponent test for memory, attention and verbal learning, and intelligent quotient (IQ) scores of the students was used.For assessment of scholastic performance, the mathematics score obtained in the final term examination was noted from the report card. The score obtained were from total 100 marks.Multicomponent test of the three groups was assessed after randomization by using PGI test\u2014(Dr. N. N. Wig & Dr. Dwarka Prasad) for testing memory attention and verbal learning  Both parPGI test\u2014(Dr. N. N. Wig & Dr. Dwarka Prasad), consisted of the following ten subtests: (I) remote memory, (II) recent memory, (III) mental balance, (IV) attention and concentration, (V) delayed recall, (VI) immediate memory, and (VII) verbal retention for similar pairs, (VIII) verbal retention with dissimilar pairs, (IX) visual retention, and (X) recognition.For assessing the intelligent quotient of the girl student's, Bhatia battery performance test\u2014(Dr. C. M. Bhatia) for intelligent quotient (I.Q) was used, which includes two subtest Kohl's block design and Pass along test .Statistical analysis: the data was analyzed with SPSS (version 16) statistical software. One-way ANOVAs test 63 of 100 girl students had hemoglobin levels less than 12\u2009gm% and 37 had hemoglobin levels above 12\u2009gm%. Thus, prevalence of anemia in school going adolescent girls was 63%. The overall mean hemoglobin in the study was 11.66 \u00b1 1.27\u2009g/dL.Out of the 63 girl students who had anemia, 56 girls (56%) had Hb values between 10 and 12\u2009gm%, 5 girls (5%) had Hb values between 7 and 10\u2009gm%, and rest of the 2 girls (2%) had Hb values below 7\u2009gm%. Thus, mild anemia (Hb 10\u201312\u2009gm%) was present in 56% of the study subjects, moderate anemia (Hb 7\u201310\u2009gm%) in 5%, and severe anemia (Hb < 7\u2009gm%) was present in only 2% of the study subjects.\u03bcg/L). So the prevalence of iron deficiency was 67%.Serum ferritin was done in 100 girl students between the age group of 12\u221215 years, 67 were iron deficient  between nonanemic noniron deficient (group III) and anemic iron deficient (group I), it was significant  between nonanemic noniron deficient (group III) and nonanemic iron deficient (group II).The difference in mathematics score was highly significant (Multicomponent test (MCT) of verbal learning, attention, memory and IQ scores of all the three groups was assessed after randomization. Tests were administered under the guidance of trained research assistant of the Department of Psychological Medicine. The person who was assessing the tests was unaware of the group assignment.P value < 0.0001) and also the scores of mental balance differed significantly  between the nonanemic noniron deficient (group III) and nonanemic iron deficient (group II). The difference in scores of attention and concentration was significant  between non anemic noniron deficient (group III) and anemic iron deficient (group I). And the nonanemic iron deficient (group II) and nonanemic noniron deficient (group III) also showed statistically significant  difference in scores of attention and concentration.The difference in scores of mental balance between the nonanemic noniron deficient (group III) and anemic iron deficient (group I) was significant , and on comparing the scores of Verbal Retention for Similar Pairs between the non-anemic iron deficient (group II) and non anemic non iron deficient (group III) the difference was also statistically significant .Non anemic non iron deficient (group III) and anemic iron deficient (group I) when compared for scores of Verbal Retention for Similar Pairs showed significant difference  and also between the nonanemic iron deficient (group II) and nonanemic noniron deficient (group III) showed statistically significant difference .The difference in scores of verbal retention for dissimilar pairs between the anemic iron deficient (group I) and nonanemic iron deficient (group III) was statistically significant , similarly the difference in scores of recognition between the nonanemic iron deficient (group II) and nonanemic iron deficient (group III) were statistically significant .The scores of recognition between the anemic iron deficient (group I) and nonanemic iron deficient (group III) showed significant difference (For assessing the intelligent quotient (IQ) of the girl students two test, that is, Kohl's block design test and Pass along test were used. After obtaining the test quotient (TQ) from these two tests the IQ was calculated.P value < 0.0001 and also between nonanemic noniron deficient (group III) and nonanemic iron deficient (group II) .The IQ levels differed significantly between nonanemic noniron deficient (group III) and anemic iron deficient (group I) with Thus, the cognitive function scores which included the mathematics score, multicomponent test scores, and IQ scores were less in iron deficient both anemic and nonanemic groups (group I and II) than the noniron deficient nonanemic group (group III).Although all the features of cognition are important but verbal learning and attention and concentration along with memory are particularly more important for academic performance.In present study, iron deficient both anemic and nonanemic students had scored less in mathematics than the normal non iron deficient students. This is in accordance to the study done by Prestonjee  wherein Multicomponent test of verbal learning, attention, and memory of all the three groups was assessed after randomization. The overall total score was less in iron deficient both anemic and nonanemic groups than noniron deficient nonanemic group.Similar findings were also seen in scores of mental balance and verbal retention for similar and dissimilar pairs. There was no difference in score of recent and remote memory, delayed and immediate recall, and visual retention subsets between iron deficient (group I and II) and noniron deficient (group III).The findings suggest that iron deficiency, even in the absence of anemia causes decrease in at least some aspect of cognitive functioning.The present findings are in accordance with the findings of a randomized trial done by Bruner et al.  on nonanThe difference of mean IQ scores between iron deficient both anemic and nonanemic groups (I and II) and nonanemic noniron deficient was statistically significant.Pollitt et al. , SoemantThe findings of the present study are iron deficient school going adolescent females both anemic and nonanemic had low scholastic performance in the form of low mathematics score and low scores in verbal learning, attention, mental balance, and recognition component of multicomponent test along with low IQ scores than their noniron deficient comparers. Iron deficiency independently leads to decreased cognitive scores. Iron deficiency without anemia is the initial stage and as the iron deficiency increases anemia manifests. The cognitive scores were lowest in the iron deficient anemic (group I). In iron deficient without anemia it was slightly more than group I but much less than group III, that is, nonanemic noniron deficient subjects. Prevalence of anemia was 63% while prevalence of iron deficiency anemia in present study was 50%.There is need to initiate programme for supplementation of iron and folic acid to school going adolescent girls for the prevention of hematological and nonhematological consequences of iron deficiency with government and private organizational efforts."}
+{"text": "To the Editor: Approximately 3,000 cases of tickborne encephalitis virus (TBEV) disease are registered annually in Europe , aseptic meningitis (3 cases), encephalitis (2 cases), meningoencephalitis (8 cases), and meningoencephalomyelitis (3 cases) (,During the past 20 years, TBEV has reemerged in several European areas that had been disease free (The implementation of a regional active surveillance system allows the highest sensitivity in assessing the epidemiologic features of TBEV infections, which are characterized by highly disease-endemic microfoci in areas free of the problem ("}
+{"text": "Down syndrome includes learning and memory deficits in all cases, as well as many other features which vary in penetrance and expressivity in different people. While Down syndrome clearly has a genetic cause - the extra dose of genes on chromosome 21 - we do not know which genes are important for which aspects of the syndrome, which biochemical pathways are disrupted, or, generally how design therapies to ameliorate the effects of these disruptions. Recently, with new insights gained from studying mouse models of Down syndrome, specific genes and pathways are being shown to be involved in the pathogenesis of the disorder. This is opening the way for exciting new studies of potential therapeutics for aspects of Down syndrome, particularly the learning and memory deficits.Chromosome copy number aberrations, anueploidies, are common in the human population but generally lethal. However, trisomy of human chromosome 21 is compatible with life and people born with this form of aneuploidy manifest the features of Down syndrome, named after Langdon Down who was a 19 Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability, occurring in approximately 1 in 700 live birthsThe additional copy of Hsa21 results in elevated expression of many of the genes encoded on this chromosome, with varying expression levels in different tissuesMouse models of DS are instrumental in identifying which genes contribute to DS phenotypes, and unraveling the mechanisms by which these phenotypes ariseIn this review, we highlight recent developments in understanding how overexpression of Hsa21 genes leads to many of the features of DS. We focus on key areas including brain, heart and cancer, as these are currently the most developed in our understanding of the molecular pathogenesis of DS.People with DS have learning and memory problems and exhibit differences in brain structure compared to the euploid populationdual-specificity tyrosine- (Y)-phosphorylation-regulated kinase 1A (Dyrk1A), potassium inwardly-rectifying channel, subfamily J, member 6 Gene (Girk2) and single-minded homologue 2 (Sim2), cause alterations in dendritic spine morphology and deficits in some behavioural testsAbcg1-U2af1) found on the Hsa21 sub-telomeric region in Ts1Yah mice  and SIM2dopey family member 2 (DOPEY2)Down syndrome cell adhesion molecule (DSCAM)The over-expression of a number of Hsa21 genes has been implicated in learning and memory deficits in single gene transgenic mouse models, suggesting that trisomy of these genes may contribute to learning disability in DS individuals. These genes include Fig.1), suggesting that this trisomic segment contains the causal dosage-sensitive genes for these detrimental developmental phenotypesNeurodevelopment is known to be altered in people with DS. Already by mid-gestation the brains of fetuses with DS are smaller than those which do not have the condition. Cerebellar granule cells in Ts65Dn mice have reduced proliferation rates and elongation of the cell cycle length which could potentially result in a decrease in brain massElevated rates of neuronal apoptosis related to oxidative stress have been reported in DSRecently, it was proposed that DYRK1A contributes to DS neural phenotypes, such as impaired dendritic growth, by disturbing neuron-restrictive silencer factor (REST/NRSF) levelsThis is a relatively new area of research in DS that is rapidly gaining momentum, and which arises from experiments carried out in mouse models in which behavioural, neurophysiological and cellular biology changes can be quantitatively assessed during development and ageing, and then modified through pharmacological intervention.Several pharmacological interventions to enhance cognition in people with DS have been suggested, based upon efficacy in the Ts65Dn mouse  occurs in people with DS, with 30-70% of DS individuals developing dementia by the age of 60APPAPP expression is also linked to enlargement of early endosomesdap160/ITSN1 (intersectin1), synj/SYNJ1 and nla/RCAN1 (runt-related tremscripthon factor 1), results in abnormal synaptic morphology and impaired vesicle recyclingNeurodegenerative phenotypes have also been observed in animal models of DSOther Hsa21 trisomic genes may also contribute to AD through different mechanisms. DYRK1A, an Hsa21 encoded kinase, phosphorylates Tau at a key priming site which may mediate its AD-related hyperphosphorylation in people with DSSix percent of children and adolescents with DS have epileptic seizuresPeople with DS have been reported to experience disturbed sleeping patterns. Studies of circadian activity in the Ts65Dn mouse model have reported conflicting results of both intactGATA binding protein 1 (GATA1) gene resulting in the synthesis of a truncated GATA1 protein termed GATA1sv-ets erythroblastosis virus E26 oncogene homolog (ERG), is required for development of the myeloproliferation defect in the Ts65Dn modelrunt-related transcription factor 1 (RUNX1) has also been proposed to regulate hematopoiesis via the phosphoinositide 3 (PI3)-kinase/AKT pathwayChildren with DS have a greatly elevated risk of developing the otherwise very rare transient myeloproliferative disorder (TMD), as well as acute megakaryocytic leukemia (AMKL) and acute lymphoblastic leukemia (ALL)Despite perturbations of hematopoietic development in the Ts1Cje, Ts65Dn and Tc1 models of DS, these mice do not develop leukaemia, even when the trisomic models also express disease-associated GATA1 mutationsmin, with mouse models of DS resulted in reduced formation of tumors, dependent on the trisomy of the Hsa21-encoded ETS2 generegulator of calcineurin (RCAN1), was shown to be sufficient to suppress tumour growth by attenuating angiogenesis via the regulation of vascular endothelial growth factor (VEGF) signalingRcan1 did not completely abrogate the effect of trisomy on tumour formation, suggesting that other Hsa21 genes also contribute to this phenotypeAlthough DS is associated with a predisposition to leukemia, people with DS have a reduced risk of developing most solid tumourscysteine-rich with EGF-like domains 1(CRELD1), a non-Hsa21 gene, contribute to the occurrence of AVSD in DSDSCAM- ZNF295 (zinc finger protein 295)] of Hsa21 may be sufficient for the development of CHDCongenital heart defects (CHD) are prevalent in 40% of children with DS and over 50% of all atrioventricular septal heart defects (AVSDs) in infancy are attributed to trisomy Hsa21DS is complex disorder and dissecting the genetic and molecular processes underlying the syndrome requires many different complementary approaches, including the study of human data and mouse and other model organisms. However, several recent breakthroughs have increased our understanding of the effects of Hsa21 trisomy. Combining information from studies of people with DS with the power of mouse models of trisomy has enabled genetic associations to be tested and continues to lead to the identification of genes that cause DS-associated pathology. Significant advances in basic research have been instrumental in determining the molecular mechanisms underlying these phenotypes leading to useful therapeutic interventions. However, many aspects of DS crucial to the health and well-being of people with the condition remain to be investigated and require study at all levels."}
+{"text": "Atypical Odontalgia (AO) is a term applied to a continuous pain in the teeth or in the tooth socket after extraction in the absence of any identifiable dental cause, under the International Classification of Headache Disorders (ICHD) and somatosensory abnormalities are common features in these patients, where Quantitative Sensory Testing (QST) are helpful tools to evaluate these cases.The aim of the pilot study was to determine the effect of topical application of anesthetic cream in quantitative sensory testing (QST) findings of AO patients.Methods Ten (7 women and 3 men) consecutive AO patients  with mean pain duration of 2.7 years . QST was performed in all patients at baseline and 3 minutes after topical application of anesthetic cream . QST included tests of mechanical detection threshold (MDT) and mechanical pain threshold (MPT) with von Frey monofilaments, dynamic mechanical allodynia with cotton swab (DMA1) and with toothbrush (DMA2), heat pain thermal detection (HPD), cold pain thermal detection (CPD), temporal summation (WUR) and controlled pain modulation (CPM). The present pain intensity was also recorded with visual analogue scale (VAS). Results were analyzed with non-parametric Wilcoxon test with significance level of 5%.QST mean values showed no differences after topical application of anesthetic cream, except for DMA2 (p=0.02) and WUR (p=0.02). Moreover mean pain in visual analogue scale relieved from 6,03 to 2,12 .In this pilot study significant changes in intraoral somatosensory function were observed in AO after topical application of anesthetic cream for dynamic mechanical allodynia, associated to a reduction of pain intensity. These results may reflect peripheral and central sensitization of trigeminal pathways.There were no conficts of interest in the performance of this study."}
+{"text": "A suitable approach to select cancer stem cells (CSC), the black seed of melanomas would enable their characterization and elimination.Cancerous tissues from primary and metastatic lesions of patients with malignant melanomas (n=150) were investigated by cell cultures and molecular genetics. Double labelled cells were sorted by BD FACSAvia Sorter. Gene expression analysis by Real Time PCR  and RNA microarray (Agilent) has been performed (n=48).90% of the cell cultures grew and cancer initiating cells could be IF FACS sorted . Colocalisation of unique GD3 sialilated glycosphingolipids and antiCD20 binding was proved. Characteristic growth pattern, spheroid forming, CSC markers  was observed Figure . We founUnique GD3 sialilated glycosphingolipids with colocalised CD20 proved to be selection markers for CSC in metastatic melanomas. Our strategy paves the way for detection and characterization of cancer stem cells and provides material for therapeutic developments to eliminate the black seeds of melanomas."}
+{"text": "Journal of Studies on Alcohol and Drugs (4), Alcoholism: Clinical and Experimental Research (3), and Addictive Behaviors (3). The authors who published most frequently on BI efficacy were \"Carey KB,\u201d \"Fleming MF,\u201d \"Floyd RL,\u201d \u201cMartens MP,\u201d \"Nilsen P,\u201d \"Saitz R,\" and \"Shang G,\u201d with two publications each. The quantitative approach was prevalent among studies, with randomized controlled trials the most frequent (35). The BIs were conducted mainly in clinical and health-services settings (18). However, interventions were also conducted via the Internet (5) and by telephone (4). Regarding the study population, 22 articles addressed BI for men and women, 14 addressed BI for women, and 9 addressed BI for pregnant women. The efficacy of BI in the reduction of alcohol consumption was confirmed in most research, but some studies showed a reduction only in men. Further specific research using a study population solely comprised of women is deemed necessary.The aim of this study was to systematically review the efficacy of brief intervention (BI) in reducing alcohol use in women. We performed an electronic search across all databases using Thomson Reuters (formerly ISI) Web of Knowledge to identify multidisciplinary content. The term \"brief intervention\" was associated with the words \"alcohol\" and \"women.\" We selected studies published between 2006-2010. Of the 95 studies found, 52 were excluded because they were presented at meetings or did not focus specifically on the subject of interest. Forty-three articles with the central theme of realization and/or evaluation of BI efficacy were included in the analysis. Abstracts of these papers underwent content analysis. The year 2007 had the most publications (13) as did the following journals:"}
+{"text": "Cluster headache (CH) is an extremely severe and debilitating trigemino-autonomic pain syndrome.About 10% of patients with CH manifest a chronic form CH (CCH). Extracts of Boswellia serrata have been clinically studied for the treatment of many inflammatory conditions such as osteoarthritis and rheumatoid arthritis (3). The resin from Boswellia Serrata contains a number of biological actives called pentacyclic triterpene acids, which give the extract its anti-inflammatory and analgesic properties, with boswellic acid the major active ingredient (4). These acids have been demonstrated to interfere with the body\u2019s natural inflammatory response by inhibiting cytokines and leukocyte activity. The present study aims to evaluate the long-term efficacy of Boswellia Serrata  on headaches and disturbed sleep in patients with CCH.In an open-label study, 4 patients with CCH and disturbed sleep received oral Boswellia Serrata.The effects were long-lasting in 3 patients (mean 15 months) and transient (6 months) in one patient. The rapid improvement of nocturnal pain within weeks is similar to the analgetic effect observed in recent trials using Boswellia Serrata in cancer pain The mechanisms of how Boswellia Serrata reduces pain in CCH remain unclear. Boswellic acids, constituents of Boswellia extract have subsequently been identified as selective redox independent noncompetitive inhibitors of both 5-lipoxygenase, the key enzyme in leukotriene biosynthesis and human leukocyte elastase. Proinflammatory cytokines, such as leukotrienes, are known to play a role in the pathophysiology of CH. This study provides Class IV evidence that oral Boswellia Serrata  reduces the intensity and frequency of headaches in patients with CCH.None"}
+{"text": "Reliable measurement of esophageal pressure is a prerequisite for analysis of respiratory system mechanics in spontaneous breathing patients. For that purpose, various types of balloon catheters exist that differ in material, size and shape. In physical models we studied the quality of pressure measurement via six different balloon catheters, three of them containing a second balloon for measurement of gastric pressure.2O) at different levels of superimposed pressure.Nine balloons of six esophageal catheters were investigated in three conditions: measurement of balloon pressure during initial inflations immediately after unpacking; measurement of static pressures at different filling volumes; and compliance estimation in physical models (27, 54, 90 ml/cmH2O if the balloon was filled appropriately. Overfilling of the balloon resulted in larger errors only in two catheters. Compliance estimations resulted in errors below 1 ml/ cmH2O. Superimposed pressure had no relevant effect on compliance estimation.During the initial inflation most catheters showed pressure artifacts resulting from material adhesion. Those artifacts disappeared during following inflations. Static pressure measurements could be performed with an error below 1 cmHThe reliability of pressure measurements and also of compliance estimation via the tested catheters is high. Only in two catheters was the filling volume a critical point for a precise measurement of pressure or for estimation of compliance. Immediately after unpacking, adhesion of the balloon material might prevent reliable pressure measurement, therefore before the first measurement overfilling of the balloon and retention of the excess gas seems strongly recommended."}
+{"text": "Evaluate the effect of myocardial scar burden, scar location, and scar transmurality on response to cardiac resynchronization therapy (CRT)not respond to cardiac resynchronization therapy (CRT). Results from these studies have varied on the importance of scar location, transmurality, and burden on response to CRT. We analyzed cardiac MRI in patients undergoing CRT from 4 centers (two in Europe and two in the US), and hypothesized that the presence of transmural scar in the posterolateral wall (the most frequent site of left ventricular lead placement in CRT) would preclude positive response to CRT.Several recent single center studies have used late Gadolinium enhancement (LGE) MRI to predict which patients would likely Cardiac MRI was performed according to standard methods and included at a minimum, cine imaging and LGE imaging using a Gadolinium-based contrast agent. All patients met current criteria for CRT . Sixty (60) patients from 4 centers were analyzed, and any patient with infarct enhancement on LGE by visual inspection was processed into an LGE bullseye map following AHA guidelines. Total scar burden (as % of LV mass) as well as the presence of transmural scar in the posterolateral or septal segments were assessed. 48% of patients (29/60) patients had LGE and 59% of those (17/29) had transmural scar in at least one AHA segment. Positive response was assessed at 6 months both by clinical  and echocardiographic (reduction of LVESV by 15%) parameters.posterolateral scar responded by clinical criteria, and only one patient with posterolateral scar responded by echocardiographic criteria . The negative predictive value for the presence of transmural septal scar or total scar burden >15% were lower (NPV = 64-67%).None of the patients with transmural non-response to CRT.The presence of transmural posterolateral scar by LGE is predictive of"}
+{"text": "The primary endpoint of the model was the probability of tumor extinction following BCG induction therapy in patients with high risk for tumor recurrence. We theoretically demonstrate that extending the duration between the resection and the first BCG instillation negatively influences treatment outcome. Simulations of higher BCG doses and longer indwelling times both improved the probability of tumor extinction. A remarkable finding was that an inter-instillation interval two times longer than the seven-day interval used in the current standard of care would substantially improve treatment outcome. We provide insight into relevant clinical questions using a novel mathematical model of BCG immunotherapy. Our model predicts an altered regimen that may decrease side effects of treatment while improving response to therapy.Intravesical Bacillus Calmette Gu\u00e9rin (BCG) immunotherapy is considered the standard of care for treatment of non-muscle invasive bladder cancer; however the treatment parameters were established empirically. In order to evaluate potential optimization of clinical parameters of BCG induction therapy, we constructed and queried a new mathematical model. Specifically, we assessed the impact of (1) duration between resection and the first instillation; (2) BCG dose; (3) indwelling time; and (4) treatment interval of induction therapy \u2013 using cure rate as the primary endpoint. Based on available clinical and  Adjuvant treatment of non-muscle invasive bladder cancer (NMIBC) using intravesical Bacillus Calmette-Gu\u00e9rin (BCG) after transurethral resection was established empirically almost 40 years ago in vitro experimental data to construct and parameterize a new stochastic mathematical model describing the interactions between BCG, the immune system, and tumor cells with the primary endpoint being the probability of tumor extinction. We did not aim for precise quantitative results but rather for a robust qualitative understanding that would remain valid for future models that could integrate increasing levels of detail. Herein, we assessed the impact of: (1) varying the time from resection to BCG instillation, (2) modulating the BCG dose used during intravesical instillation, (3) the indwelling time of BCG, and (4) the inter-instillation interval.Using a refined mathematical model that includes the adaptive effector functions of the immune system, we address several clinical parameters in order to learn about their impact for an optimal protocol of successful BCG immunotherapy. Specifically, we integrated available clinical and Although all parameters influenced treatment outcome, the most surprising result concerned the impact of the inter-instillation interval where simulations suggested that an interval two times longer than the seven-day interval used in the current standard of care, would substantially improve treatment outcome. Our study provides useful insight and testable hypotheses that could lead to improved management in NMIBC.Our mathematical model makes assumptions about the interactions triggered by BCG instillations and simulates the dynamics of populations of cells. Prior to initiation of BCG therapy, three cell populations are present: healthy urothelial tissue, tumor and innate immune cells. The interactions between these cell populations are negligible. The processes that take place for each of these cell populations before therapy are cell migration and/or local proliferation and death  varying the time from resection to BCG instillation, (2) modulating the BCG dose used during intravesical instillation, (3) the indwelling time of BCG, and (4) the inter-instillation interval. Each probability of tumor extinction was calculated by running 1,000 stochastic simulations, such that it's resulting 95% confidence interval became reasonably small. The computer code was also employed in uncertainty and sensitivity analyses for assessing the robustness of our results . Again, we find that greater exposure of the bladder mucosa to BCG results in an increased probability of tumor extinction Click here for additional data file.Figure S2Simulation of logistic tumor growth, resection and tumor re-growth. The horizontal dashed line represents the approximate size of the tumor when the tumor is visible on the bladder wall.(TIFF)Click here for additional data file.Figure S3Simulation of population dynamics of cells during and after a six-week course of intravesical BCG therapy. BCG (panel A), tumor cells (panel B), BCG-associated tumor cells (panel C), BCG-associated tissue cells (panel D), innate effector cells (panel E), adaptive effector cells (panel F). Note the modeling of the prime/boost response of the innate and adapted immune system occurring after the third instillation .(TIFF)Click here for additional data file.Figure S4Sensitivity analyses forandof the main text.A. Sensitivity analysis of Ea\u03bc. The blue, black . The black  \u200a=\u200a106, 105, 104 and 103 tumor cells. The model has been re-calibrated for each value of T(0), accordingly. These numerics suggest that our prediction of improved therapeutic outcome by a two-week inter-instillation interval is robust. C. Sensitivity analysis of T (0) \u200a=\u200a106 and 103 tumor cells, respectively.(TIFF)Click here for additional data file.Table S1State variables of the model along with their biological description. The state variables represent counts of various cell types involved in the interactions between the immune system, tumor cells and BCG.(TIFF)Click here for additional data file.Table S2Stochastic processes and their corresponding rates.(TIFF)Click here for additional data file.Table S3Parameters of the model.(TIFF)Click here for additional data file.Text S1Detailed description and numerical analysis of the stochastic mathematical model.(PDF)Click here for additional data file."}
+{"text": "Because animals can transmit some diseases to people, it is wise to be cautious around animals that carry these diseases. But how do you know which animals are carrying disease? Sometimes they appear perfectly healthy. A study of 57 apparently healthy show pigs at a 2009 US state fair found that almost 20% were carrying influenza virus and at least 4 were carrying the 2009 pandemic virus. Of concern is the possibility that different types of influenza virus\u2014pandemic, swine, avian\u2014could combine in pigs and emerge as new viruses that then spread to humans. Swine workers, veterinarians, and other persons with pig contact may be at high risk for infection with pig influenza and should receive seasonal influenza vaccines, use personal protective equipment when working with healthy pigs, and limit their contact with sick pigs. Regular monitoring of influenza virus among pigs and testing of sick persons who have been exposed to pigs are needed. Within 5 months after the earliest detection of human influenza A(H1N1)pdm09 virus, we found molecular and culture evidence of the virus in healthy US show pigs. The mixing of humans and pigs at swine shows possibly could further the geographic and cross-species spread of influenza A viruses. Cross-species infections with influenza A viruses readily occur between humans and pigs. Pigs often have been infected by human epidemic viruses  and South Dakota (2009). Exhibitors were eligible for the study if they reported working with pigs at least 1 cumulative hour per week and had no current immunocompromising condition. Enrolled participants completed a questionnaire and permitted collection of nasal swab specimens from their show pigs. Before data were collected, multiple institutional review boards, the Institutional Animal Care and Use Committee of the University of Minnesota and the University of Iowa, and state fair officials approved the study.After acquiring informed consent, we recruited persons t) values <35 were considered positive for influenza Avirus; specimens with Ct values of 35 to <40 were suspected to be positive; and specimens with Ct values >40 were considered negative. In a blinded fashion, aliquots of swab specimens from pigs were shared with the Minnesota Veterinary Diagnostic Laboratory , where rRT-PCRs for matrix, hemagglutinin (HA), and neuraminidase (NA) genes were performed. Specimens were then shared with the National Veterinary Services Laboratory  and later with CDC for further molecular and sequencing studies.We used the Centers for Disease Control and Prevention  real-time reverse transcription PCR (rRT-PCR) (http://blast.ncbi.nlm.nih.gov).Positive and suspected-positive rRT-PCR specimens were cultured in shell vials on MDCK cells by using standard techniques. Sequence-based analyses of the influenza A virus isolates were performed by the CDC influenza division, using full or partial genome sequencing approaches for all 8 gene segments. Sequences were compared by using BLASTn alignment search techniques (<1 year of pig exposure (Questionnaires were completed by 121 (98%) participants. Participants were predominantly male (71%), and their median age was 34.9 years (range 9\u201375 years); 24% of participants were <18 years of age. Some pig exhibitors were children with exposure ; others Nasal swab specimens were collected from a total of 149 pigs . Almost all (97%) swabbed pigs were <1 year of age, and 40% were female. All pigs were observed to be healthy by a veterinarian before they were permitted to enter the show.In 2008, nasal swab specimens from show pigs showed no molecular or viral culture evidence of influenza A virus. However, in 2009, a number of pigs were positive for influenza A virus. Comparing the molecular results of the 3 laboratories and using conservative rRT-PCR result interpretations on which all laboratories agreed, we determined that influenza A virus was detected in 12 (12%) of 102 swine respiratory samples by rRT-PCR; 11 (19%) of these were from among the 57 pigs swabbed at the Minnesota state fair . Viral cA follow-up telephone survey of study participants identified 2 with influenza-like illness (ILI) within 7 days after the fair: an adult, with ILI with onset 1 day after his pigs arrived at the fair (and 4 days before pig swabbing), and his daughter who developed an ILI on the last day of the fair (3 days after pig swabbing). Three pigs exhibited by the child tested positive for influenza A virus.We found a 19% prevalence of influenza A virus among the 57 show pigs swabbed at the 2009 Minnesota state fair, which occurred during the second wave of the 2009 pandemic. Temporal analysis of the results indicated that most pigs with rRT-PCR\u2013positive results were sampled within 24 hours after arriving at the fair, suggesting that they probably were infected before their arrival . None ofThese detections of A(H1N1)pdm09 virus in the United States (reflecting the ease of transmission from humans to pigs) were soon followed by multiple other detections in US pigs (Of concern is that new reassortants between A(H1N1)pdm09, enzootic SIVs, and possibly other human- or avian-origin viruses might emerge and possibly spread to humans who have contact with asymptomatic pigs (Because of the possibility of novel virus generation in pigs and of human-to-pig and pig-to-human transmission of influenza virus, routine influenza A virus surveillance among pigs and influenza A virus testing of ill persons exposed to pigs is needed to ensure timely detection of novel influenza viruses in humans and pigs ("}
+{"text": "Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease.Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen  Porphyromonas gingivalis is a periodontal pathogen strongly associated with development of destructive periodontal disease in adults. We have recently characterized the structures of novel phosphorylated dihydroceramide (PDHC) lipids produced by this organism P. gingivalis. Little is known regarding the capacity of other common human bacteria to produce these lipids and most importantly, whether these lipids can be identified in human tissues distant from sites normally colonized by these bacteria. Therefore, the purpose of this investigation was to evaluate intestinal bacterial species as well as other periodontal organisms for their capacity to produce PDHCs and to examine blood and human tissue samples for the presence of these novel TLR2-activating bacterial lipids.Bacteroides, Parabacteroides or Prevotella genera produced PDHCs and of these, most produced predominantly PE DHC lipids , whereas the remaining intestinal and oral bacteria produced negligible amounts of UnPG DHC lipids (PG DHC lipids (both the HM and LM forms) can exist with three aliphatic chains (the substituted or \u201cSub\u201d form) or can be de-esterified to a lipid class with 2 aliphatic chains (the unsubstituted or \u201cUn\u201d form) C lipids .In contrast, human tissue samples revealed significant percentages of both LM or HM UnPG DHC lipids . We nextOf note, the average total ion abundances of PDHC lipids per microgram of total lipid extract were at least 33 times higher in the control artery segments than the atheroma segments  sites. We also evaluated blood plasma samples taken from periodontally healthy subjects or subjects with destructive periodontal disease. Two-factor ANOVA revealed significantly lower percentages of HM and LM SubPG DHC lipids and significantly higher percentages of HM and LM PE DHC lipids in periodontitis gingival tissue samples versus healthy samples . SimilarFor quantification of absolute PDHC lipid levels in control and periodontitis gingival tissue samples, each tissue lipid extract was supplemented with 1.5 \u00b5g of synthetic phospholipid internal standard before analysis by MRM/MS. This analysis revealed that lipid extracts of periodontitis tissue samples contained significantly higher mean levels of HM PE DHC and LM PE DHC lipids than that recovered in healthy gingival tissue samples  until the time of lipid extraction. Human brain specimens were obtained as postmortem samples from the Colorado Brain Bank, Denver, CO.Porphyromonas gingivalis , Tannerella forsythia (generously provided by Dr. Sigmund Socransky) and Prevotella intermedia  were grown in broth culture and after pelleting bacteria by centrifugation, the bacterial pellets were stored frozen until processing. At the time of lipid extraction, samples of bacterial pellets were removed and extracted using the same phospholipid extraction procedure.Intestinal bacterial samples that were previously stored frozen were grown on blood agar plates after demonstrating purity of bacterial isolates. The plates were scraped to recover the bacterial colonies and were extracted using the phospholipid extraction procedure of Bligh and Dyer All tissue and blood samples were stored frozen until processing. Gingival tissue, atheroma and brain samples were thawed and at least 20 mg of tissue was minced and extracted for several days in organic solvent according the method of Bligh and Dyer Individual lipid samples were analyzed using a QTrap 4000 mass spectrometer (ABSciex). A standard volume of each lipid sample (5 \u00b5l) was analyzed by flow injection and HPLC solvent was run at a rate of 80 \u00b5l/min. Using previously purified lipid preparations of each phosphorylated dihydroceramide class, the instrument parameters were optimized for detection of each lipid component based on gas phase transitions depicted in Each lipid ion transition peak was electronically integrated and the percentage abundance of each lipid class was calculated from the integrated lipid ion transition peaks. For each category of tissue or blood samples, all samples within a particular tissue or blood category were analyzed during a single analysis session. One or two-factor ANOVA, or the paired student t test was used to test for significance differences between sample categories.Table S1Ion abundances of bacterial phosphorylated dihydroceramides recovered from each intestinal and oral bacterial isolate. The individual bacterial samples were processed as described in the (DOC)Click here for additional data file.Table S2Ion abundances of bacterial phosphorylated dihydroceramides recovered from individual lipid extracts of subgingival plaque samples, and human gingival tissue, blood, atheroma and brain samples. The individual tissue and blood specimens were processed as described in the (DOC)Click here for additional data file.Table S3Ion abundances of bacterial phosphorylated dihydroceramides in lipid extracts of paired common carotid (control) and carotid atheroma samples derived from human endarterectomy samples. The individual tissue specimens were processed as described in the (DOC)Click here for additional data file.Table S4Mass spectrometric calibration parameters used to quantify bacterial lipids in bacterial or human specimens. The instrument parameters for the MRM-MS analysis are listed for the 4000QTrap Instrument (ABSciex). These parameters were defined using highly purified preparations of each PDHC lipid class.(DOC)Click here for additional data file."}
+{"text": "Solanum tuberosum). Small RNAs were analysed from leaf and stolon tissues. 28 conserved miRNA families were found and potato-specific miRNAs were identified and validated by RNA gel blot hybridization. The size, origin and predicted targets of conserved and potato specific miRNAs are described. The large number of miRNAs and complex population of small RNAs in potato suggest important roles for these non-coding RNAs in diverse physiological and metabolic pathways.Micro RNAs (miRNAs) represent a class of short, non-coding, endogenous RNAs which play important roles in post-transcriptional regulation of gene expression. While the diverse functions of miRNAs in model plants have been well studied, the impact of miRNAs in crop plant biology is poorly understood. Here we used high-throughput sequencing and bioinformatics analysis to analyze miRNAs in the tuber bearing crop potato ( The recent discovery of small RNAs and their widespread roles in post-transcriptional gene regulation has changed our basic understanding of how genes are regulated during development and in different biological processes. These RNAs represent an additional layer in regulation of gene expression. The pathways and key enzyme components are well described and are highly conserved in plants and animals Increasing evidence shows that miRNAs play important roles in developmental processes and gene regulation upon biotic and abiotic stresses http://www.fao.org). Moreover, potato is being grown more extensively in developing countries with rapidly growing populations, such as those in South East Asia, so it is playing an increasing role in addressing food security issues. It is extremely important to understand the as yet poorly known molecular events in tuber development, which ultimately impact on the breeding of cultivars with improved tuber characteristics . There is a great deal of current interest and research in the molecular signals which promote tuberization in potato Potato is an important global food crop which is cultivated for its underground storage stems (tubers), rich in starch and nutrients and is unique among the major crops in tuber formation. The importance of potato globally is shown by the \u223c330 million tons production in 2010 (Solanum tuberosum group Andigena (clone ADG573) was used for small RNA library preparation and next generation sequencing. This clone was developed at The James Hutton Institute from the Commonwealth Potato Collection . ADG573 has the feature of being able to tuberize under short days (SD) but not under long days (LD), which is typical of germplasm originating from the Andes in South America. From 12 libraries of leaf and stolon materials using LD and SD conditions with three biological replicates  about 60 million raw reads were obtained and further analysed. Firstly reads were quality filtered, adaptors were removed and ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) were filtered out from the database . These miRNAs have relatively high read numbers in our database  and each originates from one locus in the genome. S. tuberosum group Andigena plants but also DM (doubled monoploid) which was used for the potato genome sequencing project S. tuberosum group Andigena \u2018Neotuberosum\u2019 clone selected for long day tuberization). PotatoMir1005047020 showed similar expression pattern in different tissues in all the plants but PotatoMir1005907528 had lower levels in roots and higher in stolons. PotatoMir1005564753 had strong expression in every tissue in the different plants. These analyses strongly suggest that the examined miRNAs exist in plants and have high expression levels in several potato tissues.To validate the presence of these miRNAs in plant tissues RNA gel blot hybridization was performed. All the examined miRNAs are highly expressed in the examined tissues . We haveWith the aim to better understand the biological role of conserved and potato specific miRNAs we searched for putative target genes by using a plant small RNA target analysis tool: psRNATarget RAP1 (Relative to APETALA2 1) RAP1) was found for all the miR172 family members as a predicted target with low expectation score and unpaired energy suggesting it to be a highly likely target. Additionally, the NL25 protein disease resistance gene transcript (PGSC0003DMT400006234) is targeted by miR482b which is present in our prediction To prove the power of our prediction we searched among the predicted targets of miR172 for the known target miRNAs play key roles in most biological processes in animals and plants The small RNA analysis of potato showed that the 24 nt length class dominates in the dataset in total number and unique sequences strongly suggesting that small RNA directed heterochromatin silencing plays an important role in this crop similar to other species Most predicted miRNAs are of 21 and 24 nt in length. 21 nt miRNAs have the canonical size for small RNAs derived from DCL1 processing but a little variation in size might originate from the inaccuracy of DCL1 processing The prediction of miRNAs in our study, in contrast with previous reports, is based on results from high-throughput small RNA sequencing. Zhang et al. (2009) predicted 21 miRNA families but our study predicted 14 additional conserved miRNA families in potato. For 6 families we have predicted more members in the same family but our high-throughput study could not confirm the prediction for 9 of the reported miRNA families. Similarly, twelve miRNA families were found in common with another study Potential targets with a wide variety of predicted functions were identified for the miRNAs in potato: transcription factors, genes with a role in defence mechanisms, kinases and ion homeostasis genes. We have predicted the mRNA/gene targets of many potato miRNAs. Some have known functions in flowering and tuberization (miR172) or guiding cleavage of transcripts of immune receptors (miR482) Solanaceae species.In summary, we have identified conserved and potato specific miRNAs and their targets for the first time at a genome-wide level. Using high-throughput sequencing technology and taking advantage of the recently published potato genome Solanum tuberosum group Andigena (line ADG573) was used for the experiments. Plants were propagated in vitro by single-node cuttings on MS 20 \u22122 sec\u22121. After the shift to cabinets, leaf (8 days at SD and LD) and stolon (12 and 16 days of SD plants) materials were collected 4\u20136 hours after dawn. For miRNA validation DM  Solanum tuberosum group Andigena, Neotuberosum) and D\u00e9sir\u00e9e were used. Plants were grown in glasshouse under LD conditions for four weeks after in vitro propagation.Total RNA was extracted from leaf and stolon material using Plant/Fungi Total RNA Purification Kit  according to the manufacturer's instructions. An Illumina TruSeq Small RNA sample prep kit  was used for the preparation of small RNA libraries according to the manufacturer's instructions starting with 1.5 \u00b5g total RNA and Illumina GAIIX sequencer for sequencing.32\u03b3-ATP. RNA was blotted onto Hybond-N membrane  using a Panther\u2122 Semi-dry Electroblotter, HEP-1  and cross-linked by N-(3-Dimethylaminopropyl)-N\u2032-ethylcarbodiimide hydrochloride  32\u03b3-ATP using T4 polynucleotide kinase  to visualize miRNAs. For sequences see For RNA gel blot hybridization of miRNAs total RNA  was separated by 15% polyacrylamide (19:1) gel with 8M urea and 1 \u00d7 MOPS  buffer. RNA markers  were end labelled by http://code.google.com/p/cutadapt/). First, low-quality ends were trimmed by applying a quality score threshold of 20. In the applied trimming method, the threshold is subtracted from all quality scores and partial sums from all indices to the end of the sequence are then computed. Sequences are cut at the indices where the sums are minimal. Adaptors were then removed by matching the first (for 3\u2032 adaptors) and last (for 5\u2032 adaptors) 8 nt of the adaptor sequences while allowing 1 nt of mismatch maximum.Quality trimming and adaptor removal of the Illumina reads were carried out using Cutadapt (http://www.phrap.org/phredphrapconsed.html). The sequences aligned to the above databases with at least 10 matched nts and a minimum alignment score of 10 were excluded from further analysis. Sequences, shorter than 17nt and longer than 35 were also discarded.Sequences were then searched against ribosomal, transfer RNAs, snRNAs and snoRNAs from Rfam, the Arabidopsis tRNA databases and plant rRNA and tRNA sequences from EMBL using cross_match (http://potatogenomics.plantbiology.msu.edu/index.html) on all of the plausible positions using Bowtie with perfect matches (0 mismatches). Then the sequences that were mapped to multiple positions in the genome were filtered based on the maximum size of potato miRNA families. The threshold was set at 30 to recover small RNAs with relatively large family sizes. 4,006,195 flanking regions of the 3,113,450 filtered sequences were retrieved from the genome using a window of 250 bps. Then the secondary structures of the flanking sequences were predicted using RNAfold Click here for additional data file.Table S1Predicted known and new miRNAs in potato. The table shows the predicted miRNAs according to the family number (family #); the super-scaffold location (chromosome id); the direction of chromosome strand where the miRNA maps (strand direction); read and precursor identification number according to the analysis ; the homologue of miRNA (miRNA family); read number for miRNAs and star sequences ; the location of miRNA and precursor RNA on the super-scaffold  and the mature, precursor and star sequences. Total read numbers of each predicted miRNAs are indicated for the different tissues which were analysed. During the analysis DNA equivalent of RNA sequence was used.(XLSX)Click here for additional data file.Table S2Summary of conserved and potato specific miRNA families. The table shows the conserved miRNA families according to the family number corresponding to our analysis. The number of family members is indicated with mature miRNA and star sequences. The homologue of miRNA is shown (miRNA family) with the length of miRNA (miRNA length). For potato specific miRNAs the family number, numbers of miRNAs in the same family, mature and star sequences and miRNA length are indicated. During the analysis DNA equivalent of RNA sequence was used.(XLSX)Click here for additional data file.Table S3Predicted target RNAs of conserved and potato specific miRNAs. The table contains the miRNAs with the read number in the libraries (miRNA_Acc.), the homologue of miRNA (miRNA family) and the targeted potato transcripts (Target_Acc.) with the predicted gene functions (target gene function annotation). Expectation score (Expectation) and unpaired energy (UPE) with a low number suggest highly likely target for the miRNA. The aligned miRNA and target start and end nucleotide is indicated with the corresponding sequences. The inhibition type (Inhibition) and the number of target sites (multiplicity) are shown. On the second sheet of the table predicted targets could be found using more relaxed prediction criteria. During the analysis DNA equivalent of RNA sequence was used.(XLSX)Click here for additional data file.Table S4Predicted targets of miR172, miR482 and validated potato specific miRNAs. Details of miR172, miR482 and the validated miRNAs are shown in the table. The predicted target transcripts are below the miRNA data. For details see (XLSX)Click here for additional data file.Table S5Oligonucleotide sequences used in this study.(XLSX)Click here for additional data file."}
+{"text": "Studies have suggested that selective microbial targets prevail in the fecal microbiota of infants with eczema. This study aims to evaluate and compare the composition of fecal microbiota of infants who developed eczema by 2 years of age and healthy controls.Eubacterium rectale-Clostridium coccoides group (Erec482), Clostridium leptum subgroup (Clep866 and the corresponding competitor probes), Bacteroides-Prevotella group (Bac303), Bifidobacterium genus (Bif164), Atopobium group (Ato291), Lactobacilli- Enterococci group (Lab158), Enterobacteriaceae family (Enter1432) and Clostridium perfringens (Cperf191). Linear mixed model was used to evaluate the longitudinal differences (i.e. 4 time points) of bacterial targets while adjusting for gender, mode of delivery, feeding up to 6 months, and allergic rhinitis and wheezing within the eczema group at 2 years of age.Children with eczema at 2 years old (n=26) and their matched  healthy controls (n=26) were selected from the placebo group of a cohort of at-risk infants participating in an randomized double-blind placebo controlled trial on the protective effects of supplemental probiotics (first 6 months) on eczema and allergies. Children with eczema were subclassified into atopic eczema (n=12) and non-atopic eczema (n=14). Molecular evaluation of fecal microbiota were conducted using Fluorescence In Situ Hybridization-Flow Cytometry (FISH-FC) for fecal samples collected at 3 days, 1, 3, and 12 months. Probes were selected to target Clostridium perfringens were also higher when subanalyzed for non-atopic  and atopic eczema  compared to healthy controls.Longitudinal analyses over four time points showed that higher relative abundance of Enterobacteriaceae  in children with eczema by 2 years of age. Similar observations were made when eczema group was subanalyzed into non-atopic and atopic eczema, where higher relative abundance of Enterobacteriaceae  and  were observed respectively as compared to healthy controls. Relative abundance of Clostridium perfringens in the fecal microbiota of infants influence the development of eczema in early childhood.Our data suggests that relative abundance of selective microbial targets particularly Enterbacteriaceaea and"}
+{"text": "Arabidopsis, the onset of SCW deposition is initiated by a nexus of NAC, MYB, homeodomain and several other families of TFs, which function in a transcriptional network regulating SCW biosynthetic genes. NAC family members SND1/NST1 and VND6/VND7 have been identified as functionally redundant master regulators of SCW formation in fibres and vessels, respectively [Arabidopsis plants overexpressing SND2, an indirect target of fibre master regulator SND1, exhibited increased SCW thickness in inflorescence stem fibres, whilst dominant repression lines exhibited a decrease in fibre SCW thickness associated with a reduction in glucose and xylose cell wall sugar content [SND2 to transactivate the CesA8 promoter [SND2 may regulate cellulose biosynthetic genes during fibre SCW formation. The evaluation of this hypothesis necessitates the identification of all downstream genes potentially regulated by SND2, and the analysis of SCW chemistry and morphology in overexpression lines. The aim of this ongoing study is to further elucidate the role of SND2 in fibre SCW formation through microarray analysis of overexpression lines and by independent confirmation of the effect of SND2 overexpression on fibre SCW chemistry and morphology in Arabidopsis plants.Transcription factors (TFs) play important roles in the regulation of secondary cell wall (SCW) biosynthesis in herbaceous and woody plants. In ectively . Arabido content . The abipromoter  suggeste2x35S::SND2 Arabidopsis thaliana Col-0 plants, screened them for CesA8 upregulation and phenotypically assessed several homozygous (T4) transgenic lines. Inflorescence stem fibre SCW thickness was measured from light and scanning electron micrographs, and the cell wall monosaccharide and Klason lignin composition of stems was determined relative to the wild type. We performed microarray analysis of the inflorescence stem transcriptomes of wild type and transgenic Arabidopsis plants using the Agilent 4x44k transcriptome array and confirmed the expression profiles of differentially expressed genes with RT-qPCR.We generated Arabidopsis (T4) lines showed no significant external phenotype, and we were unable to reproduce the increased fibre SCW thickness phenotype reported by Zhong et al.[CesA8 upregulation and moderate SND2 overexpression. Whole-transcriptome analysis of the line revealed the upregulation of several TFs and genes associated with SCW biosynthesis, which were reproducibly upregulated in an independent trial. We additionally observed possible ectopic artifacts and gene dosage effects associated with excessive constitutive expression of the SND2 gene. Chemical analysis revealed only minor changes in SCW monosaccharides, despite the upregulation of SCW biosynthetic genes.Transgenic ng et al.. We idenSND2 in the regulation of cellulosic and non-cellulosic components of fibre cell walls, and we provide a model for the position of SND2 in the transcriptional network regulating fibre SCW formation.Our results implicate"}
+{"text": "The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis (OA). The expression of chromatin protein HMGB2 is restricted to the SZ, which contains cells expressing mesenchymal stem cell (MSC) markers . Aging-rHMGB2 was detected at higher levels in human MSC as compared to human articular chondrocytes and its expression declined during chondrogenic differentiation of MSC Figure . LentiviThese results demonstrate that HMGB2 expression is inversely correlated with the differentiation status of MSC and that HMGB2 suppresses chondrogenic differentiation. The aging-related loss of HMGB2 in articular cartilage may represent a mechanism responsible for the decline in adult cartilage stem cell populations."}
+{"text": "In darkness, the dicot seedlings produce an apical hook as result of differential cell division and extension at opposite sides of the hypocotyl. This hook protects the apical meristem from mechanical damage during seedling emergence from the soil. In darkness, gibberellins act via the DELLA-PIF (PHYTOCHROME INTERACTING FACTORs) pathway, and ethylene acts via the EIN3/EIL1 (ETHYLENE INSENSITIVE 3/EIN3 like 1)-HLS1 (HOOKLESS 1) pathway to control the asymmetric accumulation of auxin required for apical hook formation and maintenance. These core pathways form a network with multiple points of connection. Light perception by phytochromes and cryptochromes reduces the activity of PIFs and (COP1) CONSTITUTIVE PHOTOMORPHOGENIC 1\u2014both required for hook formation in darkness\u2014, lowers the levels of gibberellins, and triggers hook opening as a component of the switch between heterotrophic and photoautotrophic development. Apical hook opening is thus a suitable model to study the convergence of endogenous and exogenous signals on the control of cell division and cell growth. Arabidopsis thaliana), the formation of an apical hook structure and the presence of folded cotyledons. Light exposure initiates the transition between skoto- to photomorphogenesis  is perceived mainly  by phyA, phyB and cry1. phyA is important for the early steps of this transition, which is completed by phyA itself under dense canopies and by phyB and cry1 in open places  to the active (Pfr) form and part of these Pfr pools migrate to the nucleus  in Figure A. thaliana seedlings grown in darkness, the formation phase lasts approximately 26 h after germination while the maintenance phase, where the hypocotyl remains closed, lasts another 25 h  and the concave (inner) and convex (outer) sides across the hook    or 1-naphthoxyacetic acid (1-NOA) reduces hook formation  and GH3 (GRETCHEN HAGEN 3) gene families  and AUX/IAA (AUXIN/INDOL-3-ACETIC ACID) proteins  gene encodes a N-acetyltransferase that is required for apical hook formation. The hls1 mutant fails to form the apical hook due to defects in both differential cell elongation and cell division    and PIF4 see Box , interfeSo, gibberellins are crucial for apical hook formation. Gibberellins are needed to maintain DELLA levels reduced and thus PIF and EIN3/EIL1 transcription factors are available to increase WAG2 and HLS1 which regulate asymmetric auxin accumulation.ethylene overproducer mutants    confer ethylene insensitivity and lack of an apical hook, while loss-of-function mutations  cause hypersensitivity to ethylene and exaggerated hooks after ethylene treatment , ERS1, ERS2 (ETHYLENE RESPONSE SENSOR 1 AND 2) and EIN4 (ETHYLENE INSENSITIVE 4) receptors , the enzyme that catalyzes the first limiting step in tryptophan synthesis  are higher in the inner than in the outer side  lack an apical hook in darkness  reporter gene which is involved in brassinolide synthesis, shows induced expression of the reporter gene by ethylene in apical hooks. Also, dark-grown det2 mutant seedlings treated with exogenous ethylene are not able to induce an exaggerated hook suggesting ethylene action requires brassinosteroids  that is deficient in the perception of brassinosteroids but have activated downstream brassinosteroids responses due to a dominant mutation that stabilizes BZR1, forms and apical hook similar to that of the WT  that phosphorylates ARF2 and reduces its activity, leading to the enhanced expression of auxin responsive genes  and phyB   . Since BBX23 is a repressor of photomorphogenesis required for hook maintenance in darkness, down-regulation of its expression enhances hook opening , which attenuates late hook opening possibly as part of a mechanism that avoids an exaggerated response of hook opening to light stimulus once seedlings are de-etiolated  show impaired hook opening under far-red light, but hfr1 (long hypocotyl in far-red) and laf1 (long after far-red light) mutants are affected in hypocotyl elongation but not in hook opening under far-red light  see Box . BBX23 iHY5 gene induces the expression of gibberellins-2-oxidase, the major gibberellin catabolic enzyme in plants, resulting in negatively regulation of gibberellin pathways (Weller et al., cop1 mutant of several species (Alabad\u00ed et al., Light decreases the level of gibberellins in Arabidopsis (Ait-Ali et al., In the hooks, light also affects the expression and localization of the auxin transporter ABCB19. ABCB19 localizes to the inner side of etiolated hooks but its presence fades away during hook opening under blue light (Wu et al., In summary, COP1 and PIFs are direct key targets of light signaling to control hook opening. PIFs operate downstream of gibberellins and affect auxin transport and ethylene synthesis. EIN3/EIL1 are indirect targets of light signaling, through the PIFs and DELLA pathways, operate downstream gibberellins and ethylene and affect auxin transport, synthesis and signaling. The connections between COP1 and the hormonal network that underlies the formation of the hook in darkness are not firmly established.The coordinated actions of gibberellins, ethylene and brassinosteroids control asymmetric auxin distribution to allow the correct development of the hook in darkness. This control occurs at multiple levels, including synthesis, distribution by the action of specific transporters and abundance of transcription factors involved in the control of auxin-responsive genes. PIFs and EIN3/EIL1 are key connectors of gibberellins and ethylene pathways with auxin signaling in the hooks. The repressors of photomorphogenesis PIFs and COP1 are indispensable for hook development in darkness and the activation of phytochromes and cryptochromes by light negatively regulates the activity of PIFs and COP1, leading to the opening of the hook.Considerable progress has been made in recent years in the elucidation of the signaling network that controls apical hook formation in darkness; however there still are several gaps concerning how light-regulated proteins modulate hook formation and triggers hook opening. Learning the dynamics of the hormonal networks in response to light is a challenge for future research.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A number of neurological disorders (i.e. Schizophrenia and Parkinson's disease) that result from dysfunction of striatal signal transduction pathways underline the importance of the striatum for motor function and procedural learning. Most striatal neurons are medium spiny neurons (MSN) that receive input via dopaminergic and glutamatergic terminals and project to the basal ganglia. The MSN express dopamine receptors that are either positively (D1) or negatively (D2) coupled to adenylyl cyclase therefore dopamine directly influences intracellular levels of cAMP. Participants in cAMP mediated signalling pathways are often organized in multiprotein complexes around A-kinase anchoring proteins (AKAPs). The proximity of the cyclases and phosphodiesterases (PDEs) as well as protein kinase A ensures fine tuning of cAMP levels in a given compartment and allows for selective regulation of target proteins such as NMDA or AMPA receptors by phosphorylation.2+ concentrations.According to our results PDE10 is highly expressed in striatum and responsible for 70% of cAMP degrading activity. Therefore we asked if PDE10 participates in signalling complexes at the synapse. Indeed, the immunoprecipitation via PDE10 specific antibodies revealed interactions with AKAP150 and AKAP-interacting proteins as well as subunits of the NMDA-receptor and PSD95. In the isolated complex and in striatal slices, PDE10 can be phosphorylated by activation of PKA. This phosphorylation is short lived, probably because it is reversed by permanently active protein phosphatase 1. We observed that dephosphorylation is additionally accelerated via NMDA dependent rise in intracellular Ca"}
+{"text": "This study aimed to investigate differences between the motor skills and sensory processing abilities of children between the ages of four and eight years with and without an idiopathic toe walking (ITW) gait.Children in each cohort were tested with the following norm referenced assessments:1. Bruininks-Oseretsky Test of Motor Proficiency 2nd edition (BOT-2)2. The Sensory Profile (SP)3. Six subtests of the Sensory Integration and Praxis Tests (SIPT)4. Vibration Perception Threshold (VPT)Sixty children participated in the study, 30 within each cohort. Those with an ITW gait were found to have different SP quadrant scores (p=0.002), poorer performance on the BOT-2 (p=<.001), a lower VPT (p=.001) and poorer performance on the Standing Walking Balance subtest of the SIPT (p=0.047) compared with peers.While the results did not identify a causative factor for an ITW gait, they do suggest that the toe walking gait may not be idiopathic in nature. The results of this research highlight the importance of a fuller assessment of the toe walking child compared to that traditionally conducted by podiatrists, and suggest that multiple strategies may be required to manage this gait style."}
+{"text": "Meles meles) culling as a control strategy. Our study complements previous analyses of the RBCT data (focusing on treatment effects) by presenting analyses of herd-level risks factors associated with the probability of a confirmed bTB breakdown in herds within each treatment: repeated widespread proactive culling, localized reactive culling and no culling (survey-only).The control of bovine tuberculosis (bTB) remains a priority on the public health agenda in Great Britain, after launching in 1998 the Randomised Badger Culling Trial (RBCT) to evaluate the effectiveness of badger (M. bovis positive badgers initially culled within 1500 m of a farm was the strongest predictor of the risk of a confirmed bTB breakdown.New cases of bTB breakdowns were monitored inside the RBCT areas from the end of the first proactive badger cull to one year after the last proactive cull. The risk of a herd bTB breakdown was modeled using logistic regression and proportional hazard models adjusting for local farm-level risk factors. Inside survey-only and reactive areas, increased numbers of active badger setts and cattle herds within 1500 m of a farm were associated with an increased bTB risk. Inside proactive areas, the number of The use of herd-based models provide insights into how local cattle and badger populations affect the bTB breakdown risks of individual cattle herds in the absence of and in the presence of badger culling. These measures of local bTB risks could be integrated into a risk-based herd testing programme to improve the targeting of interventions aimed at reducing the risks of bTB transmission. Mycobacterium bovisM. bovis to human health is low in most developed countries, the main causes of concern related to M. bovis in industrialized countries are epizootics in domesticated and wild mammal populations M. bovis remains a significant livestock zoonosis in the European Union where some member states experience a reemergence of the disease despite significant historical efforts to implement eradication plans. In Great Britain, the disease was eliminated from most cattle herds by 1960, with the exception of infection hotspots in southwest England, after the implementation of a herd testing and slaughter policy M. bovis in wildlife host populations, acting as reservoirs of infection, in particular badgers (Meles meles) Bovine tuberculosis (bTB) remains an important public health concern worldwide as a result of deficiencies in preventing and/or controlling measures targeting the spread of its causative agent M. bovisM. bovis than younger ones Risk factors associated with bTB have been investigated in case-control studies in Europe and the USA M. bovis can infect a wide range of wild animals Trichosurus vulpecula) are the primary wildlife reservoir of bovine bTB in New Zealand Odocoileus virginianus) in Michigan Bison bison athabascae) Syncerus caffer) in Southern Africa Sus scrofa) in Southern Europe M. bovis. The Randomised Badger Culling Trial (RBCT) was launched in 1998 to evaluate the effectiveness of badger culling as a control strategy for bTB in Britain 2) trial areas recruited as matched sets of three, known as \u201ctriplets\u201d. Detailed field surveys in all trial areas for which consent was obtained  to identify the most important bTB breakdown risk factors for herds within the RBCT areas.M. bovis) from \u201cunconfirmed breakdowns\u201d (incidents in which one or more cattle reacted to the tuberculin test but infection was not confirmed at postmortem or by culture). Herds with the same County Parish Holding Herd numbers (CPHH: unique herd identifier) which were registered in different treatment groups (n\u200a=\u200a14); herds which were archived before the start of the RBCT (n\u200a=\u200a22) and herds which showed no evidence of having had a bTB disclosing test during the RBCT (n\u200a=\u200a745) were removed from the VETNET records; leaving us with 1306 unique herds recorded in RBCT proactive areas, 1380 unique herds recorded in RBCT survey-only areas and 1320 unique herds recorded in RBCT reactive areas.The Defra animal health information system (VETNET) provided data on cattle bTB tests and herd breakdowns, distinguishing between \u201cconfirmed breakdowns\u201d .On the basis of details recorded in the RBCT database, farms were categorized into one of three enterprise types: beef, dairy and other . The median herd size was 72 animals  . The hisM. bovis positive (+) badgers culled, the number/density of active badger setts and the number/density of neighbouring cattle herds within 500, 1000 and 1500 m of all the land parcels belonging to a farm were extracted from the RBCT geodatabase   (to be) in a better position to tackle the disease\u201d Supporting Information S1Univariable models and alternative multivariable models of herd-level bTB risk.(DOC)Click here for additional data file."}
+{"text": "Irritant-induced occupational asthma suspected to occur within few hours of exposure to high concentration of gas, fume or vapour at work in oil refinery establishmen lacking safety measures. There was a relationship between asthmatic and bacterial agents causing respiratory infections.The quatitative estimation of immunoglobulin E in serum of the patient was based on solid phase enzyme-linked immunosorbent assay (ELISA).37% (74/200) of refinery patients and 19.5% (39/200) of nonrefinery hospitalized patients who had a total IgE level up to 100 IU/ml or more were considered as allergic. It was noticed that IgE level among refinery allergic patients ranged between 201-728 and 106-3266 IU/ml of refinery and nonrefinary hospitalized patients respectively.The highest incidence of allergy was recorded among refinery patients. The present study revealed that the percentages of 80 and 42 pathogenic strains were isolated from 74 and 39 allergic patients with respiratory infections from refinery and nonrefinery hospitalized patients respectively. The high incidence of asthma and respiratory infections in the oil refinery plant could be due observed lacking of safety measures."}
+{"text": "Hyperactivity of the type I interferon (IFN) pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). Immunoglobulin-like transcript (ILT3) is an immunohibitory transmembrane molecule that is induced by type I IFNs. ILT3 is expressed by plasmacytoid dendritic cells (PDCs), monocytoid dendritic cells (MDCs), and monocytes/macrophages. Given the pathogenic role of IFN in SLE, we hypothesized that the IFN-induced immunosuppressive ILT3 receptor may be dysfunctional in human SLE.In total, 132 European-derived and 79 Hispanic-American SLE patients were genotyped for two coding-change SNPs predicted to interfere with protein folding in ILT3 (rs11540761 and rs1048801). One hundred and sixteen control DNA samples and sera from healthy controls were also studied. We detected associations between ILT3 genotype and serum cytokine profiles. ILT3 expression levels on PDCs and MDCs from 18 patients and 10 controls were studied by flow cytometry.The rs11540761 SNP in the extracellular region was associated with decreased cell surface expression of ILT3 on circulating MDCs and to a lesser extent PDCs in SLE patients. The cytoplasmically located rs1048801 SNP was not associated with a change in DC expression of ILT3. Both SNPs were significantly and independently associated with increased levels of serum type I IFN activity in SLE patients. The rs1048801 SNP was also associated with increased serum levels of TNF\u03b1.Loss-of-function polymorphisms in ILT3 are associated with increased inflammatory cytokine levels in SLE, supporting a biological role for ILT3 in SLE."}
+{"text": "Staphylococcus aureus clonal complex (CC) 398. Further typing in comparison with animal isolates identified 4 clusters: 1 related to a horse epidemic and 3 to persons who had no direct contact with animals or each other. These findings may indicate unrecognized community transmission.Nationwide surveillance identified 10 human isolates of methicillin-resistant  Staphylococcus aureus (MRSA). The MRSA lineage clonal complex (CC) 398 has been reported to be common among pigs  by PCR   related to the horse epidemic; 3 human isolates  from 2 hospital districts (A and B); 5 human isolates  from 1 hospital district (C); and 7 isolates  from pigs  respectively, and there are differences in screening policies. In the Netherlands, people in close contact with pigs or cattle are screened at hospital admission. It remains to be investigated whether the low occurrence of CC398 and lack of direct animal contacts among CC398 case-patients are related to lower occurrence of MRSA in animals, sparse pig and human populations, or screening policies in Finland.The proportion of CC398 of all MRSA in humans was far lower in Finland (0.09%) than in the Netherlands (30% in 2007) . In addition, the presence of 2 different SCCmec types among t011 and nonexistent links in time and space between human cases may suggest unrecognized transmission chains in the community.Except for the isolates from the horse epidemic, human and animal isolates were distinguished from each other by using a combination of molecular typing techniques. Additional typing by the Open reading frames of African swine fever virus."}
+{"text": "This novel virus is related to arenaviruses that cause hemorrhagic fever. Peromyscus mexicanus) captured near the site of a 1967 epidemic of hemorrhagic fever in southern Mexico. Analyses of nucleotide and amino acid sequence data indicated that the deer mice were infected with a novel Tacaribe serocomplex virus (proposed name Ocozocoautla de Espinosa virus), which is phylogenetically closely related to Tacaribe serocomplex viruses that cause hemorrhagic fever in humans in South America.Arenavirus RNA was isolated from Mexican deer mice ( Arenaviridae, genus Arenavirus) comprise Bear Canyon virus, Tamiami virus, and Whitewater Arroyo virus in the United States; Tacaribe virus (TCRV) on Trinidad; Chapar\u00e9 virus (CHPV) and Machupo virus (MACV) in Bolivia; Guanarito virus (GTOV) in Venezuela; Jun\u00edn virus (JUNV) in Argentina; Sabi\u00e1 virus (SABV) in Brazil; and 9 other species  in western Venezuela is the principal host of GTOV  in central Argentina is the principal host of JUNV  cause hemorrhagic fever in humans  and 0 of 29 other cricetid rodents captured in the municipality of Ocozocoautla de Espinosa, State of Chiapas, Mexico (P. mexicanus deer mice in western Chiapas.A recently published study reported antibody against a Tacaribe serocomplex virus in 3 (25.0%) of 12 Mexican deer mice (Baiomys musculus), and 11 Jaliscan cotton rats (Sigmodon mascotensis) were tested for arenavirus by cultivation in monolayers of Vero E6 cells  and 38 antibody-negative rodents were captured on July 16, 2000, at a locality  in the municipality of Ocozocoautla de Espinosa  and 19C-cons and either AVNP42 (5\u2032-GCCGCGGACTGGGAGGGCA-3\u2032) or AVNP122 (5\u2032-GCCGCGGACTGGGGAGGCACTG-3\u2032). The second-round (heminested) PCR used MasterTaq Kit and either AVNP42 and oligont 1010C  protein gene RNA. First-strand cDNA was synthesized by using SuperScript III Reverse Transcriptase  and oligont 19C-cons (p) distances.Analyses of GPC sequences, N protein sequences, and nucleotide sequences included AV B1030026, 8 other viruses from North America, and 15 viruses from South America . Sequenc>0.95 were considered supported by the data  was 96.4% identical to the nucleotide sequence of the homologous region of the N protein gene of AV B1030026.Bayesian analyses of complete GPC gene sequences , panel ANonidentities between amino acid sequences of the GPC and N protein of AV B1030026 and amino acid sequences of homologous sequences of the 8 other viruses from North America ranged from 47.8% to 52.1% and from 44.3% to 45.4%, respectively. Similarly, nonidentities between the amino acid sequences of the GPC and N protein of AV B1030026 and homologous sequences of the 8 other members of group B ranged from 24.7% to 46.8% and from 16.1% to 32.3%, respectively . NonidenArenaviridae, genus Arenavirus  in the family The hallmark of the arenaviruses is their ability to establish chronic infections in their respective principal hosts. The failure to isolate arenavirus from Mexican deer mice in this study could be caused by small sample size or poor specimen quality. Alternatively, a cricetid rodent other than the Mexican deer mouse is the principal host of Ocozocoautla de Espinosa virus (OCEV).Members of the rodent family Cricetidae, subfamily Sigmodontinae (Baiomys taylori) captured in Texas and northern Mexico (The presence of OCEV in Mexico suggests that the last common ancestor of the 9 viruses in group B  emerged P. mexicanus deer mouse is a relatively common species in forests of southern Mexico (The history of the State of Chiapas includes an outbreak of a highly lethal hemorrhagic fever in 1967 (It is generally accepted that humans usually become infected with arenaviruses by inhalation of virus in aerosolized droplets of secretions or excretions from infected rodents. Another source of infection may be ingestion of infected rodents (Human consumption of wild rodents is common in rural areas in some regions of Mexico. For example, Mexican deer mice and other cricetid rodents are consumed by the Tzeltal Indians in the highlands of Chiapas ("}
+{"text": "Hepatitis C virus (HCV) infection is the second viral cause for chronic liver disease (CLD) in the world and nearly 170 million people are infected worldwide . The hisIn 2006, we started a project for control of hepatitis C infection in dialysis patients . Iran He"}
+{"text": "Paracoccus (Alphaproteobacteria). Complex analysis of 25 strains representing 20 species of this genus led to the capture and characterization of (i) 37 insertion sequences (ISs) representing 9 IS families , (ii) a composite transposon Tn6097 generated by two copies of the ISPfe2 (IS1634 family) containing two predicted genetic modules, involved in the arginine deiminase pathway and daunorubicin/doxorubicin resistance, (iii) 3 non-composite transposons of the Tn3 family, including Tn5393 carrying streptomycin resistance and (iv) a transposable genomic island TnPpa1 (45 kb). Some of the elements  were shown to contain strong promoters able to drive transcription of genes placed downstream of the target site of transposition. Through the application of trap plasmid pCM132TC, containing a promoterless tetracycline resistance reporter gene, we identified five ways in which transposition can supply promoters to transcriptionally silent genes. Besides highlighting the diversity and specific features of several TEs, the analyses performed in this study have provided novel and interesting information on (i) the dynamics of the process of transposition  and (ii) structural changes in DNA mediated by transposition (e.g. the generation of large deletions in the recipient molecule upon transposition of ISPve1 of the IS21 family). We also demonstrated the great potential of TEs and transposition in the generation of diverse phenotypes as well as in the natural amplification and dissemination of genetic information  by horizontal gene transfer, which is considered the driving force of bacterial evolution.Several trap plasmids (enabling positive selection of transposition events) were used to identify a pool of functional transposable elements (TEs) residing in bacteria of the genus  Transposable elements (TEs) are components of nearly all prokaryotic genomes. They are mobilized to change their location in DNA by the action of a transposase (TPase), an enzyme which catalyses transposition, i.e. recombination that does not require sequence homology between the TE and the target site. The presence and activity of TEs may lead to structural changes in both the size and composition of a genome. TEs can generate (i) various mutations, such as insertions, deletions, duplications, inversions and translocations of even large DNA fragments, and (ii) replicon fusions The simplest TEs are insertion sequences (ISs), which are highly abundant in bacteria. They carry only genetic information that is necessary and sufficient for transposition and its regulation. The majority of ISs are composed of a single open reading frame (ORF), encoding a transposase, flanked by two inverted repeat sequences (IRs) that are recognized by the TPase during transposition. In most cases, the transposition of ISs causes duplication of the target site, so that the inserted element is bordered by two short (2\u201315 bp) identical direct repeat sequences (DRs) Bacillus cereusISs are also able to form more complex TEs such as (i) composite transposons consisting of random segments of genomic DNA (core region) bordered by a pair of ISs, or (ii) transposable modules (TMos) and ISCR elements composed of one IS copy, which can mobilize an adjacent DNA segment for transposition 3 and Tn7 families. Besides a transposase, the Tn3 elements contain a site-specific recombination module encoding a resolvase , while the Tn7 elements are known for their complex transposition machinery (they encode five transposition proteins) There is another widely distributed group of TEs called the non-composite transposons, which is divided into the TnLarge-scale genome sequencing projects have led to an explosion in the number of annotated prokaryotic and eukaryotic TEs . This genus currently comprises 31 species, which have been isolated from many geographical locations and from different environments. Paracoccus spp. are physiologically among the most versatile bacteria, and are able to perform a number of different growth modes. Many are aerobic chemoorganoheterotrophs utilizing a wide variety of organic compounds, including potential pollutants like acetone, N,N-dimethylformamide and methylamine Paracoccus spp. are facultative chemolithoautotrophs utilizing reduced sulfur compounds, molecular hydrogen and Fe(II) as energy sources In 2009 we initiated a project aimed at identifying functional transposable elements harbored by bacteria belonging to the genus Paracoccus spp., it is tempting to speculate that their physiological heterogeneity might result from various transposition events.Although there is no direct evidence linking the presence of TEs with important phenotypic traits of Paracoccus species were analyzed. For the identification of functional TEs we used trap plasmids, which are convenient tools enabling the direct identification of even phenotypically silent elements (reviewed by Solyga and Bartosik) P. pantotrophusP. solventivoransP. marcusiiP. methylutensPme2, ISPpa2, ISPpa3, ISPpa4, ISPso2, ISPso3 (IS5 family), ISPpa5 (IS66 family), ISPpa1, ISPso1 (IS256 family) and IS1247a, ISPme1 (IS1380 family), ISPmar4 (ISAs1 family) 3 family \u2013 cryptic Tn3434 and streptomycin resistant Tn5393Ppa1, whose transposition is mediated by two copies of Tn34341380-family element and adjacent fragments of genomic DNA of various lengths Paracoccus spp. strains. We also analyzed the structure, frequency of transposition, specific features and distribution of the captured TEs, which allowed us to draw more general conclusions concerning their evolutionary impact, as well as the direction and frequency of horizontal gene transfer in this group of bacteria.In this study, TEs residing in strains representing 20 r) derivatives of the wild-type strains of Paracoccus spp. (listed in Escherichia coli TG1 Paracoccus spp.) or 37\u00b0C (E. coli). P. homiensis DSM 17862 was cultivated in Marine Broth (Difco). Where necessary, the medium was supplemented with sucrose (10%) and with antibiotics at the following concentrations (\u00b5g\u00b7ml\u22121): kanamycin, 50; rifampicin, 50; tetracycline, 0.3\u201335 (depending on the strain).For identification of transposable elements rifampicin-resistant  a silent tetracycline resistance gene tetA under the control of the bacteriophage lambda pR promoter, and (ii) the gene encoding the lambda cI repressor. Inactivation of the repressor gene (e.g. through insertion of an IS), results in constitutive expression of tetracycline resistance r version pEBB10, contains the sacB gene of Bacillus subtilis, coding for levan sucrase \u2013 an enzyme that catalyzes sucrose hydrolysis and levan extension. The products of this reaction are toxic for gram-negative bacteria. Therefore, cells carrying the functional sacB gene are sucrose sensitive (Sucs) and their cultivation in medium containing sucrose results in cell lysis sacB mutants (Sucr) (e.g. carrying inserted TEs), whose growth is not affected under these conditions, thus enabling positive selection of transposition mutants. The BHR trap plasmid pCM132TC, contains a promoterless tetracycline resistance gene tetA. In this case, the transposition of TEs containing strong promoters upstream of the tetA gene can initiate its expression, resulting in tetracycline resistance in cells carrying such mutated plasmids Ppa1 were (i) pBBR1MCS-3 oriV of pMAR4 of P. marcusii DSM 11574; oriT RK2; Kmr), (iii) pDIY703 oriV RA3; oriT of RK2; Kmr), (v) pMAO-MS  oriV RA3; oriT of pIGRK of K. pneumoniae 287-w; Kmr) For the identification of TEs, the following trap plasmids were used: pMEC1 Paracoccus spp. strains by triparental mating as previously described E. coli cells was performed according to the method of Kushner DNA was introduced into Paracoccus spp. was isolated by the procedure described by Chen and Kuo Plasmid DNA was isolated using a standard alkaline lysis procedure r strains of Paracoccus spp. The overnight cultures of the transconjugants were spread on plates with solidified LB medium supplemented with tetracycline  or sucrose (pMAT1 or pEBB10). Appropriate dilutions of the cultures were also spread on LB medium in order to determine the frequency of transposition. For each strain, the plasmids of at least 100 Tcr or Sucr clones were analyzed. Three classes of plasmids were distinguished carrying (i) potential insertion sequences (inserts <3 kb), (ii) putative transposons (inserts >3 kb) or (iii) point mutations (replicons of the same size as the trap plasmid). The insertion sites of the elements were localized by performing PCRs with the trap plasmid insertion derivatives (as template DNA) and previously described sets of cassette-specific primers Trap plasmids were introduced into the RifParacoccus ferrooxidans NCCB 1300066 digested with restriction endonucleases NcoI or XhoI. The digested DNA preparations, purified using a Clean Up kit (A&A Biotechnology), were then self-ligated overnight at 16\u00b0C with T4 DNA ligase (Fermentas). The ligation mixture was used as the template for amplification by PCR of the DNA flanking Tn6097 in the host genome. The synthetic oligonucleotides used in PCR were LIPCRPF2 and RIPCRPFE (Templates for inverse PCR (IPCR) were prepared from total DNA of RIPCRPFE .Dot blot analysis was performed using a Bio-Dot apparatus (Bio-Rad) according the manufacturer's instructions. To determine copy number of TEs in parental strains Southern blotting was carried out as described by Sambrook and Russell tetA gene in this vector) were analyzed to localize the TE-derived promoters. Deletion analysis was performed for two of the analyzed elements (Tn5393 and Tn6097), by removal of different parts of the inserted TE by digestion with appropriate restriction enzymes, followed by religation and characterization of the resistance phenotype. The constructed mutants contained different parts of the 3\u2032-end of the transposon, adjacent to the promoterless tetA gene. For the insertion sequences ISPam1, ISPkr1 and ISPaes3, PCR was applied to amplify (i) the terminal 3\u2032-end DNA fragments of the elements  and (ii) analogous fragments with an attached short DNA region of the trap plasmid, adjacent to the target site of transposition (identification of possible hybrid promoters). The amplified DNA fragments were cloned into pCM132TC (Tcs) upstream of the promoterless tetA gene or into pCM132 upstream of promoter-less lacZ reporter gene. The presence of a promoter (tested in Paracoccus spp. hosts) resulted in a Tcr phenotype (pCM132TC) or expression of \u03b2-galactosidase (pCM132). \u03b2-galactosidase activity was measured as previously described A pool of derivatives of the trap plasmid pCM132TC (containing inserted TEs able to drive transcription of a promoterless http://www.ncbi.nlm.nih.gov/). G+C plots were created using the program Artemis 6097 and Tn6122 was assigned by the Tn Number Registry website  according to the generally accepted nomenclature Nucleotide sequences of TEs were determined using a dye terminator sequencing kit and an automatic sequencer (ABI 377 Perkin Elmer). A combination of vector-derived primers and primer walking was used to obtain the entire nucleotide sequences. Similarity searches were performed using the ISfinder The nucleotide sequences of the elements identified in this study have been submitted to the ISfinder and GenBank databases. Accession numbers of the sequences are given in Paracoccus spp. we used mobilizable trap plasmids pMEC1, pMMB2, pMAT1, pEBB10 and pCM132TC carrying three types of cassette enabling positive selection of transposition events (see cI-tetA or sacB cassettes) enable the capture of all types of TEs, irrespective of their structure, specific features and genetic load. In contrast, pCM132TC only permits the identification of elements containing strong outwardly oriented promoters or those able to generate hybrid promoters, which drive the transcription of nearby genes.To identify functional TEs of ents see . The plaParacoccus spp. and pools of clones carrying mutated plasmids were obtained and analyzed as described in 3 family .The trap plasmids were introduced by conjugation into 25 strains of 3 family  and 2. TThe nucleotide sequences of the captured ISs were subjected to detailed analysis. All contained a transposase gene(s) and terminally placed inverted repeat sequences (IRs). Moreover, all were able to generate DRs at the target site of transposition . Since tParacoccus spp. ISs identified in this study. Analogous analysis was also used to compare the nucleotide sequences of the terminal IRs of the ISs , which contain three conserved residues (two aspartate and one glutamate) constituting the DDE motif , that is highly conserved in the majority of bacterial TPases  the ISs .1248f, ISPko1a, ISPpa3a, ISPpa5a and ISPve1a. In only four cases we found completely identical elements residing in different bacterial strains \u2013 ISPpa2, IS1247, IS1248 and ISPpa8. The identified ISs and their characteristics are presented in Preliminary analysis revealed that the vast majority (32) of the identified ISs were novel elements. In five cases, we captured ISs that were highly related to known elements  \u2013 ISParacoccus spp. could be classified into the following families: (i) IS3 family (IS407 group) \u2013 4 captured elements, (ii) IS5 family  \u2013 22 elements, (iii) IS6 family \u2013 2, (iv) IS21 family \u2013 3, (v) IS66 family \u2013 2, (vi) IS256 family \u2013 1, (vii) IS1182 family \u2013 1, (viii) IS1380 family \u2013 1, and (ix) IS1634 family \u2013 1.Based on the results of these comparative analyses, the ISs of 407 group of the IS3 family and IS427 group of the IS5 family) carry two overlapping ORFs and possess a conserved frameshift motif (1 of E. coli) 1 and IS3 families As shown in ft motif , which i427 group of the IS5 family  is a natural point mutant, because, in contrast to other elements of this group, it carries a single large ORF encoding a functional DDE transposase.Interestingly, we found that one of the members of the IS21 and IS66 families  besides the transposase gene(s). In most cases, the specific role of the predicted proteins encoded by these ORFs is unknown, although it is highly probable that they are involved in the regulation of the process of transposition. Such multi-ORF structures are typical for members of the ISfamilies .427 group of the IS5 family (8 ISs) contain, within their left IR , a sequence partially matching the consensus sequence of the integration host factor (IHF) binding site (5\u2032- WATCAANNNNTTR -3\u2032) 10427 group.We also performed a detailed inspection of the nucleotide sequences of the captured ISs in order to predict any DNA sequences that may constitute a site of interaction with host-encoded factors. This analysis revealed that the majority of the elements of the IS6097 , which was captured in P. ferrooxidans NCCB 1300066 using the trap plasmid pCM132TC. A summary of the predicted ORFs of Tn6097, including their position, the size of the encoded proteins, and their closest homologs is presented in The only composite transposon identified in this study was a novel element, designated Tn6097 into the selective cassette of pCM132TC generated 6-bp DRs. This transposon contains two identical, convergently oriented copies of ISPfe2 (1884 bp), that are responsible for its mobility  (Betaproteobacteria), share 51% aa sequence identity.Transposition of Tnmobility . Using tPfe2 flank the large core region of Tn6097, comprised of 13,991 bp. The average G+C content of this region is 63.6 mol%, which is lower than that of the total DNA of the native host P. ferrooxidans NCCB 1300066 (67 mol%). The core region contains 12 ORFs whose putative products show similarity to proteins conserved in many bacteria, including some involved in the metabolism of nitrogen compounds and resistance to chemotherapeutics. Based on the predicted functions of the ORFs, they may be divided into three clusters, which can also be differentiated by the G+C content of their nucleotide sequences (data not shown).The two copies of ISP. pantotrophus5-formyltetrahydrofolate and ATP into 5,10-methenyltetrahydrofolate, ADP and phosphate, which results in the creation of carbon-nitrogen bonds due to the cyclo-ligase activity The first cluster contains four ORFs (ORF2-ORF5)  encoding6097 contains four ORFs (ORF6-ORF9)  arginine/ornithine antiporter (ArcD), (ii) arginine deiminase (ArcA), (iii) ornithine carbamoyltransferase (ArcB) and (iv) carbamate kinase (ArcC), respectively. The arcABCD operon of Tn6097 exhibit the highest nucleotide sequence similarity (76%) and synteny to homologous genes in plasmid pOANT03 of Ochrobactrum anthropi ATCC 49188 (accession no. NC_009671).The second cluster of TnF6-ORF9)  with sig6097 consists of three ORFs (ORF10-ORF12)  adjacent to the right-hand copy of ISPfe2, which encodes a putative NAD-dependent epimerase/dehydratase that is most similar (85% aa identity) to a protein of P. denitrificans PD1222 (The third putative genetic module of Tn0-ORF12)  encodings PD1222 .6097 is present in one copy in the P. ferrooxidans NCCB 1300066 genome (data not shown). Using inverse PCR (IPCR) we determined the nucleotide sequence of its original target site in the host genome (see 6097 is located within a gene (disrupted upon transposition), whose predicted product shows similarity to a number of bacterial proteases. The highest identity (67%) was observed with a htpX gene of Polymorphum gilvum SL003B-26A1 (accession no YP_004302375). The transposon was flanked by 6-bp long DRs (5\u2032-GGCTCG-3\u2032), confirming that it had been incorporated into the host genome by means of transposition.DNA hybridization analysis revealed that Tn3 family of transposons. Two of the identified transposons (Tn6122 and Tn3434a) were identified as cryptic elements, solely encoding genetic information required for transposition  was the presence of two putative genetic modules (responsible for transposition and resolution of cointegrates resulting from replicative transposition), which are highly conserved in members of the Tnposition .6122 (3792 bp) was captured in P. halophilus JCM 14014 using the trap plasmid pMEC1. This element is composed of (i) identical 39-bp IRs, (ii\u2013iii) two divergently oriented ORFs encoding a large transposase protein  and a resolvase (TnpR) as well as (iv) an AT-rich putative recombination site (res) separating the ORFs (this region is involved in cointegrate resolution and regulation of expression of the tnpA and tnpR genes) Alphaproteobacteria: (i) Sulfitobacter sp. NAS-14.1, (ii) Ruegeria sp. PR1b and (iii) Roseovarius sp. TM1035. These transposons encode highly related transposases and resolvases, and are bordered by IRs identical to those of Tn6122 (data not shown).Tn3434a (3695 bp), identified using pEBB10 in P. aminophilus JCM 7686, is an isoform of the transposon Tn3434, that we trapped previously in P. pantotrophus DSM 11072 3434 (36 mismatches). The resolvases encoded by these elements are 100% identical, while their transposases differ in 30 aa (data not shown).The second trapped cryptic transposon, Tn3434a is also related to Tn6122. As shown in TnP. pantotrophus LMD 82.5 contains a non-composite transposon Tn5393, which is another member of the Tn3 family 3434a and Tn6122, carries two streptomycin resistance genes (strA and strB) placed downstream of the tnpR gene  and their sequence identity is only 50% (14 mismatches). In contrast, the IRs of Tn5393 are much longer (81 bp with 4 mismatches between IRL and IRR), but their termini show significant similarity to those of Tn3434a, Tn6122 and other members of the Tn3 family , which was previously identified in this strain During analysis carried out in Analyses performed using trap plasmids not only enabled the capture of many functional TEs but also identified specific features of several elements, including their ability to (i) activate transcriptionally silent genes, (ii) generate deletions within the target sites of transposition and (iii) transpose at unusually high frequency.903 group of the IS5 family (ISPam1 and ISPpa8), (ii) the IS407 group of the IS3 family (ISPam3 and ISPfe1), (iii) the IS21 family  and (iv) the IS256 family (ISPaes3). We also captured two transposons: (i) Tn5393 of the Tn3 family and (ii) the novel composite transposon Tn6097 bordered by two copies of ISPfe2 (IS1634 family).Using the trap plasmid pCM132TC (contains a promoterless tetracycline resistance gene as the selection cassette) we identified several TEs that are able to drive the transcription of promoterless genes placed downstream of the target site of transposition. The majority of the elements identified in this way were insertion sequences from four different groups: (i) the ISr clones, as described in 5 (IS903 group), IS3 (IS407 group) and IS21 families (256 member) (5393 of the Tn3 family)  a  member) , (iii) t family) , or (iv)y)  which naturally occurs in strain DSM 11073.An unexpected phenomenon was observed upon selection of TctetA gene). The inserted trap plasmid was bordered by two copies of the insertion sequence IS1248 (IS427 group of the IS5 family), which strongly suggests that co-integrates were generated upon replicative transposition of this IS  the appearance of a DNA band corresponding to the resolved trap plasmid. In contrast, we were never able to detect individual replicons when plasmid DNA was isolated from bacteria grown in medium supplemented with tetracycline, which strongly suggests that this antibiotic provides selection for the maintenance of the co-integrates.1248. When introduced into the strain DSM 11073, this plasmid (pCM132TC::IS1248), did not confer the Tcr phenotype, which precludes the possibility that a promoter of the IS may drive transcription of a nearby gene.DNA sequencing of the selection cassette of the resolved trap plasmid confirmed the presence of an inserted copy of IStetA gene in the co-integrate is driven by a promoter located within pKLW1. This conclusion is supported by the DNA sequence of regions flanking the original insertion site of IS1248 within pKLW1 and the detection of activity of the upstream promoter (These observations indicate that expression of the promoter .Pmar2 of P. marcusii DSM 11574 and ISPve1 of P. versutus UW400) into selection cassettes could be accompanied by deletions at the transposition target site.The transposition of the vast majority of TEs identified in this study resulted in the simple insertion of the elements into the trap plasmids and the generation of DRs. However, we found that the insertion of two ISs (ISPmar2 (IS407 group of the IS3 family) we identified only one deletion mutant . The deletion (15 bp) occurred at the 3\u2032-end of the inserted IS, and therefore the intact element was not bordered by the DRs, in contrast to the other clones tested.In the case of ISPve1 (IS21 family), which frequently generated much larger deletions within the selection cassettes of various trap plasmids. Initial analysis of a pool of Tcr clones of strain UW400 (obtained with pMEC1) revealed the presence of two types of pMEC1 mutants representing either (i) simple insertion of ISPve1 (7% of Tcr clones), or (ii) insertion of ISPve1 associated with deletions within the trap plasmid (16%). The remaining Tcr clones did not contain any TEs.More interesting was the case of ISPve1 resulted in the generation of 8-bp long DRs. Moreover, in both the insertion and deletion mutants, the element was always placed in the same orientation within the cI gene of pMEC1  and in each case, the location of the replication system was the factor limiting the range of deletions generated within the plasmid  was observed for ISPaes3 of P. aestuarii DSM 19484. In contrast, the element most dynamic in transposition was Tn5393 (P. pantotrophus LMD 82.5), which transposed into the selection cassette of the trap plasmid pCM132TC at a very high frequency (10\u22123). This is in agreement with our previous observations performed in the strain LMD 82.5 with pMEC1 In most cases, the frequency of transposition of the captured TEs ranged from 10rain see . The lowP. pantotrophus DSM 11072. Surprisingly, in this case, the vast majority of the transconjugants (92%) did not contain pMEC1 (9.4 kb) but they carried a very large replicon (>50 kb), that was not originally present in DSM 11072. The remaining transconjugants (8%) contained intact pMEC1. DNA hybridization followed by DNA sequencing revealed that the large nascent plasmids are in fact insertion mutants of pMEC1. They were generated by transposition into the trap plasmid of a large previously described composite transposon TnPpa1  3 family transposon Tn3434, which border the core region of the element containing a set of genes conserved in the chromosomes of many bacteria  Ppa1 into pMEC1. Intriguingly, all the transposon insertions were detected in randomly tested Kmr transconjugants, i.e. without applying positive (tetracycline) selection for the identification of transposition events. DNA sequencing of several insertion derivatives of pMEC1 confirmed that transposition of TnPpa1 had targeted random parts of the trap plasmid. In each case the inserted element was bordered by DRs, of a length typical for other members of the Tn3 family (5 bp) (data not shown).TnPpa1 is able to transpose as frequently into other replicons. For this purpose, several mobilizable plasmids were transferred into strain DSM 11072R. The plasmids contained different replication systems derived from (A) three broad host range replicons \u2013 (i) RA3 , (ii) RK2 (pCM132TC) and (iii) pBBR1 , as well as from (B) three plasmids originating from Paracoccus spp. \u2013 (i) pMAR4 of P. marcusii DSM 11574 (pDG12), (ii) pAMI7 of P. aminophilus JCM 7686 (pDIY703) and (iii) pTAV1 of P. versutus UW1 (pMMB2).We also tested whether TnPpa1 into plasmids containing replication systems of pMAR4 and pAMI7 as well as into all derivatives of RA3 , but not into the other tested plasmids (data not shown). This strongly suggested that the observed transposition phenomenon is dependent on the nature of the incoming replicon.Analysis of the plasmid content of the obtained transconiugants revealed massive transposition of TnSouthern blotting and DNA hybridization analysis were performed to examine the copy number and genomic location (plasmid/chromosome) of the identified TEs in their natural hosts.Paracoccus spp., which most probably reflects the replicative transposition of some of these elements. As shown in 427 group of the IS5 family , (ii) the IS903 group of the IS5 family , (iii) the IS407 group of the IS3 family , and individual members of (iv) the IS21 family (ISPve1a) and (v) the IS66 family (ISPpa7). Some of the detected IS copies displayed different signal intensities in the hybridization analysis, which most probably reflects divergence in the nucleotide sequences of closely related elements or the presence of truncated copies of the same element (data not shown).The analysis revealed that most of the identified insertion sequences were present in multiple copies in 5 family , (ii) the IS6 family  and (iii) the IS256 family (ISPaes3), as well as for the identified transposons .In contrast, a low copy number (1\u20132 copies) was observed for all members of (i) the IS5 group of the ISP. aminophilus JCM 7686, P. halophilus JCM 14014, P. kondratievae NCIMB 13773T, and P. marcusii OS22  that were available in 2009, when this project started. In total, we tested approximately 7000 individual clones to identify trap plasmid insertion derivatives. However, despite the complexity of this analysis, it is obvious that not all the TEs residing in Paracoccus spp. were defined; we only identified those that are the most dynamic in transposition, i.e. elements of highest evolutionary impact. As a result, we captured 41 elements representing (i) insertion sequences, (ii) an IS-driven composite transposon and (iii) non-composite transposons of the Tn3 family.The genus Paracoccus spp. As expected, the vast majority of the captured elements were insertion sequences. We identified 47 elements, representing 10 IS families: IS3, IS5, IS6, IS21, IS66, IS256, IS1182, IS1380, IS1634 and ISAs1. Interestingly we did not encounter elements of the IS1, IS4, IS91 or IS110 families, which are widely distributed among other bacteria In total, together with our previous studies Paracoccus spp. were members of the IS5 family (26 elements), while only single elements from the ISAs1, IS1182 and IS1634 families were captured. However, dot blot DNA hybridization revealed that TEs are much more abundant in Paracoccus spp. than we had expected. These results suggest that each tested strain carries elements belonging to several different families .Southern blotting and DNA hybridization analysis revealed that most of the ISs identified in 6097 carries two putative conserved genetic modules. Specific functions of closely related modules have previously been determined in other bacterial hosts. One of the modules carries most probably genes involved resistance to daunorubicin and doxorubicin (used in the treatment of some types of cancer arcABC genes), which enable bacteria to grow anaerobically in the presence of arginine. The enzymes mediate the conversion of arginine to ornithine, NH3, and CO2, with the generation of ATP. It has been shown that this pathway constitutes a major source of energy for several microorganisms, e.g. strains of Mycoplasma spp., Pseudomonas spp. and Bacillus spp. TnP. ferrooxidans NCCB 1300066 (host strain of Tn6097) is unable to grow anaerobically in the presence of arginine (data not shown), which suggests that the arcABCD operon may be not functional. It has been previously demonstrated that anaerobic expression of the closely related operon of Pseudomonas aeruginosa, requires a transcriptional activator 6097. It is therefore possible that the ADI module of Tn6097 may be functional exclusively in the strains encoding a compatible transcription regulator.However, we have observed that 3 family, which represent different stages in the evolution of this group of transposons. It is believed that the Tn3 transposons originate from progenitor IS elements , which acquired an additional genetic module involved in site-specific resolution of cointegrates (intermediates of replicative transposition) as well as other genes whose products can directly affect the phenotype of their host We have also identified several non-composite TEs of the TnParacoccus spp. we identified two cryptic transposons (Tn6122 and Tn3434a) that contain the conserved module for site-specific recombination. We also captured the transposon Tn5393 (closely related to Tn3434a), which apart from the resolvase module, carries two additional streptomycin resistance genes  of P. pantotrophus DSM 11072, which can be considered a composite transposon generated by two copies of the non-composite Tn3434Ppa1 provides evidence that the Tn3-family transposons (similarly to ISs) are able to mobilize large segments of genomic DNA for transposition. The generation of such composite elements seems to be very rare because of transposition immunity (a phenomenon that is thought to apply to members of the Tn3 family), which precludes transposition of more than one copy of the element into a single replicon Ppa1, composed of two identical copies of Tn3434, has a unique structure and, to our knowledge, is the only element of this type identified so far.The next step in the evolution of TnPpa1 is able to transpose into random sites of several mobilizable plasmids with unusually high frequency, not previously observed for any other bacterial TE. Our observations strongly suggest that the massive transposition of TnPpa1 might result from the specific features of the transferred plasmids. Irrespective of the precise mechanism of TnPpa1 transposition, it is clear that targeting of mobilizable or conjugal plasmids contributes to the dispersal of this element among bacterial populations. Within its core region, TnPpa1 carries a number of genes , whose presence may potentially improve the ecological fitness of the host cells Alphaproteobacteria  In this study, we found that Tn\u22123) of another member of the Tn3 family: the streptomycin resistance Tn5393 (P. pantotrophus LMD 82.5) \u2013 far higher than that observed for other non-composite members of this family (3434 was 10\u22126) 5393 explains the wide dissemination of this transposon in many bacterial isolates In this study, we also observed very frequent transposition , and (ii) a transposon of the Tn3 family (the aforementioned Tn5393).We showed that activation of nearby genes is a typical feature of insertion sequences of the ISr phenotype (activation of the promoterless tetA gene of pCM132TC) were examined in detail. This analysis revealed that transposition-mediated delivery of promoters to transcriptionally silent genes can occur in at least five ways , which was prone to generate deletions within target DNA molecules . This indicates that transposition may significantly shape plasmid genomes and promote plasmid diversity, which could have significant evolutionary implications.Another interesting phenomenon observed in this study was connected with the insertion sequence ISolecules . The tra21 family identified in this study, including ISPve1a, an isoform of ISPve1 from P. bengalensis DSM 17099 (99% identity at the nucleotide sequence level). The high frequency of deletions generated by ISPve1 (in comparison with \u201cpure\u201d insertion events) might therefore be a specific feature of this element. Alternatively, it might result from the presence of host factors, which stimulate such deletions. The latter hypothesis is supported by data recently published by Kusumoto et al.Pve1 and the strain P. versutus UW400 are necessary to determine the likelihood of these two possibilities.Interestingly, this \u201cdeletion\u201d phenomenon was not observed for other members of the ISPme1Paracoccus spp. It should also be borne in mind that many TEs (including composite transposons and TMos) cannot be distinguished in bacterial genomes by classical in silico sequence analysis, unless they have been inserted into a highly conserved genetic context (e.g. a trap plasmid selection cassette), to enable precise definition of their termini. For this reason, the identification of functional TEs using trap plasmids may produce many interesting and surprising findings even when carried out in bacteria whose genomes have been fully sequenced.To conclude, the analysis performed in this study together with our previous work concerning the identification of diverse TMos generated by a single copy of ISParacoccus spp. has also generated considerable interesting and unique data concerning the dynamics of the process of transposition  of IS-families identified in Paracoccus spp. . The sequences used for the comparisons were obtained from the ISfinder database (http://www-is.biotoul.fr/is.html). Sequence alignments were performed with the Pictogram program . The size of the letter in Pictogram represents the frequency of the occurrence of that nucleotide at each position. In the consensus sequences, shown below each Pictogram, uppercase letters indicate conservation within the IS family, lowercase letters indicate the predominant nucleotides, and dots indicate non-conserved residues. The family and group specific DDE motifs determined by multiple alignment of the amino acid sequences of the transposases of ISs present in the ISfinder database has been shown in the middle of the figure (Paracoccus spp.(TIF)Click here for additional data file.Table S1Oligonucleotides used in this study.(DOC)Click here for additional data file.Table S2ORFs located within Tn6097 of Paracoccus ferrooxidans NCCB 1300066.(DOC)Click here for additional data file.Table S3Rate of transposition of the TEs of Paracoccus spp. identified in this study.(DOCX)Click here for additional data file."}
+{"text": "To establish the clinical spectrum of food related  gastroenteropathy in children.30 children with allergic bowel disease were identified from general and paediatric allergy outpatient clinics and studied retrospectively from the bowel as well as other allergy and management point of view.24 of the children (80%) exhibited symptoms of gastro-oesophageal reflux disease, 28 children (93%) had lower GI symptoms and 23 children (77%) had significant sleep problems. 19 out f the 30 children (63%) had other atopic disorders. The most common food trigger was cow\u2019s milk others included egg, soya, wheat, fish, and nuts. Family history of atopy was seen in 24 children (80%). Skin prick tests were positive in only 7 children (23%) suggesting this is a non-IgE mediated phenomenon. Management of these children included diet exclusion, anti-reflux and anti-allergy medication. 12 children (44%) responded poorly to treatment and required steroids and 8 (30%) required biopsies. In families with more than one child with allergic gastroenteropathy, diagnosis and treatment with anti-reflux, diet exclusion and anti-allergy medication was started much earlier (2m-2yrs) in the younger sibling.In children the triad of upper and lower GI symptoms, other atopic disorder and a strong family history of atopy suggests a diagnosis of allergic bowel disease . This condition is diagnosed commonly as Gastroesophageal reflux disease with milk allergy but this fails to recognise the significant mid and lower bowel component in most of these children, which can be considered as an allergic inflammatory bowel disease. It is neither necessary nor essential to biopsy all these children in view of the response to anti allergy and anti inflammatory measures as well as the large number of children with this problem. Biopsies when positive may have esoinophils, hence this may represent the milder end of the spectrum of eosinophilic gastrointestinal disorder (EGID). The management of allergic gastroenteropathy ranges from dietary exclusion, anti-reflux & anti-allergy medication to immunomodulators in severe cases."}
+{"text": "The purpose of this study was to analyse assessment of the axilla in patients with primary operable breast cancer in a one-stop symptomatic breast unit.A retrospective review of 229 patients diagnosed with new primary operable breast carcinoma over a 12-month period. All patients underwent axillary ultrasound (US). All cases with normal US had subsequent sentinel lymph node biopsy (SLNB). All cases with abnormal US underwent fine needle aspiration cytology (FNAC). Findings were correlated with SLNB and axillary node clearance histology.A total of 128 patients had normal US and subsequent SLNB, this was positive in 29 (23%); 12 (40%) had micro metastases; primary tumour size was >2 cm in 22 (76%). Positive predictive value for US and FNAC was 97%. Negative predictive value was 75%. False positive and negative rates for US axilla are discussed with analysis of tumour subgroups and pattern of positive nodes.The combination of US and FNAC is a powerful predictive tool of axillary disease . Disappo"}
+{"text": "Traumatic brain injury (TBI) is a major cause of permanent disability and death in young patients. Controversy exists regarding the optimal cerebral perfusion pressure (CPP) required in TBI management. A tool for monitoring autoregulation and determining an optimal CPP is the pressure reactivity index (PRx), defined as a moving correlation coefficient between the mean arterial blood pressure (MAP) and intracranial pressure (ICP) at a frequency of at least 60 Hz. This requirement of high frequency has constrained its use to a few academic centers. An association was shown between outcome and continuous optimal CPP based on 4 hours of PRx . We presA total of 182 patients from the Brain-IT [On the Brain-IT database, LAx resulted in an optimal CPP for 90% of the first 48 hours. Table The differences in optimal CPPs derived from PRx and LAx were not clinically significant. LAx allowed for recommendations to be computed for longer periods. Significantly better outcome Table  was obse"}
+{"text": "The purpose was to assess factors that may influence the use of IM modalities by ID physicians in their practice.In a 2010 national survey of 1000 practicing ID physicians, participants were asked to report the extent  to which the following considerations played a role in their recommendation/referral of IM modalities: (1) Knowledge of how and when to use them; (2) Amount of clinical research showing clear benefit; (3) Insurance; (4) Cost; (5) Reliable referral base; (6) Concern for professional reputation; (7) Fear of judgment from colleagues; (8) Insufficient regulatory oversight of supplements; and (9) Potential drug interactions with botanicals/supplements.A total of 311 (31%) ID physicians responded to the survey. The mean age was 49 and 64% of respondents were male. Their responses to the questions are listed below.For ID physicians, factors that were considered a major influence on the use of IM modalities included: potential drug interactions, clinical research, knowledge of IM modalities, and regulatory oversight. Factors that played a minor/no role in the use of IM modalities included fear of judgment and concern for professional reputation."}
+{"text": "Objective: The immunochromatographic rapid tests facilitate the early diagnosis of dengue by providing evidence of the presence of virus specific proteins (antigens/ antibody) in human blood. Many products for rapid dengue diagnosis are available in the market; the performance of few selected products was evaluated and compared with enzyme linked immuno sorbent assays (ELISA).Methods: Sera from a large number of patients (n=184) admitted to National Institute of Blood Diseases & Bone Marrow Transplantation (NIBD) were used to determine the efficiency of non-structural (NS) 1, IgA, IgG and IgM based rapid test devices for dengue diagnosis.Results: The dengue NS1 antigen based device was least efficient while among the antibody based devices the dengue IgA rapid test (RDT) was comparatively better . This device could detect both primary and secondary dengue infection and was found to be the most sensitive device at all point of sample collection.Conclusion: The dengue IgA RDT could be a cost effective and efficient rapid test device for timely dengue diagnosis at all levels of healthcare settings. DHF is a vasculopathy characterized by capillary leakage and haematological deregulation; may result in fatal outcomes.8 An early and accurate diagnosis of dengue is important which assist not only in patient management by directing clinical attention but also in initiating community scale preventive measures for vector control to alleviate further dengue transmission. Commercial ELISA tests as well as immunochromatographic tests (RDT) that detect anti-dengue antibodies and the dengue NS1 antigen in plasma/sera have provided a new avenue for diagnosing dengue.9,10 In addition to this, the inexpensive and accurate dengue RDTs may also be useful in dengue epidemiological studies in resource limited countries. The primary and secondary dengue infections are diagnosed by the detection of either IgM or IgG or both in patient\u2019s serum.8 These anti-dengue antibodies appear late in serum i.e. after 5-6 days of infection so NS 1 protein is detected in routine diagnosis during this period. The NS1 antigen appears in high concentration during the first few days of illness and it stays in serum after the infection subsides i.e. up to 14 days.10,11 Beside viral antigen detection a newer approach to dengue diagnosis is the use of anti-dengue IgA based RDT devices.12 IgA is the principal secretory antibody and human serum contains very low concentration of IgA1. During secondary dengue infection considerable increase in serum anti-dengue IgA is observed. The anti-dengue IgA is documented as the first antibody to appear in case of secondary dengue infection prior to IgG and IgM production while in case of primary infection it is produced after the anti-dengue IgM antibody due to class switching.13In the past few decades dengue has become a global health problem infecting millions of individuals annually.14 In this report three commercially available rapid diagnostic test devices were compared. Serological tests for dengue NS1 antigen, dengue IgA, dengue IgG/ IgM antibodies were carried out to demonstrate the potential application of these kits in early laboratory diagnosis of dengue infection with the special emphasis on utility of dengue IgA RDT as one of the new dengue diagnostic markers.12 The results were also compared with more specific and sensitive gold standard methods of dengue diagnosis i.e. IgG and IgM capture ELISAs.In Karachi, most of the clinical diagnostic facilities are using commercial immunochromatographic rapid tests (RDT) from international manufacturers relying only on the supporting literature on the efficiency of these devices. No local data on the efficacy and sensitivity of most of these tests is documented.Study design: A panel of 184 dengue disease suspected human serum samples was used for the evaluation of efficacy of dengue immunochromatographic tests (RDT).8 The study was conducted during the period of August to December 2010 at National Institute of Blood Diseases (NIBD). A signed informed consent form and detailed questionnaire were obtained from patients involved in this study following institutional review board (IRB) policies. Age range of the study population was 2-65 years.8 In the present study any sample positive for either dengue specific-antigen (NS1) or antibodies (IgM or IgG or IgA) by RDT screening was considered as positive dengue case. All samples were characterized using dengue acute diagnostics: NS1 Ag Rapid Test , ASSURE\u00ae dengue IgA Rapid Test  and dengue Duo Cassette . The efficiencies of all these devices were evaluated by comparing with dengue IgM capture ELISA  and dengue IgG capture ELISA . Complete blood count (CBC) was performed; after proper mixing by automated hematological analyzer; Sysmex XE-2100 ; to evaluate the clinical parameters of dengue diagnosis .A probable dengue case may be a patient with presentation of defined clinical symptoms and history of acute febrile illness of 2\u20137 days with or without haemorrohage.Dengue Antibodies ELISAs: Dengue IgM-Cap ELISA and IgG-Cap ELISA were used to detect dengue antibodies as per manufacturer\u2019s instruction. Briefly, 100 \u00b5l/well of patient sera (diluted 1:100) and controls were added to the assay plate coated with either anti-human IgM or anti-human IgG to capture the IgM or IgG. Both plates were incubated for one hour at 37C. Then the plates were washed and 100 \u00b5l/well of enzyme conjugate was transferred to the assay plates except the blank wells. After 10 minutes, the reaction was stopped by addition of 100 \u00b5l/well 1 M phosphoric acid. The OD values were determined at 450 nm. A sample was defined as positive when ratio of sample absorbance and calculated cut-off value was > 1.Dengue NS1 Ag Rapid Test: Dengue NS1 Ag Rapid Test is a one-step chromatographic assay which uses murine monoclonal antibodies to capture dengue virus NS1 antigen in human serum or plasma and detected by NS1 antigen polyclonal antibodies conjugated with gold colloid. Assays were conducted and results were interpreted according to the instruction of manufacturers.Dengue IgA Rapid Test: ASSURE\u00ae Dengue IgA Rapid Test (WO 2009/139725 ) is a reverse flow technique (US Patent-6316205) immunochromatographic rapid test for the qualitative detection of anti-dengue IgA from patient\u2019s biological samples . In this platform, test sample migrates upwards from the sample well and eventually form antibody-antigen complexes with dengue virus antigens in the test window. The bound antibody-antigen complexes is subsequently detected by goat anti-human IgA gold conjugate carried by chase buffer that flows downwards giving a pink-purplish color line in the test window. Control line which contains protein L captures human IgA from patient\u2019s sample and binds with the anti-human IgA-gold conjugate, resulting in pink-purplish color line in the control window. The appearance of control line indicates the proper addition and migration of serum sample and chase buffer. The test was performed as per manufacturer\u2019s instruction for use (IFU) and results were interpreted according to the intensity scale provided with the kit box without knowledge of the results of other tests.Dengue Duo IgM/IgG Cassette: Dengue Duo Cassette is a lateral flow based immunochromatographic rapid test for the qualitative detection of anti-dengue IgM and IgG from patient\u2019s biological samples . The device is designed to detect IgM antibodies to dengue, as well as elevated IgG titers that are indicative of a secondary infection. The rapid tests were read and interpreted according to the manufacturers' instructions. The positivity of individual marker were calculated separately (IgM or IgG) as well as in combination (IgM and IgG).Statistical analysis: The quantitative variables were expressed as mean, standard deviation, confidence interval and minimum and maximum range. The qualitative variables were mentioned as percentages. The sensitivity and specificity of immunochromatographic tests were analyzed by 2x2 table using MedCalc statistical software, version-11.5 . Kappa value was used to test the efficiency and reliability of the rapid devices.Characteristics of the study population: The characteristics of the study population (n = 184 cases) that contributed acute sera to the test panel is shown in Sensitivity and specificity of dengue immunochromatographic tests versus reference dengue tests: The sensitivities and specificities of three RDTs against the reference tests i.e. dengue IgM-cap ELISA and IgG-cap ELISA are presented in Immunochromatographic tests sensitivity in primary or secondary infection: The detection of both dengue primary and secondary infected patients by dengue IgA RT was significantly higher than Panbio IgM/IgG Duo RDT and is presented in Sensitivity of Immunochromatographic tests by day of illness: The sensitivity of three RDTs was also evaluated based on the duration of onset of dengue fever, categorized into 6 groups  and 86.05% (80.95%) respectively. Additionally, the level of detection of infection at all stages of disease by IgA RDT was far better  false negative results. Dengue NS-1 antigen can be found in patient\u2019s serum until the production of anti-NS-1 IgG or in some instances a few days after defervescence. The variable levels of NS-1 antigen in different phases of infection might be due to the immune-complex formation of NS1 antigen with anti-dengue IgG resulting in less sensitive dengue detection in acute-phase secondary infection as reported previously.21We conclude that the serological testing for early diagnosis of dengue infections could be accomplished by using IgA based RDT at all heath care settings during any stage of infection cycle. Moreover, it partially overcomes the limitations associated with ELISAs like handling of single sample without delay."}
+{"text": "The cGMP-dependent protein kinase (PKG) is widely expressed in mammalian tissues and serves as an integral component of second messenger signaling in a number of biological contexts including vasodilation, motility and memory . PKG assHere we report the 2.5 \u00c5 crystal structure of a regulatory domain fragment containing both tandem cGMP binding sites of PKG I\u03b1 (amino acids 78-355). The overall domain topology of this structure shows a distinct and segregated architecture. The cGMP binding sites are separated by an extended central helix and offer limited interdomain communication. However, a previously uncharacterized helical domain (switch helix) promotes the assembly of a dimeric interface between PKG I\u03b178-355 protomers. Disruption of this interface by alanine scanning mutagenesis in full length PKG resulted in a marked reduction of activation constants.Our results offer new insight about PKG holoenzyme assembly as they provide the first detailed molecular view of tandem cGMP-binding domains and characterize the switch helix as a critical site of interchain communication between PKG protomers. The biological integrity of PKG appears to be mediated by this interface as it is necessary for the maintenance of kinetic fidelity. This structure highlights the critical importance of dimer communication in PKG biology and will likely serve as an improved platform for the strategic development of therapeutic agents aimed at treatment and prevention of cGMP-dependent pathologies."}
+{"text": "This is a case report of a previously undescribed 20q chromosomal deletion (del(20q)) in marginal zone lymphoma (MZL). A 54-year-old Caucasian male presented with an enlarging neck mass and multiple violaceous skin nodules over his chest. Biopsy of the neck mass and cervical lymph nodes revealed MZL. Cytogenetic evaluation of both lymph node and bone marrow tissue revealed del(20q). This was an unexpected finding, as del(20q) is associated with myelodysplastic syndromes and myeloproliferative neoplasms and rarely seen in diffuse large B-cell lymphoma, follicular lymphoma, and T-cell lymphoma, but has not previously been described in MZL. We describe the case presentation and histologic findings and discuss the significance of this novel finding. Del, near 20q12 . There wNodal MZL is one of three subtypes of MZL and its incidence is relatively rare, comprising only 1.5% of all lymphomas , charactThe finding of a del(20q) in both the lymph node tissue and bone marrow samples was an unexpected finding in this case; a diagnosis of nodal MZL could confidently be made by lymph node histological features, IHC and flow cytometric immunophenotyping. The literature has not previously reported del(20q) in MZL. This finding may represent a specific cytogenetic abnormality in this nodal MZL with an aggressive morphology and high-stage disease. In conclusion, this case of nodal MZL with 20q deletion is a novel finding which can expand the breadth of knowledge of chromosomal abnormalities in MZL."}
+{"text": "Salmonella enterica serovar Bovismorbificans from isolates associated with the 2011 hummus-borne multistate outbreak. All six genome sequences indicate the presence of two plasmids, one of which demonstrates similarity to the 93-kb pSLT2 IncF-type plasmid of Salmonella\u00a0enterica serovar Typhimurium.We present six draft genome sequences of  Salmonella outbreak investigations [http://www.cdc.gov/salmonella/outbreaks.html]). In August through November of 2011, sesame seed paste (tahini) and hummus containing a rare serotype of Salmonella enterica caused illness in 23 people in 7 states and the District of Columbia   pattern that was distinctly different from those of other isolates of serovar Bovismorbificans recorded in the Pulse Net Database  from patient stool samples, two from hummus samples (SAL616 and 617) from the District of Columbia Public Health Laboratory, and one clinical isolate (SAL682) from the Michigan Department of Health.There are more than 40,000 cases of salmonellosis reported in the United States each year (see the CDC reports of de novo assembly of the paired-end reads to 100 contigs. The genomes were annotated by use of the RAST server (Genomic DNA from each strain was extracted from overnight cultures using QIAcube (Qiagen). The DNA library was constructed according to the Illumina recommended protocol for Nextera XT DNA sample prep and sequenced using Illumina Miseq . CLC bio software version 6.0.1  was used for the trimming and T server .S.\u00a0enterica serovar Typhimurium. In addition to this virulence plasmid, an integration and conjugative element (ICE) similar to ICESb1 found in Salmonella bongori .The draft genome sequence accession numbers for these six"}
+{"text": "Massive fluid resuscitation followed by hypoperfusion abnormalities in the ICU is a risk factor for development of intra-abdominal hypertension (IAH). The aim of our study was to determine what influence would have the control of daily fluid balance on the incidence of IAH in patients after extensive abdominal surgery or after abdominal trauma.n = 22) or after abdominal surgery (n = 60). During first 7 days the fluid intake and balance was monitored and corrected at 6-hour intervals not to exceed 1,500 ml positivity over 24 hours . IAP was measured from admission twice daily . A sustained elevation of the IAP above 12 mmHg in two consecutive measurements was considered as IAH.A prospective observational study included a total of 82 adult patients , number of patients with intra-abdominal pressure (IAP) above 12 at admission: 23 (28%), admitted to a single ICU with the diagnosis of abdominal trauma (The incidence of IAH in relation to daily fluid intake and daily fluid balance is shown in Figure The incidence of IAH in patients after abdominal surgery or abdominal trauma may exceed the value of 40%, especially in situations associated with massive fluid resuscitation . We have"}
+{"text": "Migraine is 2-3 times more prevalent in women than in men, with frequent perimenstrual attacks. TRPV1 receptors on sensory nerve endings of the trigeminal track are important in mediating migraine attacks by releasing the vasodilator calcitonin gene-related peptide (CGRP). Variation in estrogen levels during the menstrual cycle may have an influence on the sensitivity of the TRPV1 receptor or on the amount of CGRP in perivascular nerve terminals and hence on CGRP release. Capsaicin, the active ingredient of hot chili peppers, stimulates the TRPV1 receptor and causes CGRP-dependent vasodilatation ["}
+{"text": "To compare the presence and quantity of cervicovaginal HIV among HIV seropositive women with clinical herpes, subclinical HSV-2 infection and without HSV-2 infection respectively; to evaluate the association between cervicovaginal HIV and HSV shedding; and identify factors associated with quantity of cervicovaginal HIV.Four groups of HIV seropositive adult female barworkers were identified and examined at three-monthly intervals between October 2000 and March 2003 in Mbeya, Tanzania: (1) 57 women at 70 clinic visits with clinical genital herpes; (2) 39 of the same women at 46 clinic visits when asymptomatic; (3) 55 HSV-2 seropositive women at 60 clinic visits who were never observed with herpetic lesions; (4) 18 HSV-2 seronegative women at 45 clinic visits. Associations of genital HIV shedding with HIV plasma viral load (PVL), herpetic lesions, HSV shedding and other factors were examined.10 copies/mL) was closely associated with HIV PVL  and HSV shedding  but not the presence of herpetic lesions .Prevalence of detectable genital HIV RNA varied from 73% in HSV-2 seronegative women to 94% in women with herpetic lesions . In paired specimens from HSV-2 positive women, genital HIV viral shedding was similar during symptomatic and asymptomatic visits. On multivariate regression, genital HIV RNA (logHIV PVL and HSV shedding were more important determinants of genital HIV than the presence of herpetic lesions. These data support a role of HSV-2 infection in enhancing HIV transmissibility. Herpes simplex virus type-2 (HSV-2) infection is lifelong and a common cause of genital ulcers In vitro studies provide evidence of the effect of HSV-2 infection on HIV replication The frequency of recurrent episodes of clinical herpes and of subclinical viral shedding varies both between individuals and over time within the same individual The objectives of this study were to compare the presence and quantity of cervicovaginal HIV in HIV seropositive women living in Mbeya Region, Tanzania with clinical episodes of herpes, subclinical HSV-2 infection and without HSV-2 respectively; to examine the association between genital shedding of HIV and HSV-2; and to investigate factors influencing the quantity of HIV genital shedding.As part of a study of the determinants of HIV super-infection in Mbeya Region, Tanzania, an open cohort of 600 female barworkers aged 18 to 35 years was established in late 2000. Study procedures have been described previously Treponema pallidum particle agglutination assay  and the rapid plasma reagin test .A diagnostic algorithm including two different enzyme-linked immunosorbent assays  and a Western Blot assay  was used to determine HIV serostatus. Type-specific serological testing for HSV-2 was also performed by enzyme immune assay . Syphilis testing was carried out using the Serodia HIV-1 plasma viral load (PVL) was quantified by transcription polymerase chain reaction (PCR) , with a detection threshold of 50 HIV-RNA copies/ml.T pallidum, H ducreyi and HSV A single dry swab was taken from genital ulcers and multiplex PCR (M-PCR) was used for the detection of 6 cells for HIV-1 DNA. Cervicovaginal specimens were also tested for prostate specific antigen (PSA) using the VITROS immunodiagnostic product PSA reagent and calibrator packs on the automaton Ortho-Clinical Diagnostics VITROS Eci , and for traces of haemoglobin using Multistix 8 SG strips .Cervicovaginal secretions (CVS) were collected from all women at every study visit using standard vaginal lavage procedures Trichomonas vaginalis by direct microscopy of a wet mount preparation and Candida albicans by wet mount preparation and gram stain.Vaginal swabs were tested for CVS specimens collected from HIV seropositive women at 3-monthly study visits were excluded from analyses if (i) the woman had a genital lesion of non-herpetic origin (12 specimens were excluded for confirmed syphilis and 7 specimens excluded for chancroid), (ii) there were traces of haemoglobin in the specimen or (iii) the specimen was positive for PSA. Specimens from (i) were excluded as HSV shedding may have been influenced by other ulcerative STIs, and those from (ii) and (iii) were excluded as any HIV-RNA or HIV-DNA found in the genital tract may not have been attributable to genital shedding from the woman. Specimens were categorised into four study groups according to the woman\u2019s HSV-2 serostatus and the presence or absence of confirmed herpetic genital lesions at the time of specimen collection. Women who experienced PCR-confirmed herpetic lesions at one or more study visits contributed to two study groups: Group 1  included CVS specimens collected in the presence of herpetic lesions; Group 2 , included specimens taken from the same women at follow-up examinations at least 6 months after or 6 months before the visits at which herpetic lesions were detected. In Group 3 (\u201cnever lesions\u201d) a random sample of specimens were taken from HSV-2 seropositive women who never had herpetic genital lesions or a history of genital lesions at any of the study visits. Group 4 (\u201cHSV-2 negative\u201d) was randomly chosen from specimens taken from women not infected with HSV-2.10) transformations were applied to plasma and genital viral loads for HIV and HSV-2 to obtain approximately normal distributions, geometric means (GM), and 95% confidence intervals (95%CI). Differences in mean viral loads between groups were assessed using a random effects linear regression model to account for correlations within subjects. Correlations between viral loads  were assessed using Spearman\u2019s rank correlation coefficient.Differences between study groups in proportions of CVS specimens with HIV-1 (RNA and DNA) and HSV DNA above the detection threshold were tested using random effects logistic regression modelling to account for correlations within subjects. Analyses of quantity of genital viral shedding were restricted to specimens with viral loads above the threshold of detection. Logarithmic .Initial analyses suggested that HSV shedding was a strong determinant of genital HIV shedding. We regrouped specimens of HSV-2 seropositive women in the subclinical and never lesions groups according to the presence of HSV shedding (asymptomatic HSV shedders) or absence of HSV shedding (HSV non-shedders). We then used random effects linear regression, accounting for multiple observations from the same individual, to examine the association of log-transformed HIV genital viral loads with HSV shedding status as well as other potential risk factors, including age, laboratory-diagnosed non-ulcerative sexually transmitted infections (STI), signs or symptoms of sexually transmitted diseases (STD), enlarged lymph nodes and HIV plasma viral load. In this analysis, specimens with HIV or HSV genital viral load below the threshold of detection were assigned a value of half the threshold.Analyses were performed using Stata 11.0 . The study was approved by the national ethics review committee of the National Institute for Medical Research of the United Republic of Tanzania and the LSHTM Ethics Committee . It was conducted within the framework of the Mbeya Medical Research Programme. All participants provided written, informed consent to participate in the study.Analyses were based on 221 eligible CVS samples from 131 HIV seropositive women. The four study groups comprised 57 women at 70 study visits with clinically manifest genital herpes (Group 1), 39 of the same women at 46 study visits when they did not have visible ulcers (Group 2), 55 HSV-2 seropositive women at 60 study visits who were never observed with herpetic lesions (Group 3), and 18 women at 45 study visits who were HSV-2 seronegative (Group 4) .Thirty-five women contributed to both Groups 1 and 2; four other women in Group 2 were not sampled at the time of clinical herpes. Three women were HSV-2 seronegative (Group 4) and later seroconverted, two with an episode of clinical herpes (Group 1) and one with no episode of clinical herpes (Group 3). Thirty-three women contributed more than one specimen to the same study group (up to 7 specimens from one HSV-2 seronegative woman).Mean age was around 28 years for HSV-2 positive women and 25 years for HSV-2 negative women. Slightly higher proportions of women were using hormonal contraception among those who had never had lesions, and those who were HSV-2 negative, but this difference was not statistically significant (p\u200a=\u200a0.35).C Albicans was most common in the never lesions group (p\u200a=\u200a0.08), but other STI or clinical signs of STD at the time of specimen collection did not differ significantly by study group  in samples from women uninfected with HSV-2 and highest  in samples from women with confirmed herpetic lesions. TPPA seropositivity, indicating past or current syphilis, was also lower in the HSV-2 uninfected group (p<0.001), and dy group .The prevalence of detectable genital HIV RNA was lowest in the HSV-2 negative group (73%) and highest in the clinical herpes group (94%) . The gen6 cells) and the lowest in the never lesions group (GM\u200a=\u200a141 copies per 106 cells) . The pattern was less clear than for HIV RNA, but the highest viral load was seen in the clinical herpes group (GM\u200a=\u200a252 copies per 106 cells) .All women with detectable genital HIV RNA also had detectable plasma HIV RNA. Among women with detectable genital HIV RNA, quantities of plasma and genital HIV RNA were significantly correlated .As expected, the prevalence of detectable genital HSV DNA varied substantially between the three study groups of HSV-2 positive women, with a much higher prevalence among women with clinical herpes (77%) than in the subclinical herpes (20%) and never lesions (12%) groups (p<0.001). HSV DNA viral load showed a similar, though non-significant trend .Of the 35 women who had specimens taken during clinical episodes of herpes and also at visits when they were asymptomatic, 30 (86%) had detectable HIV RNA on both occasions, while all 29 women with paired specimens analysed for HIV DNA were positive on both occasions. There was no evidence of a difference in the quantity of genital HIV shed between clinical and subclinical phases of herpes . AlthougTo explore whether signs of clinical herpes or HSV-2 viral shedding were more important determinants of HIV shedding, we re-categorised the specimens into four new groups: clinical herpes, HSV-2 seropositive with detectable genital HSV DNA shedding (asymptomatic HSV shedders), HSV-2 seropositive without detectable genital HSV shedding (HSV non-shedders at that visit), and HSV-2 seronegative. In all four groups, the majority of specimens had detectable HIV RNA and HIV DNA, and the prevalence was highest in samples taken during clinical or subclinical shedding episodes . OverallAmong specimens with HSV DNA shedding (with or without lesions), the genital viral loads of HIV RNA and HSV DNA were positively correlated . The correlation of genital HIV DNA and HSV DNA was weaker , as was the correlation between plasma HIV RNA and genital HSV DNA . A positive correlation between genital and plasma viral loads of HIV was seen in all women . While tGenital HIV RNA viral load increased with quantity of HIV PVL (p<0.001) and presence and quantity of genital HSV DNA . AlthougSimilarly, genital HIV DNA viral load increased with both HIV PVL (p<0.001) and genital HSV DNA viral load . AlthougIn this study we determined the frequency and quantity of cervicovaginal HIV and HSV using specimens collected from 131 HIV infected women who were followed up every three months for up to 30 months. The prevalence of detectable genital HSV DNA in asymptomatic HIV positive women was similar to studies from elsewhere in Africa The main objective of our study was to determine whether genital shedding of HIV occurred more frequently in the presence of genital herpetic lesions. A strength of the study was the long follow-up period, providing an opportunity to observe women both during and between clinical episodes of herpes. Clinical herpes was associated with higher levels of genital HIV shedding, but only partially as there were episodes of herpetic ulceration where HSV genital shedding was not recorded, and conversely episodes of HSV genital shedding in asymptomatic women. In the multivariate analysis, we clearly saw that herpetic ulcers were not independently associated with genital shedding of HIV RNA , whereas there remained a clear association between HSV genital shedding and genital shedding of HIV RNA , suggesting that this increase was related to the quantity of genital HSV and the HIV plasma viral load rather than to the presence or absence of herpetic lesions. In paired specimens taken from women with clinical herpes and from other study visits when they were asymptomatic, no difference was seen in HIV genital shedding at the two visits. When the original study groups were rearranged to examine the effect of genital HSV shedding, there was a clear difference in HIV genital shedding between HSV shedders and non-shedders, but no additional increase in HIV shedding in those with clinical herpes. Similarly, when risk factors for HIV genital shedding were examined in a multivariate regression analysis, the quantity of genital HIV RNA or DNA was significantly associated with HIV plasma viral load and HSV shedding, but after adjustment for these factors was not associated with clinical herpes.Our findings are consistent with results from a study carried out in Bangui, Central African Republic, where among HIV positive women shedding HSV, there was a significant correlation between genital HIV RNA shedding and genital shedding of HSV The observational design of these studies limits inferences about causality, but stronger evidence concerning the effect of herpes on HIV infectivity comes from seven recently completed randomised controlled trials of herpes suppressive therapy. Four trials, using valacyclovir or high dose acyclovir (800 mg b.i.d.), found significant reductions in PVL as well as significant reductions in rectal and cervicovaginal HIV-1 RNA concentrations Our results are consistent with previous reports of an association between HSV-2 shedding and HIV PVL, and suggest that clinical and subclinical herpetic reactivations might increase genital HIV shedding not only through a direct viral interaction at the genital level, but also through their systemic effect on plasma HIV viral load In this study we used cervicovaginal specimens as a marker of genital shedding, and did not find evidence of increased HIV shedding in the presence of genital lesions. However, HIV shedding may also occur directly from a herpetic lesion, and we cannot exclude the possibility that overall HIV infectivity is increased in the presence of lesions, particularly as 64% of herpetic lesions seen in this study were found on the vulva T pallidum or H ducreyi) were excluded from this analysis, as were specimens with traces of blood or semen, although we cannot rule out the possibility that some HIV or HSV detected in CVS originated from infected sexual partners. Some CVS were collected from women with non-ulcerative STI, and this may have led to underestimation of the association between herpetic lesions and HIV shedding, as cervicovaginal secretion of HIV-1 has been associated with the presence of non-ulcerative STI such as gonorrhoea and Chlamydia and found to decrease after effective treatment Genital specimens from women with ulcers of other confirmed aetiology (Increased genital HIV-1 viral load has been shown to be associated with immunosuppression in some studies In conclusion, this study adds to the accumulating evidence that HSV-2 infection increases genital shedding of HIV, and may therefore increase the infectivity of HIV infected individuals to their sexual partners. Our data suggest that the increase in HIV shedding is related to the quantity of HSV shedding rather than to the presence of clinical lesions of herpes. These findings emphasise the importance of developing and evaluating effective interventions to control herpes in populations where HSV-2 may account for a substantial proportion of HIV transmission."}
+{"text": "Energy therapies in the hospital setting are met with various levels of acceptance due to questions of efficacy and evidence base. This prospective randomized controlled study quantifies the impact of one form of energy therapy on post-operative anxiety and pain in the lumbar spine surgery population.After meeting inclusion and exclusion criteria, patients that consented to participate in the study were randomized into standard post operative care (Control), standard post operative care plus a Healing Touch therapy intervention (Treatment), and standard post operative care plus an attention-control intervention (Sham). Patients were asked to complete the Visual Analog Anxiety Scale, Visual Analog Pain Scale, and Hospital Anxiety Depression Scale (HADS) both prior to and after receiving four consecutive sessions of Healing Touch intervention, attention-controlled intervention, or the standard of care. Baseline data were compared among the three groups using the chi-square test. The Sham and Treatment group were compared in terms of average change  in HADS, anxiety and pain scores using the t-test.A total of 75 patients were included: 25 in the Control group (33%), 24 (32%) and 26 (35%) in the Sham and Treatment groups, respectively. The three groups were similar in terms of baseline factors (p>0.05). Results from comparing the Sham and Treatment group in terms of the change in anxiety and pain scores showed marginally statistically significant differences in anxiety scores in session 2, statistically significant differences in anxiety in session 3, and statistically significant differences in pain scores measured in sessions 2, 3 and 4. No differences were observed between the two groups in terms of the change in HADS (p>0.05).Healing Touch demonstrated a statistically significant reduction in post-operative pain and is a viable adjunct in the care of patients undergoing lumbar spine surgery."}
+{"text": "To develop a tool for self-assessment of HH resources, practice and promotion in healthcare facilities (HCF), based on the key components of the WHO Multimodal Hand Hygiene (HH) Improvement Strategy (MHHIS).A task force (TF) of HH experts developed the tool and identified the following desired features: 1) to reflect the 5 components of the WHO MHHIS; 2) to include measurable indicators based on scientific evidence and expert consensus; 3) to be in the format of a user-friendly questionnaire; 4) to be associated with a score; 5) to be usable repetitively over time. Tool development steps were: 1) identification of indicators, score and format; 2) usability and reliability pilot testing; 3) review and finalization.The tool was named HH Self-Assessment Framework (HHSAF) and structured in 5 sections corresponding to the WHO MHHIS components . 27 indicators were included and points assigned according to available evidence and importance attributed by experts. WHO implementation tools suited to the improvement of each indicator were referred to within the HHSAF. A score of maximum 100 points was established per each HHSAF section. According to the overall score, 4 HH situation levels were identified: inadequate; basic; intermediate; advanced. Additional leadership criteria for HH reference centres were included. The draft was finalized according to results of usability and reliability tests.Through a thorough development process, all desired features identified for an optimal HH self-assessment tool at HCF level were successfully fed into the HHSAF.None declared."}
+{"text": "Human species and guinea pigs have to obtain vitamin C (VC) from food because they are unable to synthesize ascorbic acid due to the absence of the gene that encodes L-gulonolactone oxidase (Gulo). The spontaneous bone fracture (sfx) mouse is a mouse model which is deficient in the synthesis of VC because of the deletion in Gulo gene. Because muscle forces are a strong determinant of bone structure, particularly during the process of growth and development, we examined the gene expression of muscle in sfx mice.In order to identify the genes that regulate muscle development through Vitamin C (VC) pathway, we analyzed the gene expression profile in mouse muscle from femur. For microarray analysis, muscle from three age-matched, wild-type +/+ Balb/By, inbred strain mice (WT) and 3 female and 3 male homozygous sfx/sfx mice were used.Our results indicated that 1) The expression of Myogenic factor 6 (Myf6) gene in sfx mice is increased in both female and male mice, while the increase in male mice is much higher than that in female mice. 2) Some of dystrophin relevant genes are also affected in the sfx mice. The expressions of adenylate kinase (Ak1), creatine kinase sarcomeric mitochondrial (Ckmt2), and calcium-and integrin-binding protein 2 (Cib2) are decreased. The expression of creatine kinase muscle type (Ckb) and Cdc42 binding protein kinase beta (Cdc42bpb), on the other hand, although at a low level are increased in both sfx and wild type mice. Pathological analysis suggests that the diameters of male and female of sfx mice are smaller than that of Wt mice.Suggesting a deficiency in muscle development and potentially function.There is a significant difference in myopathy and gene regulations in muscle of sfx mice between female and male mice."}
+{"text": "The most significant SNP, rs7952106 , was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene . Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5\u2019 CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0x10 Sickle cell disease (SCD) is an inherited hemoglobin disorder affecting approximately 1 in 600 individuals of African American ancestry in the United States  and contStudies of familial aggregation provide significant evidence that blood pressure is a highly heritable trait ; howeverThis study includes two unrelated admixed African American ancestry SCD cohorts. Study protocols of both cohorts were approved by the Institutional Review Board (IRB) of Johns Hopkins University and Boston Medical Center. Additionally, IRB approval was acquired from all of the participating sites for subject enrollment and conducted in accordance with institutional guidelines.http://sitstudy.wustl.edu/) . These studies suggest that the DRD2 locus is plausibly involved in the regulation of SBP. Our results support these findings and the suggestive association from the DRD2 region SNPs may represents a true signal associated with SBP in SCD patients.) have reactive oxygen species (ROS)-dependent hypertension [44]. In addition, the pression  and showRecently, several large and well powered studies from European ancestry populations have identified 29 genomic loci associated with blood pressure -23. We sCACNB2 (5\u2019) locus showed the consistent nominal significance for both SBP and SCI .A quantile-quantile (Q-Q) plot showing the distribution of observed \u03c7The black diagonal line indicates expected results under the null hypothesis.(TIFF)Click here for additional data file.Figure S2Comparison of the effect size of variants from the reported regions associated with SBP in the ICBP meta-analysis and SCD cohort.(TIFF)Click here for additional data file.Figure S3Power calculation to detect genome-wide significant SNPs  for systolic blood pressure in the combined SIT Trial and CSSCD cohort, utilizing 1617 SCD samples.The authors thank the staff, clinicians and patients for their participation in the Silent Infarct Transfusion (SIT) Trial study. Genotyping services for the SIT Trial were provided by the Center for Inherited Disease Research (CIDR) at Johns Hopkins University and the Division of Blood Disorders at the Centers for Disease\u00a0Control and Prevention (CDC). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.(TIFF)Click here for additional data file."}
+{"text": "The consistent retention of habitat variables in our predictive models supports the area of refuge hypothesis which posits reduced extinction rates in the Coral Triangle. This does not preclude support for a center of origin hypothesis that suggests increased speciation in the region may contribute to species richness. In addition, consistent retention of sea surface temperatures in models suggests that available kinetic energy may also be an important factor in shaping patterns of marine species richness. Kinetic energy may hasten rates of both extinction and speciation. The position of the Indo-Pacific Warm Pool to the east of the Coral Triangle in central Oceania and a pattern of increasing species richness from this region into the central and northern parts of the Coral Triangle suggests peripheral speciation with enhanced survival in the cooler parts of the Coral Triangle that also have highly concentrated available habitat. These results indicate that conservation of habitat availability and heterogeneity is important to reduce extinction of marine species and that changes in sea surface temperatures may influence the evolutionary potential of the region.Range overlap patterns were observed in a dataset of 10,446 expert-derived marine species distribution maps, including 8,295 coastal fishes, 1,212 invertebrates (crustaceans and molluscs), 820 reef-building corals, 50 seagrasses, and 69 mangroves. Distributions of tropical Indo-Pacific shore fishes revealed a concentration of species richness in the northern apex and central region of the Coral Triangle epicenter of marine biodiversity. This pattern was supported by distributions of invertebrates and habitat-forming primary producers. Habitat availability, heterogeneity, and sea surface temperatures were highly correlated with species richness across spatial grains ranging from 23,000 to 5,100,000 km Persistent questions remain regarding the origins of the uneven distribution of marine species richness across the tropical Indo-Pacific The tropical Indian and Pacific Oceans encompass about two thirds of the earth\u2019s equatorial circumference and include two distinct marine zoogeographic regions The observation that peaks in marine species richness throughout geologic time follow changing concentrations of available habitat is an extension of the area of refuge hypothesis, one of the numerous hypotheses invoked to explain the current epicenter of marine biodiversity in the Coral Triangle In addition to area of refuge, other hypotheses used to explain the current epicenter of marine biodiversity can be summarized as: 1) center of origin A neutral hypothesis has also been tested relating to the mid-domain effect The area of refuge hypothesis was primarily formulated as an alternative to the well-established center of origin hypothesis which heavily relies on assumptions about dispersal One component of the area of refuge hypothesis is habitat heterogeneity, which has long been considered important in shaping species diversity patterns It has long been established that there are latitudinal gradients in species richness with highest species richness in the tropics linked to multiple potential factors A number of different methods have been used to examine causes of the uneven distribution of marine species across the Indo-Pacific The study range covers the entire Indian Ocean (including Red Sea and Persian Gulf) and the entire Pacific Ocean between 30\u00b0N and 30\u00b0S. All data layers were projected onto the World Cylindrical Equal Area coordinate system centered at 130\u00b0 longitude.2/grid cell, except for the grids located along upper and lower edges of the study area which cover less area. To compare the effect of area distortion, we used, five different equal area grids: small , medium , large , extra large , and largest . The use of different grid sizes was not to test for the best possible grain but to test at which grain the predictors are likely to operate The study area was divided into equal grids of different horizontal resolutions  and the commonly-used Universal Transverse Mercator (UTM) grid to test the grid choice effects on relationships between predictors and species richness. Different orientations of centroid location were tested and found to have minimal effects , S2 so tThe aim of this study was to test for effects of available nearshore habitat on species diversity, and therefore, relates to pelagic, benthic, or demersal species found primarily over continental or island shelves. The total number of species maps produced in this study was 10,446  of which2) from a 200 m bathymetry layer processed from ETOPO1  raster data Using a Geographic Information System (GIS), we calculated the amount of continental shelf or shallow water area (SW)  for each habitat and N\u200a=\u200atotal habitat area .The SST layer was developed from the monthly long-term SST data derived from the National Oceanic and Atmospheric Administration Optimum Interpolation dataset. This product was constructed from two intermediate climatologies to produce a 1\u00b0 resolution dataset with a 1961\u20131990 base period y is fitted as a Poisson variable. Using the log of y we fit the GLM as below:o, \u03b21\u03b2, 2\u03b2, 3\u03b2, and 4\u03b2 are the parameter estimates. For SLM, we used maximum likelihood estimation of spatial simultaneous autoregressive error model in the form:Range overlap maps and environmental layers were combined to form grid matrices with the corresponding values of species richness, habitat availability , two habitat heterogeneity indices , SST and NPP in each cell. Statistical analyses were performed to test the relationship between the environmental variables versus four different species richness subgroups: combined all species, all fish species, all habitat-forming species , and all invertebrate species. We modeled the influences of habitat area and heterogeneity to each subgroup using both a generalized linear model (GLM) and a spatial linear model (SLM) to account for spatial autocorrelation \u03b2 is the vector of coefficient for intercept and explanatory variable X; \u03bb is the spatial autoregression coefficient; W is the spatial weights; \u03bc is the spatially-dependent error term; and \u03b5 is the error vector. Likewise, the Poisson response variable y was also fitted as a log function.2R values were used as a guide to model selection by evaluating the amount of variation explained. Since an equivalent 2R does not exist in spatial analysis with a logistic regression, we used pseudo-2RIWe performed SLM with spatial distance weights derived from five nearest-neighbor cells. We used five and not eight nearest neighbors since most of the cells  are isolated creating coastal and island effects. The presence of isolated cells will create a bias in spatial weight distance calculation. To normalize the data, all variables (dependent and independent) were log-transformed. Pearson correlation coefficients were generated for all between-variable comparisons. We tested individual habitat predictors versus each subgroup using single-predictor models. Then we used multiple-predictors model to test the effects of the combination of different habitats in each subgroup. The effects of multiple predictors were further explained by identifying the minimal-adequate model using backwards elimination method. Model fit was assessed using t-values (GLM) and z-values (SLM) for both single and multiple-predictor relationships. In GLM, adjusted Species richness across the Indo-Pacific showed the expected pattern of highest richness in the Coral Triangle . The cenGreatest shallow water area (SW) and longest coastline (CL) per unit area , 3A wereAverage SST values were highest (over approximately 29\u00b0C) around and east of the Solomon Islands and northern Australia and were also high (over approximately 28\u00b0C) in eastern central Indonesia, western Sumatra and northwestern Madagascar . SpeciesPredictor variables were consistently highly correlated with one another at all scales, with some notable exceptions . SW and Species richness of all taxonomic sets was significantly correlated with most environmental variables at all scales in single predictor GLM and SLM with the exception of insignificant correlations with SST at the smallest grid sizes, insignificant correlations with NPP at nearly all grid sizes, and HDIa and some other variables at the larger grain sizes . CL mostI indicated significant autocorrelation at all grains sizes except the largest grain size. As expected with increasing grains size and decreasing sample sizes, R2 and pseudo-R2 increased (less variation to explain) and AIC values decreased with larger grain sizes (less entropy to account for). However, when comparing equal grain sizes between GLM and SLM the correction for significant autocorrelation always improved the model (higher pseudo-R2 versus R2 and lower AIC). CL was consistently retained in all SLM for all taxonomic sets at all grain sizes except in the largest grain size. In SLM across all taxa most consistently retained were SW at smallest and largest grain sizes, HDIa at smallest grain size and variably in large grain sizes, HDIn and SST mostly at all grain sizes except small and medium, and NPP negatively correlated and variably retained at larger grain sizes.Multiple regression results were similar to single predictor results in that many environmental variables were significant and retained in models . GLM andRange overlap  of 10,44The pattern of species richness in this study  is dominThe high correlation among our predictor variables  and the I test shows significant effects of autocorrelation in our data (R2 than R2) and more entropy removed from the model (lower AIC). When comparing models based on the same grid size, correction for autocorrelation resulted in a lower AIC, and therefore, SLM is the preferred model The choice of best predictors for species richness  is influour data  similar our data  consisteR2 values increase with increasing grid size over the same area since there is less variation to explain with smaller sample sizes  is not statistically defensible le sizes . Similar2 a habitat heterogeneity index similar to HDIn may suffice in addition to CL as a proxy for habitat availability. Differences in how the different habitat complexity indices behave in models are a result of the form of complexity they emphasize. Our HDIa index is based on the relative proportion of area for our different habitat types  in a grid. Heterogeneity is negatively correlated with shallow water area  and the available kinetic energy predictor variable (SST) are consistently retained as positive significant predicator variables across species groups and grid sizes, accounting for autocorrelation . Coastliter area  because ter area . HDIn ister area . FurtherThe position of the Indo-Pacific Warm Pool appears to be a primary reason that available kinetic energy, as exemplified by SST, is most consistently retained in models with autocorrelation considered . LatitudOur results suggest that kinetic energy, habitat availability, and habitat complexity are all important in shaping species richness patterns across the Indo-Pacific but the relationship of these variables to area of refuge, area of accumulation, and center of origin hypotheses is not straightforward. The striking pattern of diminishing species richness away from the epicenter in the Coral Triangle was a factor in formation of both the center of origin and area of accumulation hypotheses, both mediated primarily by dispersal out of or into the Coral Triangle An alternative explanation for the pattern of increasing species richness into the Coral Triangle from the east and the correlation of SST with species richness is that the position of the Indo-Pacific Warm Pool is only a coincidence and does not influence speciation and extinction rates. If speciation within the Coral Triangle is the dominant factor then dispersal out of the Coral Triangle would rely on stepping stones of available habitat counter to prevailing currents over geologic time periods. There is some evidence for gene direction out of the Coral Triangle Habitat availability is central to both the center of origin and area of accumulation hypotheses but also to the neutral and eclectic hypotheses as well. The observed correlations among species richness, habitat availability, and habitat heterogeneity may simply be a function of the well-known species-area relationship This complex view of the area of refuge hypothesis supports the concept that both area of available habitat and complexity of available habitat are potentially important in models seeking to predict and conserve tropical marine species diversity. Shallow water area, as a measure of available habitat, is a significant component in shaping species richness in the region across different taxonomic groups. However, the largest shallow water area (the Sunda and Arafura shelves), does not coincide with the location of highest species richness . Available habitat in terms of shallow water area alone is not the optimal explanation for variation in species richness because coastline length and habitat heterogeneity are significant explanations for variation in species richness . BellwooAnother factor that may profoundly influence the role that available shallow water area plays in shaping biodiversity in the Coral Triangle is local extinction from glacial maxima and concomitant sea level lows. Marine life was extirpated on the extensive tropical sea floor represented by the Sunda and Arafura shelves several times during the Pleistocene Tittensor et al. (2010) th century Our findings further support previous studies based largely on different distribution databases Available habitat and habitat complexity both significantly explain variation in species richness, and therefore, the loss of these attributes may reduce diversity. Advances in our understanding of the different components of area of refuge may help more clearly define distinctions between available habitat and complexity of habitat. For example, more accurate mapping of presumptive keystone structures such as seagrass beds, mangrove areas, and coral reefs may improve the accuracy of habitat diversity indices. Testing additional types of habitat indices may also improve our understanding. Finding a practical alternative to grid-based spatial analyses may also improve resolution of the degree to which habitat availability components and factors such as SST explain variation in species richness. It is clear that habitat-based conservation efforts targeted at preserving biodiversity should aim to preserve both area and complexity of habitats. This effort is most crucial in the Coral Triangle where species richness is at its peak but it may also be very important in preserving the evolutionary potential of isolated islands, particularly those in the Indo-Pacific Warm Pool. Habitat destruction is a key factor linked to species threats in the Coral Triangle but fortunately, destruction is less intense at present in the islands of Oceania Figure S1Distribution pattern of shallow water extent in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the amount of shallow water area recorded in each cell such that cells in red have the largest amount of shallow water area, and cells in blue have the lowest amount of shallow water area. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S2Distribution pattern of coastal length extent in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the amount of coastal length recorded in each cell such that cells in red have the largest amount of coastal length, and cells in blue have the lowest amount of coastal length. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S3Distribution pattern of the habitat heterogeneity index using area in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S4Distribution pattern of the habitat heterogeneity index using number in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S5Distribution pattern of the mean sea surface temperature in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the highest temperature, and cells in blue have the lowest temperature. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S6Distribution pattern of the mean net primary productivity in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the highest productivity, and cells in blue have the lowest productivity. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S7Combined adjacent cells (red color) against the regular sized cells (yellow color). (A) Small grid, (B) Medium grid, (C) Large grid, (D) UTM, (E) UTM shifted north/south, (F) UTM shifted east/west, (G) UTM shifted northeast/southwest. There are no adjacent cells that were combined in extra large and largest grids.(PDF)Click here for additional data file.Figure S8The two types of basemaps used in this study. (A) Visualization basemap consisting of 200 m depth and 100 km buffer, (B) Bathymetry basemap showing the 200 m depth used in analyses of species richness versus independent variables.(PDF)Click here for additional data file.Figure S9Distribution pattern of coastal length extent in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the amount of coastal length recorded in each cell such that cells in red have the largest amount of coastal length, and cells in blue have the lowest amount of coastal length. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S10Distribution pattern of the habitat heterogeneity index using area in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S11Distribution pattern of the habitat heterogeneity index using number in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S12Distribution pattern of the mean sea surface temperature in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the highest temperature, and cells in blue have the lowest temperature. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S13Distribution pattern of the mean net primary productivity in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the highest productivity, and cells in blue have the lowest productivity. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Table S1Single predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) results at different UTM grid orientations. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001); ns (not significant). UTM NS\u200a=\u200acentroid shifted on a North-South plane, UTM EW\u200a=\u200acentroid shifted on an East-West plane and UTM NE\u200a=\u200acentroid shifted along a Northeast-Southwest plane. Sample size for each grid (n) is shown. The highest adjusted 2R (GLM) and pseudo-2R  value within each grid size are highlighted in boldface.(PDF)Click here for additional data file.Table S2Multiple predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) results at different UTM grid orientations. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001). UTM NS\u200a=\u200acentroid shifted on a North-South plane, UTM EW\u200a=\u200acentroid shifted on an East-West plane and UTM NE\u200a=\u200acentroid shifted along a Northeast-Southwest plane. Sample size for each grid (n) is shown. 2R values are for GLM results, while pseudo-2R (p\u20132R) values are for SLM results.(PDF)Click here for additional data file.Table S3List of families with the number of species distribution maps used in this study.(PDF)Click here for additional data file.Table S4Single predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) complete results at different grid sizes. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001); ns (not significant). Sample size for each grid (n) is shown. The highest adjusted 2R (GLM) and pseudo-2R  value within each grid size are highlighted in boldface.(PDF)Click here for additional data file.Text S1Methods and results for UTM grids shifted to different centroid orientation.(PDF)Click here for additional data file.Text S2Sources for species range used in producing the distribution maps.(PDF)Click here for additional data file."}
+{"text": "Fever is a common observation during critical illness ,2 and maAn online scenario-based questionnaire survey was distributed to medical and nursing members of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG) and their intensive care colleagues. Main outcome measures: the choice of drug and preferred threshold temperature for intervention with antipyretics in clinical practice and in a clinical trial.There were 588 email invitations distributed through the ANZICS-CTG and Research Coordinator mailing list. Four hundred and forty-seven responses were received from 308 nurses (69%), 137 doctors (31%), and two others (0.5%). The majority of respondents having more than 8 years of experience 62%) worked in mixed medical and surgical units (84%) in a metropolitan or tertiary hospital setting (77%). The primary findings of our survey suggest that fever management is highly variable. Most clinicians administer an intervention to reduce temperature at or below 39\u00b0C (Figure % worked This survey suggests there is considerable clinical variability in fever management in patients with sepsis and without neurological injury or hyperthermic syndromes. At present, no particular management strategy is known to be superior to any other and it remains possible that current practice may be harming substantial numbers of patients. A temperature threshold of up to 40\u00b0C may be acceptable to clinicians for the design of a future randomized controlled trial. Further observational data may be informative for the design of such clinical trials."}
+{"text": "Time-series data collected over a four-year period were used to characterize patterns of abundance for pelagic fishes in the northern Gulf of Mexico (GoM) before (2007\u20132009) and after (2010) the Deepwater Horizon oil spill. Four numerically dominant pelagic species  were included in our assessment, and larval density of each species was lower in 2010 than any of the three years prior to the oil spill, although larval abundance in 2010 was often statistically similar to other years surveyed. To assess potential overlap between suitable habitat of pelagic fish larvae and surface oil, generalized additive models (GAMs) were developed to evaluate the influence of ocean conditions on the abundance of larvae from 2007\u20132009. Explanatory variables from GAMs were then linked to environmental data from 2010 to predict the probability of occurrence for each species. The spatial extent of surface oil overlapped with early life habitat of each species, possibly indicating that the availability of high quality habitat was affected by the DH oil spill. Shifts in the distribution of spawning adults is another factor known to influence the abundance of larvae, and the spatial occurrence of a model pelagic predator (blue marlin) was characterized over the same four-year period using electronic tags. The spatial extent of oil coincided with areas used by adult blue marlin from 2007\u20132009, and the occurrence of blue marlin in areas impacted by the DH oil spill was lower in 2010 relative to pre-spill years. Pelagic fishes that frequent open oceans are valuable economically and influence the structure and resilience of offshore ecosystems 6 (\u00b120%) barrels of oil into the northern Gulf of Mexico (GoM) [9). Oil trajectory models predicted that surface or near surface oil covered a large region of the continental shelf and slope In April 2010, the Deepwater Horizon [DH) oil spill resulted in the release of approximately 4.4\u00d710Thunnus atlanticus), blue marlin (Makaira nigricans), dolphinfish (Coryphaena hippurus), and sailfish (Istiophorus platypterus). We first explored temporal variability during early life by contrasting larval abundances of each species before (2007\u20132009) and after (2010) the DH event. Next, generalized additive models (GAMs) were developed from 2007\u20132009 data to assess habitat associations, and then to predict the probability of occurrence the following year (2010) in relation to surface oil . Finally, patterns of occurrence for a model pelagic predator (blue marlin) over the same four-year period were examined using pop-up archival transmitting (PAT) tags, and light-based geo-locations from tags were used to compare the distribution of adults before and after the DH oil spill. Our working hypothesis was that the distribution and abundance of pelagic fishes in our study area, both early life and adult stages, may have changed in 2010 due to changes in habitat condition or other activities related to the DH oil spill. We fully recognize that natural environmental variability is known to influence the distribution and abundance of pelagic fishes in the northern GoM The aim of the present study was to assess possible impacts of the DH oil spill on four pelagic fishes that commonly inhabit outer shelf and slope waters of the northern GoM: blackfin tuna  and the oceanographic factors that influence the abundance of larvae, inter-annual variability was investigated with separate models for June and July. In June surveys, a significant year effect was observed for all four species: blackfin tuna (p\u200a=\u200a0.030), blue marlin (p\u200a=\u200a0.001), dolphinfish (p\u200a=\u200a<0.001), and sailfish (p\u200a=\u200a0.006). Despite the fact that the mean density of each species was lower in June 2010 than any of the other June surveys , this yea concentration, depth, distance to feature, feature classification, salinity, sea surface temperature, sea surface height anomaly) on the occurrence of larvae varied across species and within species when contrasting June and July models  and 44.3% (July). Final GAMs for dolphinfish  retained three explanatory variables in the June model and four in the July model, with depth being the only variable common between the two models. Percent deviance explained for dolphinfish GAMs was 13.2% (June) and 13.5% (July). Final GAMs for sailfish  included three common explanatory variables in June and July models , and percent deviance explained was 20.3% (June) and 15.3% (July).GAMs based on presence/absence data developed for each species indicated that the influence of 7 oceanographic factors  varied markedly among species . The spaectively . High qu2 in both June and July.The spatial extent of surface oil from the DH event was viewed in relation to the total available area of high quality habitat predicted with GAMs to determine whether suitable habitat of each species was exposed to oil contamination. In June 2010, the estimated overlap between high quality habitat and surface oil was relatively low for blue marlin (0%) and sailfish (4.5%). Conversely, percent overlap for blackfin tuna and dolphinfish was considerably higher, with 15.3% and 13.9% of the predicted high quality habitat exposed to surface oil in the northern GoM. Species-specific patterns for July 2010 were similar, and again the percentage of high quality habitat exposed to surface oil was considerably lower for blue marlin (0.2%) and sailfish (7.2%) when compared to blackfin tuna (19.4%) or dolphinfish (11.4%). Given the predicted overlap observed for blackfin tuna, it is not surprising that the areal coverage of high quality habitat exposed to surface oil was relatively large, exceeding 60,000 km2 (9.3%) of the core use area in 2007\u20132009 was exposed to surface oil in 2010. Based on daily mean positions, we also observed that use of a region subsequently closed to fishing in 2010 by the National Oceanic and Atmospheric Administration  and after (2010) the DH oil spill . From 20Both the abundance and percent occurrence of fish larvae for selected pelagic fishes declined in 2010 relative to the three years prior to the DH oil spill, suggesting that changes in environmental conditions, possibly linked to the presence of oil and dispersants, may have contributed to observed inter-annual variability. Previous studies have demonstrated a clear relationship between these contaminants and the demographics of a wide range of marine organisms including invertebrates, fishes, birds, and mammals Although results from this study suggest a possible connection between reduced abundance of pelagic fish larvae in 2010 and the DH oil spill, inter-annual variability is relatively common for cohorts of pelagic larvae in the GoM Variability in mesoscale circulation has been shown to influence the spatial distribution of larvae in the GoM Determining the primary cause of annual fluctuations in the abundance of pelagic fish larvae is challenging, and establishing a direct link between the abundance of larvae and the DH oil spill is not possible given the data available. However, our estimates of overlap between surface oil and high quality habitat of billfish, dolphinfish, and tuna larvae, support the premise that highly suitable nursery areas (or spawning areas) of these taxa were impacted by the DH oil spill. Oil contamination occurred across several hundred thousand square kilometers of suitable habitat of pelagic fish larvae, accounting for approximately 10\u201320% of the available high quality habitat for blackfin tuna and dolphinfish in the northern GoM. Estimates of percent overlap were lower for billfish larvae , and suitable habitat for these taxa appeared to be more limited in coverage and farther offshore , possibly out of reach of significant oil contamination from the DH oil spill. While the presence of surface oil may have impacted larval survival within a restricted area, the majority of the high quality habitat for each species occurred in areas of the northern GoM unaffected by the oil spill. Therefore, anticipated effects of the DH oil spill on early life survival or reduced larval abundance are expected to be relatively modest, which interestingly is in accord with observed annual patterns of abundance.Apart from early life processes that directly impact the dispersal and survival of larvae, differences in the demographics (age structure) and abundance (spawning stock biomass) of spawning adults can also influence the abundance of larvae within a given area The influence of direct  and/or indirect  effects of the DH oil spill on the abundance and distribution pelagic fishes is currently unresolved, and caution must be exercised when interpreting time-series data that are limited in scope and duration. While larval abundances of all four species examined were lower in 2010 relative to the three-year baseline sample, abundance in 2010 was statistically similar to at least one of the other years surveyed, suggesting that observed declines are within the bounds of expected natural variability. Despite the fact that we cannot explicitly link observed inter-annual trends in the abundance of larvae to the DH oil spill, we can conclude that large areas of high quality habitat of pelagic fishes were exposed to oil contamination. In turn, oil contamination may have contributed to observed temporal patterns of abundance, but the main driver  of observed temporal patterns is unknown.Ichthyoplankton surveys were conducted over a four-year period (2007\u20132010) from approximately 26.5 to 28.0\u00b0N latitude and 87.5 to 92.0\u00b0W longitude in the northern GoM. Summer surveys were conducted each year during the same two months , which corresponds to the primary spawning periods of many pelagic fishes in the GoM Thunnus atlanticus (family Scombridae), blue marlin Makaira nigricans and sailfish Istiophorus platypterus (family Istiophoridae), and dolphinfish Coryphaena hippurus (family Coryphaenidae). Density at each station was determined by combining numbers of individuals in both 500 and 1200 \u00b5m mesh nets and adjusted to reflect a sampling depth of 0.75 m. Average volume of water sampled with both nets at each station was approximately 3500 m3. Percent occurrence at the species level was also determined and based on the number of stations where selected taxa were present divided by the total number of stations sampled.Fish larvae were sorted in the laboratory, and density and occurrence were determined for blackfin tuna Thunnus) to species was based on sequence variability of mitochondrial DNA [41) and High Resolution Melting (HRM) assays based on fixed nucleotide differences among species Thunnus larvae to determine the abundance of blackfin tuna (T. atlanticus) in our collections. Two congeners were also present in our collections , and blackfin tuna accounted for nearly 90% of the Thunnus larvae collected.Fish larvae were identified visually to family level based on anatomical and morphometric features Temporal differences in the densities of larvae collected over the four-year period were compared with a Kruskal-Wallis (rank sums) one-way analysis of variance (ANOVA). This non-parametric method does not assume a normal distribution, which was required due to the large number of zero values in our data set (skewed distribution). Species-specific models were developed for each species in both June and July to investigate temporal differences in larval density for all four species. Non-parametric multiple comparison tests (Wilcoxon method) were run to determine which factor levels or years differed from others. Statistical significance for all tests was based on \u03b1\u200a=\u200a0.05.a, depth), and parameters related to mesoscale oceanographic features   were used to investigate the influence of environmental conditions on the occurrence of each species. Presence/absence models were fit with a binomial distribution using a logit link function in R software feature) . MesoscaA manual backwards stepwise procedure based on minimizing the Akaike Information Criterion  tags were deployed opportunistically on blue marlin from sport fishing vessels in the GoM from 2007\u20132010, following methods previously described Daily mean position estimates from the primary spawning season of blue marlin (May\u2013July) were compared before (2007\u20132009) and after (2010) the DH oil spill. PAT tag data from deployments prior to the DH oil spill (n\u200a=\u200a13) ranged from 60 to 365 days. Daily mean positions of adult blue marlin after the spill were based on geo-location estimates generated from 1-year tag deployments on blue marlin (n\u200a=\u200a4). These fish were tagged in summer/fall 2009 and the tags released from fish during or after July 2010. Our analysis is based on the assumption that individuals return to the same general spawning area the following year, which is supported by long-term tag deployments on blue marlin and white marlin before or after 2010 . GriddedFigure S1Spatial and temporal variability in the density of pelagic fish larvae collected from 2007 to 2010 for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus). June (red) and July (blue) survey shown and colored lines represent the observed margin of the Loop Current during each sampling trip (coded by color). Density (larvae. 1000 m\u22123) denoted by circle size.(TIF)Click here for additional data file.Figure S2Response plots from final presence/absence generalized additive models (GAMs) based on June data for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus).(PDF)Click here for additional data file.Figure S3Response plots from final presence/absence generalized additive models (GAMs) based on July data for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus).(PDF)Click here for additional data file.Figure S4Map showing the region closed to fishing on June 21, 2010 by the National Oceanic and Atmospheric Administration due to the Deepwater Horizon oil spill.(TIF)Click here for additional data file.Figure S5Long-term tracks (ca. 1 year) of individual A) white marlin  and B) blue marlin (Makaira nigricans) from pop-up archival transmitting (PAT) tags deployed in the Gulf of Mexico. Blue shading depicts kernel density (95% volume of utilization distribution shown) based on daily mean positions the first month of the deployment (dark blue) and the same month the next year (light blue). Colored symbols represent quarterly geo-location estimates for each individual over the deployment period and all geo-location data were generated using state-space models that implemented the Kalman filter algorithm from light-based location data generated from PAT tags. Estimated weights of white marlin (ID: WM-09-01) and blue marlin (ID BM-10-02) shown here were 30 and 120 kg, respectively.(TIF)Click here for additional data file.Table S1(DOCX)Click here for additional data file."}
+{"text": "Although postsynaptic and transmembrane currents over local neuronal populations are considered the main factors for shaping local field potential (LFP) and current source density (CSD) fluctuations , high-frFirstly, we employ a spiking network model of the CA3 and CA1 hippocampal areas that reproduces key features of SWRs based on synchronous CA3 population bursts and strong, fast-decaying CA1 recurrent inhibition . The emein vivo, from multiple locations in areas CA3 and CA1 of the rat hippocampus while animals run on a linear track with resting areas at both ends. The spiking activity of detected place cells, firing in sequence during the running sessions, is replayed in either forward or reverse order during SWRs occurring at the resting areas [Next, we apply our analysis to a set of LFPs and unit activity, recorded ng areas . We tracThis work provides a deeper understanding of the nature of extracellular fields and offers a new approach to the decoding of ongoing cell assemblies based on extracellular current flows. Differences in the emerging SWR field activity may play an important role in information processing during memory consolidation."}
+{"text": "Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions. Cardiovascular disease is the number one cause of death worldwide and remains a burdensome health problem. Understanding the underlying molecular mechanisms of cardiovascular disease will provide valuable information for the design of novel drugs for pharmacological therapies.As a central player of the canonical NO-sGC-cGMP pathway, sGC controls important physiological functions such as smooth muscle relaxation, platelet aggregation, and hemostasis   NO is formed via two primary pathways. NO is generated when endothelial nitric oxide synthase (eNOS) is activated by Cain vitro and cell lysates  further mediates membrane localization of sGC in cardiomyocytes . Riociguat raises the potency of sGC activation by NO and has been approved for the treatment of pulmonary arterial hypertension   mice but not in CD36\u2212/\u2212 mice  that putatively inactivated/inhibited sGC through phosphorylation at a yet to be determined residue  signaling  and cystathionine \u03b3-lyase (CSE)   and hydrogen peroxide (H2O2) that in turn modify proteins and adversely alter their function . TSP1 is a more potent stimulator of ROS compared to the classic activators phorbol myristate acetate and angiotensin II. The CD47 targeting peptide 7N3 that contains the Val-Val-Met sequence also increased VSMC O\u00b7\u22122 production -mediated activation of sGC and subsequent dephosphorylation of myosin light chain 2 (the kinase responsible for vasoconstriction) while increasing immuno-reactive F-actin in cultured VSMC  TSP1\u2212/\u2212 mice maintained a more normal cardiovascular profile compared to wild type animals with less change in right ventricular systolic pressure, less right ventricular hypertrophy and less pulmonary vascular smooth muscle cell hyperplasia. This observation was further associated with less pulmonary ROS production  10SDG2600345 (Elsa D. Garcin), 13PRE17000045 (Franziska Seeger) and 13POST14520003 (Natasha M. Rogers) and by the Intramural Research Program of the NIH/NCI (David D. Roberts). This work was further supported by the Institute for Transfusion Medicine, the Hemophilia Center of Western Pennsylvania and the Vascular Medicine Institute (Jeffrey S. Isenberg).Jeffrey S. Isenberg is Chair of the Scientific Advisory Boards of Vasculox, Inc.  and Radiation Control Technologies, Inc.  and holds equity interest in the same. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The female genital tract is an important site of HIV acquisition, but the epithelial and submucosal tissue factors associated with HIV susceptibility have not been defined.Ectocervical biopsies were obtained from HIV-exposed seronegative (HESN) women (n=20) and HIV-seronegative lower risk controls (n=20). Epithelial thickness and tissue distribution of immunological markers were assessed in situ by immunohistochemistry and measurement of mRNA expression was performed by quantitative PCR.The thickness of the ectocervical epithelium was significantly higher in HESN vs. lower risk subjects. CD4 and DC-SIGN mRNA expression was significantly lower in HESN than lower risk women, and in situ immunohistochemical analysis confirmed the reduced CD4 expression in HESN participants. In addition, immunohistochemistry demonstrated lower CCR5 and higher Langerin expression in the HESN subjects.A thicker epithelial barrier and altered expression of HIV binding receptors in the ectocervix of HESN women may contribute to protection against HIV transmission."}
+{"text": "NUAK2 as a member of the AMPK family has several intriguing aspects both as an oncogene and as a tumor suppressor gene. Here we review genomic aberrations of melanomas focusing on acral melanomas to emphasize the possible roles of NUAK2 in tumorigenesis in general and suggest that NUAK2 has pivotal roles in acral melanomagenesis.Recent technological advances in cancer genomics make it possible to dissect complicated genomic aberrations of melanomas. In particular, several specific genomic aberrations including 11q13 amplification and KIT aberrations have been identified in acral melanomas. We recently identified NUAK2 at 1q32 as a promising oncogene in acral melanomas and reported its significant roles in tumorigenesis in melanoma cells using both  The identification of genes that participate in oncogenesis has facilitated recent development of molecular targeted therapies against cancer (reviewed in -3). In tThe SNF1/AMP-activated protein kinase (AMPK) family functions to control the balance of cellular metabolisms, and is activated by the cellular AMP:ATP ratio that is regulated by metabolic stresses such as hypoxia and glucose deprivation , 18. AMPRecent tenacious efforts by investigators have accelerated the elucidation of genomic alterations in melanoma cells. The first step to decipher enigmas in complex genomic alterations in melanoma cells had started by taking advantage of techniques that had been utilized to elucidate chromosomal abnormalities in hematopoietic malignancies -39. ThosAcral melanomas occur on nailbeds and plantar regions such as the palms of the hands and soles of the feet . The hisCGH combined with analyses of clinical parameters are a powerful approach to identify genomic loci that have significant impact on the clinical outcome of melanoma patients. Both the classical cytogenetic approach and the CGH approach share the same implication that the long arm of chromosome 1 and the short arm of chromosome 6 may have a profound effect on the tumorigenesis of melanomas since both chromosomal regions have a significant impact on the clinical outcome of patient survival Fig. 50, 61], 6150, 6NUAK2 is the fourth member of the AMPK family of kinases and shares a similar catalytic domain of the sucrose-non-fermenting protein kinase (SNF1)/AMP-activated protein kinase (AMPK) family of serine/threonine protein kinases. The NUAK2 gene resides at 1q32 and encodes 630 amino acid residues that are translated into a protein of approximately 76 kDa . In geneCaenorhabditis elegans, participates in maintaining the integrity of components of myosin filaments. Disruption of unc-82 by mutations causes defects in cytoskeleton reorganization during embryogenesis [The amount of knowledge about the regulation and function(s) of NUAK2 is quite limited compared to AMPK-\u03b11 and AMPK-\u03b12. However, several important functions related to myosin filaments and cytoskeleton organization have been revealed. Myosin phosphatase target subunit 1 (MYPT1) was identified as a specific substrate for NUAK2. MYPT1 is phosphorylated by NUAK2 at sites other than Thr696 and The853, which are known as Rho-kinase (ROCK) phosphorylation sites . Furtherogenesis . Anotherogenesis . As the ogenesis , 81. Musin vitro and tumor growth in vivo in melanomas, and the extent of those reductions of cell proliferation varies depending on the different genomic aberrations of melanoma cells [in vivo from the profile of the proliferating cell population [Disruption of the normal regulation and function(s) of NUAK2 may lead to the dysregulation of proliferation and migration in cancer cells. However, the exact effects and mechanisms participating in tumorigenesis remain to be elucidated due to the lack of sufficient molecular studies of NUAK2. Several conflicting results on tumorigenesis including cell proliferation, apoptosis and migration have been reported. The knockdown of NUAK2 using siRNA or shRNA reduces cell proliferation ma cells . Anotherpulation . Over-expulation . This fupulation , 84. Howpulation . NUAK2 apulation . CD95 stP = 0.0036), and multivariate analysis using multiple Cox regression analysis also showed the impact of NUAK2 on relapse-free survival . Interestingly, those impacts of NUAK2 on melanoma patient survival are significant at relapse-free survival of acral melanomas compared to weak significances at Non-CSD melanomas and overall survival. Those observations lead to the speculation that NUAK2 has more profound effects on cell migration resulting in worsening relapse-free survival of acral melanoma patients as suggested by both a migration assay and a wound healing assay [UV irradiation is one of the major causes of cutaneous melanomas, but acral and mucosal melanomas are protected from exposure to UV irradiation due to their anatomical locations. Thus, the molecular pathogenesis of acral and mucosal melanomas should be different from that of cutaneous melanomas arising from sun-exposed areas such as Non-CSD melanomas, and causes other than UV irradiation, such as reactive oxygen species (ROS), may play an important role in the melanomagenesis of acral and/or mucosal melanomas. The HGF/SF transgenic mouse model is prone to develop cutaneous melanomas following UV irradiation . In thatng assay .The recent identification of KIT mutations in acral, mucosal and CSD melanomas led to the development of therapeutic modalities using imatinib mesylate to target KIT activation. Although initial studies achieved only poor responses using imatinib mesylate against melanomas, the stratification and appropriate selection of patients based on KIT activation by mutations and amplifications have improved responses of melanoma patients to imatinib mesylate , 98. As"}
+{"text": "Gastric tube after esophagectomy can be the site of local recurrence or the development of second primary tumor which implies poor prognosis. The study presents an extremely rare case of a patient after Ivor-Lewis esophagectomy for squamous cell carcinoma, in whom there was detected local recurrence in the anastomosis associated with metachronous primary tumor in gastric tube. Esophageal reresection with the upper part of the stomach was performed. Left colonic segment supplied by middle colic vessels transposed through retrosternal route was used as new esophageal substitute. Esophagectomy with lymph node dissections combined with adjuvant therapy remains the basic method of esophageal cancer surgical treatment. The stomach is the most commonly used esophageal substitute after esophagectomy. Owing to the availability of new, more precise diagnostic techniques and to the improvement of the late outcomes of esophageal cancer treatment, there increases the detectability of the cases of second primary malignancies in the stomach . The coeThe surgical treatment of a cancer diagnosed in the gastric tube after esophagectomy is a difficult and rarely undertaken surgical challenge associated with the risk for severe complications and high mortality.A female patient, MZ, aged 61\u2009years, referred primarily for surgical treatment due to esophageal cancer detected in the epicardial region. Endoscopic examination revealed a primary tumor located 30\u2009cm from the incisors. Endoscopic evaluation of the stomach lumen was impossible due to esophageal stricture at the tumor level. Histopathological examination of tumor specimens led to the diagnosis of squamous cell carcinoma. Preoperative thoracic computed tomography (CT) detected neither tumor infiltration on the surrounding tissues nor the enlargement of the regional lymph nodes in the thorax and abdominal cavity.Based on the results of diagnostic investigations which confirmed the possibility of local excision of the tumor, the patient was qualified for surgical treatment.3N0M0, Stage II A). Microscopically esophageal and gastric rings were free from neoplastic cells. The proximal resection margin was 4\u2009cm. Eighteen lymph nodes of the following groups were removed: upper thoracic paraesophageal lymph nodes (2), right thoracic paratracheal lymph nodes (1), bifurcation lymph nodes (2), middle thoracic paraesophageal lymph nodes (2), right pulmonary hilar lymph nodes (1), lower thoracic paraesophageal lymph nodes (2), diaphragmatic lymph nodes (1), posterior mediastinal lymph nodes (2), lesser curvature lymph nodes (3), left gastric artery lymph nodes (1), and common hepatic artery lymph nodes (1). All lymph nodes were free of cancer cells. The patient\u2019s postoperative course was uncomplicated and she was discharged from hospital after 17\u2009days. After surgery, the patient did not report for further treatment at an oncological center.Partial Ivor-Lewis esophago-gastrectomy was performed with conventional two-field en block lymphadenectomy using a gastric tube as an esophageal substitute. The esophagogastroplasty was performed in the right pleural cavity. The postoperative histopathological examination showed squamous cell carcinoma keratodes G-2 invading the adventitia without lymph node metastasis (pTThe follow-up endoscopy performed 6\u2009months after esophagectomy showed: (A) mucosa at the site of anastomosis: uneven, congested with superficial lesions covered with fibrin, unchanged esophageal mucous membrane proximal to anastomosis. About 3\u2009cm below the anastomosis was a stocky polyp of 10 to 12\u2009mm in diameter (B) surrounded by normal gastric mucosa. Congested mucosa without lesions were in the gastric tube distal segment. The results of histopathological examinations revealed: (A) gastric mucosa segment with the features of foveolar hyperplasia, (B) polyp from the gastric tube - squamous cell carcinoma keratodes . The result of CT after esophagectomy was . En bloc dissection of residual esophagus was performed to the level of the apex of the chest and then the esophageal stump was cut 8\u2009cm above the anastomosis Figure\u2009. The esopT2N0Mx (primary focus), the tumor sounded by normal gastric mucosa; and (c) lymph nodes from the thoracic area (7) and neck (4) without tumor cells.The results of postoperative histopathological examination were (a) distal esophageal stump with anastomosis: recurrence of squamous cell carcinoma keratodes G-2, tumor emboli in lymphatic vessels, proximal esophageal stump free of tumor infiltration; (b) tumor located in gastric tube, squamous cell carcinoma Eight weeks after surgery, in the course of the second cycle of chemotherapy, dysphagia developed. Endoscopy revealed no anastomotic stenosis. Within a 3-week period an effective endoscopy-guided dilatation with a balloon was performed twice. Six months after reoperation no recurrence of the neoplastic process was observed in follow-up diagnostic tests.The use of the stomach as an esophageal substitute after esophagectomy is commonly accepted by the majority of surgeons ,5. The sIn the case of metachronous tumors located in the gastric tube the therapeutic management depends on the depth of tumor infiltration to the gastric wall -12. In tet al.[Gastric tube resection requires reconstruction of gastrointestinal tract with the useof colonic or small intestine conduit. In such situations colon graft is preferred owing to its proper length, reliable blood supply, and fewer complications ,12,15. Iet al.. The nonGastric tube resection with the creation of a new esophageal substitute from the colon is a difficult but possible treatment option in selected cases of recurrence or second primary cancer of the stomach detected in postoperative follow-up..Written informed consent was obtained from the patient for publication of this report and any accompanying imagesThe authors declare that they have no competing interests in this paper.SJ composed the case report, prepared and edited this manuscript, contributed it conception, collected the data and conducted a literature search. \u0141P and MW participated in the data collection and gave final approval for this version of the manuscript. All authors read and approved the final manuscript."}
+{"text": "Nilaparvata lugens  and Laodelphax striatellus  are two of the most important pests of rice. Up to now, there was only one mitochondrial genome of rice planthopper has been sequenced and very few dependable information of mitochondria could be used for research on population genetics, phylogeographics and phylogenetic evolution of these pests. To get more valuable information from the mitochondria, we sequenced the complete mitochondrial genomes of BPH and SBPH. These two planthoppers were infected with two different functional Wolbachia (intracellular endosymbiont) strains (wLug and wStri). Since both mitochondria and Wolbachia are transmitted by cytoplasmic inheritance and it was difficult to separate them when purified the Wolbachia particles, concomitantly sequencing the genome of Wolbachia using next generation sequencing method, we also got nearly complete mitochondrial genome sequences of these two rice planthoppers. After gap closing, we present high quality and reliable complete mitochondrial genomes of these two planthoppers.N. lugens (BPH) and L. striatellus (SBPH) are 17, 619 bp and 16, 431 bp long with A + T contents of 76.95% and 77.17%, respectively. Both species have typical circular mitochondrial genomes that encode the complete set of 37 genes which are usually found in metazoans. However, the BPH mitogenome also possesses two additional copies of the trnC gene. In both mitochondrial genomes, the lengths of the atp8 gene were conspicuously shorter than that of all other known insect mitochondrial genomes . That two rearrangement regions (trnC-trnW and nad6-trnP-trnT) of mitochondrial genomes differing from other known insect were found in these two distantly related planthoppers revealed that the gene order of mitochondria might be conservative in Delphacidae. The large non-coding fragment (the A+T-rich region) putatively corresponding responsible for the control of replication and transcription of mitochondria contained a variable number of tandem repeats (VNTRs) block in different natural individuals of these two planthoppers. Comparison with a previously sequenced individual of SBPH revealed that the mitochondrial genetic variation within a species exists not only in the sequence and secondary structure of genes, but also in the gene order (the different location of trnH gene).The mitogenomes of The mitochondrial genome arrangement pattern found in planthoppers was involved in rearrangements of both tRNA genes and protein-coding genes (PCGs). Different species from different genera of Delphacidae possessing the same mitochondrial gene rearrangement suggests that gene rearrangements of mitochondrial genome probably occurred before the differentiation of this family. After comparatively analyzing the gene order of different species of Hemiptera, we propose that except for some specific taxonomical group (e.g. the whiteflies) the gene order might have diversified in family level of this order. The VNTRs detected in the control region might provide additional genetic markers for studying population genetics, individual difference and phylogeographics of planthoppers. The mitochondrial genome is the most commonly used molecular marker for phylogenetic studies, population genetics and dynamics, phylogeography  and evenThe order Hemiptera is the largest group of the hemimetabolous insects  and inclNilaparvata lugens and the small brown planthopper (SBPH), Laodelphax striatellus (Hemiptera: Delphacidae) are two of the most important pests in rice fields of many Asian countries. By transmitting virus diseases [Wolbachia[Wolbachia strains, we also obtained nearly the complete mitochondrial genomes of BPH and SBPH. The Wolbachia strain wStri infecting SBPH can induce complete Cytoplasmic Incompatibility (CI), a reproductive modification that typically results in embryonic lethality between crosses of infected males and uninfected females. On the other hand, the Wolbachia strain wLug infecting BPH cannot induce CI at all.The brown planthopper (BPH), diseases  and causdiseases . These tWolbachia which caWolbachia,24. WhiltrnH gene) were verified using natural populations. In addition, comparing mitochondrial genome of SBPH sequenced in this study with a previously sequenced individual revealed a remarkable variability between these two individuals.After gap-closing, the complete mitochondrial genomes of these two most important rice piercing and sucking type pests, BPH and SBPH were determined. We analyzed the nucleotide composition, codon usage and genomic rearrangement of these two mitochondrial genomes and compared them with mitochondrial genomes of other hemipteran species. Some special characteristics of mitochondria of these two planthoppers  in \u2018A + T\u2019 rich regions; location of N. lugens (BPH) mtDNA and another scaffold containing 3 contigs of L. striatellus (SBPH) were identified in the assemblage of the wLug and wStri genome  which were reported so far. The unusual length of the mitochondrial genome in N. lugens is partly due to a long putative control region and a long repeat region containing three repeats of trnC gene  of BPH, trnS2 (UCN) of SBPH which harbor a simple loop in the dihydrouridine (DHU) arm and trnH of SBPH could have a loop-stem structure like trnT of BPH  that forms a loop is found in many Hemiptera [trnS1 (AGN) has a completed loop-stem structure while that of trnS2 (UCN) has a loop. In contrast, the trnS1 (AGN) has a loop and trnS2 (UCN) has a completed loop-stem structure in previously reported SBPH [trnH gene of SBPH which formed a weak loop-stem structure of the T-arm (T\u03a8C) in this study possessed a stable loop-stem structural of the T-arm (T\u03a8C) in previous study [All of the tRNA genes have the typical cloverleaf secondary structure, except for emiptera ,18,27-30emiptera . For SBPted SBPH . Furtherus study .trnS2 (UCN) (SBPH) and 57 bp for trnS1 (AGN) (BPH) to 71 bp for trnK (BPH and SBPH) and trnV (BPH)  and rrnL . They are located between trnL1 (CUN) and an A+T-rich region, separated by trnV.The length of all tRNA genes ranged from 56 bp for trnC-trnW and nad6-trnP-trnT) associated with tRNAs and PCGs were found in both of BPH and SBPH . But the most striking feature was the different locations of the trnH gene in two individuals of SBPH. The trnH gene is located between nad5 and nad4 genes in this study just as in all other hemipteran species sequenced so far, but Song and Liang (2009) previously reported that this tRNA gene is located between nad4L and nad6 genes . This feature is common in hemipteran insects [The mtDNAs of BPH and SBPH contain the full set of PCGs usually presented in animal mtDNA. Except for the  Insects   were the shortest in insects known so far. In fact, the longest atp8 gene (228 bp) was found in Bemisia tabaci (Hemiptera: Aleyrodidae) [Pachypsylla venusta) [Lymantria dispar) [atp8 gene had a length of about 160 bp. Taking into account the length of atp8 gene of planthoppers discovered in this study, it seems that the length distribution of atp8 gene in Hemiptera was wider (From 99 bp to 228 bp) than that of all other orders of insects reported so far. The sequence alignment of atp8 gene with other insects revealed that nearly 60 bp length of sequence in the 3\u2032end of this gene was lost in these two planthoppers. Does the short length of this gene change the structure of its encoded protein? Does length change of this gene alter the functions or efficiency of this gene? These aspects are worth further studying.It is worth mentioning that the lengths of rodidae) . In almovenusta)  to 183 b dispar) . In mostThe abundance of codon families and Relative Synonymous Codon Usage (RSCU)  in PCGs rrnS and trnI-trnQ-trnM gene cluster  in the A+T-rich region. This poly \u201cT\u201d structure might be conservative in Delphacidae and be responsible for the control of replication and transcription of mitochondria.Neuroctenus parus) to 86.3% (Aleurodicus dugesii). These two extreme A+T content species were inferring gene arrangement [The composition of the majority strand (J-strand) of SBPH mtDNA is A = 7099 (43.2%), T = 5581 33.97%), G = 1527 (9.29%) and C = 2224 (13.54%). The composition of the J strand of BPH mtDNA is A = 7393 (41.96%), T = 6165 (34.99%), G = 1661 (9.43%) and C = 2400 (13.62%). Similarly to most hemipteran insects, the nucleotide compositions of the two planthopper mitogenomes are significantly biased toward A and T . Comparing with 48 mitochondrial genomes of hemipteran species, we found that there is considerable variation in base composition among different hemipteran species: ranging from 68.9%  to 0.2765 (Lycorma delicatula) with the BPH and SBPH mtDNA exhibiting a slight different AT-skew (0.0909 for BPH and 0.119171 for SBPH). The GC-skews of hemipteran species vary from \u22120.2827 (Acyrthosiphon pisum) to 0.2086 (Neomaskellia andropogonis) with the BPH and SBPH mtDNAs exhibiting very similar GC-skew (\u22120.1826 for BPH and \u22120.1842 for SBPH). Similarly, the AT/GC-skew values exhibit different ranges among three suborders: AT-skew: Heteroptera, 0.0642 - 0.2181,\u2009Sternorrhyncha,\u2009-0.1812\u2009- 0.0956, Auchenorrhyncha, 0.0623\u2009-T\u20090.2765;\u2009GC-skew:\u2009Heteroptera,\u2009-0.2656\u2009-(\u22120.0965),\u2009Sternorrhyncha,\u2009-0.2810\u2009-\u20090.2086,\u2009Auchenorrhyncha,\u2009-0.2827 - (\u22120.0783).The hemipteran AT-skews vary from \u22120.1812  of Sternorrhyncha, all species of Aleyrodidae exhibit converse AT/GC-skew values Figure\u00a0 as descrrrnL gene and rrnS gene with the entire mitochondrial genome, PCGs show more significant positive correlation (R2 = 0.9674) than rrnL gene (R2 = 0.8873) and rrnS gene (R2 = 0.7189) , complete trnH gene (62 bp), two intergenic nucleotides and a portion of nad4 gene (96 bp). All sequenced individuals  have an identical sequence of the trnH gene which was the same with that of the mitochondrial genome of SBPH sequenced in this study. Considering the low probability of many different sites in the trnH gene related sequences caused by PCR or sequencing, we still cannot exclude the possibility that some sporadic individuals of SBPH possessing the same location of trnH gene as previous study exist in some special regions in China. Anyway, according to the mutation sites  of all sequences of the region compassing trnH gene, 16 haplotypes of the sequence were identified  were observed in natural populations  and one ATP synthase gene (atp8). Because of the different locations of trnH gene, positions of the start codon of nad5 and nad6 genes and the end codon of nad4 and nad6 genes had been changed. Comparing the region (from nad5 to nad6) of mitochondrial genomes of SBPH with that of previous study, we found the differences were 57 bp deletion in the front of nad5 gene, 21 bp deletion at the end of nad4 gene and 84 bp insert in the front and 55 bp deletion at the end of nad6 gene. Furthermore, there also existed 21 bp absent in the nad2 gene and 60 bp absent at the end of atp8 gene  of mitochondrial genome of these two SBPH, the other eight PCGs and two ribosomal RNA genes represented significant difference in the evolution rates  showed the fastest mutation rate among these genes. The mutation rates of the other PCGs ranged from 0.0022 to 0.0076. The evolution rate of rrnS gene (0.8%) was five times faster than rrnL gene (0.16%). In general, except the trnH and two trnS genes, the other tRNA genes were conserved (only few of them have single variant site).Excluding five length distinct genes  detected in the control region might provide additional genetic markers for studying population genetics, individual difference and phylogeographics of planthoppers. The comparative analyses of two sequenced mitochondrial genomes of SBPH revealed that rearrangements of genes in the mitochondrial genome could have occurred in the same species. On account of the different locations of trnH gene, the start and end codon of its neighboring genes had been changed. Even the same tRNA gene (e.g. trnS1 (AGN) and trnS2 (UCN) genes) could form different secondary structures in these two different individuals of SBPH. All these characteristics reveal that great divergence of mitochondrial genome could occur in different individuals of a species.The rearrangement of mitochondrial genome of planthoppers reported in this study adds more examples of the rearranged pattern of genes in the mitochondrial genomes of hemipteran insects studied so far. The fact that the rearrangement was conserved in Delphacidae suggests that gene rearrangements of mitochondrial genome probably occurred before the differentiation of this family. Compared with other hemipterans and other insects, the extreme short lengths of Laodelphax striatellus  and Nilaparvata lugens  for mitochondrial genome sequence were collected in China. Other natural populations which were used to validating location of trnH of SBPH and detecting the variable number of tandem repeats (VNTRs) in control regions of BPH and SBPH were collected in different locations of China  generated from the PCR-free random shotgun-sequencing libraries of average insert size 500 bp, one scaffold composed of three contigs of mitochondrial genome of SBPH  and one scaffold composed of four contigs of mitochondrial genome of BPH  were generated  were determined based on alignments and secondary structures of rRNA sequences of other hemipteran species. The boundaries of the ribosomal rrnL gene were assumed to be delimited by the ends of the trnL1 (CUN) and trnV. The 3\u2032 end of rrnS gene was assumed to be delimited by the start of trnV while the 5\u2032 end was determined through comparison with orthologous genes of other hemipteran species sequenced so far. The base composition, the Relative Synonymous Codon Usage (RSCU) values of BPH and SBPH were calculated with MEGA 4 program [After finished the gap closing work, we annotated the mitochondrial genomes of BPH and SBPH. All PCGs were identified by ORF Finder implemented at the NCBI website with the invertebrate mitochondrial genetic codes. Finally pair-wise comparisons with orthologous proteins from other hemipteran insects were performed to better define the limits of PCGs. The transfer RNA (tRNA) genes were identified using both of the tRNAscan-SE  and ARWE program .trnH rearrangement types really exist in natural populations, we sequenced a region of mitochondrial genome encompassing the trnH gene from 309 individuals of SBPH which were collected from 15 natural populations and also checked the Wolbachia infection status of each individual  to calculate the frequency of each haplotype of the sequence of this region. The sequences of each haplotype are deposited in the GenBank database under the Accession No. KC006945 - KC006960.After downloaded other mitochondrioal genome sequence  were not calculated for the variant length of these genes in these two individual mitochondria.The mutation rates of each gene between mitochondrial genomes of two individuals of Click here for fileNilaparvata lugens and Laodelphax striatellus used in this study. Collection information for natural populations of Click here for file"}
+{"text": "S)-PD172938 and arylated analogues with hypnotic sedative activity, obtained in good overall total yield (50%) and high enantiomeric purity (95% ee). The synthetic routes developed herein are particularly convenient in comparison with the current methods available in literature and are particularly promising for large scale applications.New bifunctional chiral ammonium salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as the Belliotti ( The enantiomeric excess was determined by derivatization of the compound into methyl ester 12 or amide 16.File 11H NMR, 13C NMR and HPLC traces.Complete experimental details and procedures, spectroscopic data, copies of"}
+{"text": "Azadirachta indica L.) leaf has been widely used in ayurvedic system of medicine for fertility regulation for a long time. The molecular mechanism by which neem leaf regulates female fertility remains poorly understood. Animal studies suggest that aqueous neem leaf extract (NLE) induces reactive oxygen species (ROS) - mediated granulosa cell apoptosis. Granulosa cell apoptosis deprives oocytes from nutrients, survival factors and cell cycle proteins required for the achievement of meiotic competency of follicular oocytes prior to ovulation. Under this situation, follicular oocyte becomes more susceptible towards apoptosis after ovulation. The increased level of hydrogen peroxide (H2O2) inside the follicular fluid results in the transfer of H2O2 from follicular fluid to the oocyte. The increased level of H2O2 induces p53 activation and over expression of Bax protein that modulates mitochondrial membrane potential and trigger cytochrome c release. The increased cytosolic cytochrome c level induces caspase-9 and caspase-3 activities that trigger destruction of structural and specific proteins leading to DNA fragmentation and thereby oocyte apoptosis. Based on these animal studies, we propose that NLE induces generation of ROS and mitochondria-mediated apoptosis both in granulosa cells as well as in follicular oocyte. The induction of apoptosis deteriorates oocyte quality and thereby limits reproductive outcome in mammals.Neem ( Azadirachta indica L.) has been considered as one of the most important medicinal plants worldwide. The medicinal utility of this plant are listed in ancient documents \u2018Charak-Samhita\u2019 and \u2018Susruta-Samhita\u2019 that are considered as the foundation of the Indian system of natural treatment, Ayurveda  during final stages of folliculogenesis and ovulation, while their effects are neutralized by active enzymatic antioxidant system  in rat ovary  of NLE  leaf extract-induced egg apoptosis in rat\u201d funded by Department of Science and Technology, Ministry of Science and Technology, Government of India, New Delhi.Author SKC is the Principal Investigator of a project entitled \u201cStudies on neem ("}
+{"text": "Myocardial infarction was experimentally induced in rat hearts and harvested immediately, 7, 14 and 28 days after the infarction induction. Anterior wall infarct samples underwent biaxial tensile and uniaxial compressive testing. Orientation of collagen fibres was analysed following mechanical testing. In this paper, we present the tensile and compressive stress\u2013strain raw data, the calculated tensile and compressive moduli and the measured angles of collagen orientation. The presented data is associated with the research article titled \u201cCharacterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression\u201d  [1]. Specifications TableValue of the data\u2022Full presentation of biaxial mechanical data and collagen fibre orientation for healing myocardial infarcts.\u2022The presented data demonstrates the mechanical and structural anisotropy of the healing myocardial infarcts.\u2022First report to characterize the compressive properties of the healing rat myocardial infarcts.\u2022Presentation of collagen fibre orientation in healing myocardial infarcts.\u2022The presented mechanical and structural data can be utilised in constitutive modelling of healing myocardial infarcts for rats.1The data being shared describe the mechanical and structural properties of healing rat myocardial infarcts from individual samples in several post-infarct time points: immediately (i.e. 0 day), 7, 14 and 28 days after the induction of myocardial infarction. The mechanical data are composed of biaxial tensile stress\u2013strain relationships , Fig. 4,2The details of the experimental work and materials are provided in"}
+{"text": "To the Editor: Marburg virus (MARV) and Ravn virus (RAVV), collectively called marburgviruses, cause Marburg hemorrhagic fever (MHF) in humans. In July 2007, 4 cases of MHF  occurred in miners at Kitaka Mine in southern Uganda. Later, MHF occurred in 2 tourists who visited Python Cave, \u224850 km from Kitaka Mine. One of the tourists was from the United States (December 2007) and 1 was from the Netherlands (July 2008); 1 case was fatal (Rousettus aegyptiacus bats (Egyptian fruit bats).Longitudinal investigations of the outbreaks at both locations were initiated by the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention  in collaboration with the Uganda Wildlife Authority (UWA) and the Uganda Virus Research Institute (UVRI). During these studies, genetically diverse MARVs and RAVVs were isolated directly from bat tissues, and infection levels of the 2 viruses were found to increase in juvenile bats on a predictable bi-annual basis  Figure. R. aegyptiacus colonies in the area. Although minor colonies of small insectivorous bats were found, the only identifiable colony of R. aegyptiacus bats was found inside the re-opened Kitaka Mine, albeit at much reduced size, perhaps 1%\u20135% of that found before depopulation efforts.In October 2012, the most recent known marburgvirus outbreak was detected in Ibanda, a town in southwest Uganda. Ibanda is \u224820 km from the Kitaka Mine and is the urban center that serves smaller communities in the Kitaka area. This MHF outbreak was the largest in Ugandan history: 15 laboratory-confirmed cases occurred  were positive for marburgvirus RNA by quantitative reverse transcription PCR (32/233 [13.7%] adults and 21/167 [12.6%] juveniles; Of the 400 Phylogenetic analysis of viral RNA genome fragment sequences in this study showed high marburgvirus genetic diversity, including the presence of RAVVs and MARVs. Sequences for isolates from 3 bats were nearly identical to those of the MARV isolates obtained from patients in the 2012 Ibanda outbreak (Photographs taken during August 2008\u2013September 2009 of bat extermination efforts at Kitaka Mine, and table showing demographic characteristics of bats captured during a Marburg hemorrhagic fever outbreak investigation at the mine in November 2012, Uganda."}
+{"text": "Although extensively studied and indeed emotionally discussed for more than two decades the role of C-reactive protein (CRP) in cardiovascular disease remains controversial. Three major questions are still not yet resolved. (1) Is CRP a clinically relevant marker of cardiovascular risk? (2) Is CRP even more than a risk marker, that is, a risk factor in cardiovascular disease? (3) Finally, is CRP a cardiovascular drug target?This special issue comprises four review articles and three research articles that reflect the ongoing controversy over the subject. The review articles discuss CRP as a cardiovascular risk marker, CRP in animal models, CRP in its native and nonnative conformation, and CRP in human arteriosclerosis. The research articles deal with CRP as a cardiovascular risk marker in non-ST elevation acute coronary syndrome and with CRP as a drug target. The discussion climaxes in two research articles describing the use of CRP specific antisense oligonucleotides (ASOs) for the treatment of cardiovascular disease in animal models. The conclusions are indeed contradictory. When looking at the two articles, three general points may have to be taken into consideration. (1) Is the statistical power of the animal experiments adequate to draw definitive conclusions? (2) Are there off-target effects of the ASOs that may confound the results? And (3) is it necessary to design studies incorporating multiple on-target ASOs?Specific CRP inhibition followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease."}
+{"text": "To the Editor: The earliest clinical cases of Zika virus infection were reported from continental South America in 2015  tests specific for dengue . Of these 50 patients, 30 (60%) were female. Most of these patients reported illness onset during December 9\u201327, 2015  were female. A total of 22 (8%) samples were positive for dengue; 2 were positive for chikungunya. Of the remaining 252 patients, 50 (20%) had 27, 2015  Figure 1The most commonly reported signs and symptoms were fever (86%), exanthema (72%), and headache (62%). The clinical characteristics of these infections showed no statistically significant difference with those associated with dengue and chikungunya virus infections and with cases found to be negative for all 3 viruses, suggesting that the negative cases could represent Zika virus infections  Table. OBy using Vero E6 cells (American Type Culture Collection), we isolated Zika virus from 9 samples . Phylogenetic analysis of 5 Zika virus sequences  placed these isolated (GenBank accession nos. KU724096\u2013100) within the Asian lineage, the lineage involved in the spread of Zika virus in the Americas  Figure 2By using molecular methods, we confirmed diagnoses in 27% of patients during this outbreak. The distribution of positive results suggests that Zika virus was the predominant etiologic virus in this cohort, but we cannot firmly conclude this because most specimens tested negative for Zika, dengue, and chikungunya viruses.Although results from patient sampling and laboratory testing are not comparable, an assessment in Puerto Rico was able to detect Zika virus RNA by rRT-PCR or IgM by ELISA in 19% of 155 patients with suspected Zika virus infection (Several reasons might exist for the high proportion of specimens testing negative for Zika virus. Viremia is often low and short-lived in persons infected with Zika virus (The Panama Ministry of Health is following up with known pregnant women of the Guna Yala region who report Zika virus infection symptoms and is testing urine samples by using Zika virus\u2013specific rRT-PCR within 14 days of symptom onset. Pregnant women confirmed to have Zika virus infection will receive ultrasound monitoring; however, the test has relatively low positive predictive value for detecting microcephaly (Distribution of symptoms by patients with Zika, dengue, and chikungunya virus infections in the Guna Yala region of Panama, November 27, 2015\u2013January 22, 2016; epidemiologic curve for the outbreak of Zika virus infection in this region; and maximum-likelihood tree of the Zika virus isolated during the outbreak."}
+{"text": "Alcohol screening and brief interventions (SBI) have a history and good evidence of efficacy in primary care settings . EfficacThis study aimed to discuss, and present for debate, challenges and opportunities relating to alcohol SBI in new settings from published and previously unpublished studies of recent SBI implementation in Scotland and England.A narrative review was conducted of evidence from diverse studies including research into training and implementation of alcohol SBI outside of primary care .The challenges and opportunities can be conceptualised in terms of questions that should be asked before considering implementation of alcohol brief interventions in a new setting: (1) Is there a need for SBI delivery in this service? (2) How are practitioners currently addressing alcohol use - how when, where does SBI fit in? (3) Will SBI work/do harm in this setting? (4) Will SBI be perceived as legitimate by practitioners and acceptable to service-users? (5) Will practitioners have the ability to deliver SBI? (6) What support will be needed? (7) What will support routine implementation of SBI in this setting?Careful consideration should be given to every aspect of the design, purpose, context and evaluation of alcohol SBI in any given setting preferably by robust stepwise research prior to widespread implementation. Avoiding assumptions, including about screening methods and intervention goals, is likely to be important for effectiveness, implementation and avoiding unintended harms."}
+{"text": "The body sodium imbalance (dysnatremias) may be associated with increased mortality of critically ill patients. Evidence suggests that changes in the serum sodium level on admission to the intensive care unit (ICU), may lead to a poor outcome.The objective of this study was to evaluate the ability of APACHE II and serum sodium levels to predict mortality of surgical critically ill patients.One hundred and ninety-five surgical patients  admitted to the ICU in the post-operative phase were retrospectively studied. The patients were divided into survivors (n=152) and nonsurvivors (n=43). APACHE II, and serum sodium levels at admission, 48-h and discharge were recorded. The capability of each index  to predict mortality of surgical patients was analysed by receiver-operator characteristic curves (ROC). Odds ratios (OR) and 95% confidence interval (CI) for hyponatremia (Na< 136 mmol/L) and hypernatremia (Na>144 mmol/L) were calculated.Comparison of data between survivors and nonsurvivors is summarized in Table Even though APACHE II was the most effective index to predict mortality in the surgical critically ill patients, the serum sodium levels on admission may also be used as predictor of outcome."}
+{"text": "Chronic migraine (CM) affects 2% of the population and Botox is the only licensed treatment for prevention of adult patients with CM.In the UK, National Institute for Clinical Excellence (NICE) approved its use on the NHS in patients who failed three preventive medications.NICE recommends continuing treatment beyond cycle 2 in those with 30% reduction in headache days (negative stopping rule) and the treatment is stopped when migraine become episodic (positive stopping rule).However, the long-term outcome ie duration of required treatment remains uncertain.To ascertain the duration of treatment with Botox for the prevention of chronic migraine in responders as per NICE criteria.Adult patients with CM attending the Hull migraine clinic were offered Botox based on clinical needs and maintained a headache diary.Data were extracted for headache, migraine, and headache-free daysResponder rate was assessed applying NICE criteriaPatients (N=67) who commenced treatment between July 2010 and June 2012 were followed up for at least 18 months.30 Patients stopped treatment at Cycle 2 as per negative stopping rule by NICEOf 37 responders, only 12 were still on treatment at 18 months. Nearly half of the patients stopped treatment by the 4th Cycle (positive stopping rule).We continue to follow all patients who receive Botox for prevention of chronic migraine and aim to present 2 year follow up on a larger cohort at the EHMTIC September 2014."}
+{"text": "Electronic medical records (EMR) form a rich repository of information that could benefit public health. We asked how structured and free-text narrative EMR data should be combined to improve epidemic surveillance for acute respiratory infections (ARI).Eight previously characterized ARI case detection algorithms (CDA) were applied to historical EMR entries to create authentic time series of daily ARI case counts (background). An epidemic model simulated influenza cases (injection). From the time of the injection, cluster-detection statistics were applied daily on paired background+injection (combined) and background-only time series. This cycle was then repeated with the injection shifted to each week of the evaluation year. We computed: a) the time from injection to the first statistical alarm uniquely found in the combined dataset (Detection Delay); b) how often alarms originated in the background-only dataset ; and c) the number of cases found within these false alarms (Caseload). For each CDA, we plotted the Detection Delay as a function of FAR or Caseload, over a broad range of alarm thresholds.CDAs that combined text analyses seeking ARI symptoms in clinical notes with provider-assigned diagnostic codes in order to maximize the precision rather than the sensitivity of case-detection lowered Detection Delay at any given FAR or Caseload.An empiric approach can guide the integration of EMR data into case-detection methods that improve both the timeliness and efficiency of epidemic detection. Epidemics of acute respiratory infections (ARI), whether due to influenza Electronic data offer the opportunity for more timely and complete gathering of health information compared to what has historically been achieved through manual, paper-based reporting To gain insight on the conduct of surveillance in an EMR environment, we previously evaluated how EMR entries should be assembled to discover individuals with ARI The Institutional Review Boards of the Veterans Administration (VA) Maryland Health Care System and the University of Maryland approved this study. The study was granted a waiver of consent as risks were limited to information confidentiality and the work would not have otherwise been feasible, given the large number of EMR records screened for possible ARI. All EMR information was anonymized and de-identified prior to simulations and analyses, which used only daily case counts.Historical EMR data were extracted from the Veterans Integrated Service Technology Architecture (VistA) repository using the MDE software  and transferred to a Structured Query Language (SQL) relational database .th Revision, Clinical Modification, ICD-9) either used by the original Centers for Disease Control and Prevention (CDC) \u201cBioSense\u201d surveillance system Outpatients with possible ARI were identified by applying previously developed ARI case-detection algorithms (CDAs) et al. To create a plausible ARI outbreak to be discovered by the surveillance system, we developed an epidemic model of influenza . The model included 30 contiguous ZIP codes centered on Baltimore, Maryland, and consisted of a coupled series of differential equations to describe the overall epidemic http://www.r-project.org). Starting on the day when the synthetic epidemic was injected into a CDA-specific authentic background time series, and then daily for a total of 80 days, a statistical outbreak detection method (see below) was applied in parallel to corresponding time series that included either: a) both background and epidemic cases  W2c We computed three performance benchmarks at any given statistical alert threshold: 1) the Detection Delay, the time from the injection of the synthetic outbreak to the first true positive alarm, averaged for the 52 surveillance cycles of the evaluation year; 2) the false alarm rate (FAR), the average daily number of unique alarms issued in the background-only time series during the evaluation year; 3) the Caseload, defined as the total yearly number of cases included in the above false alarms. Corresponding Detection Delays, FARs and Caseloads were obtained for a range of statistical alert thresholds adjusted iteratively to focus on a FAR range felt to be of practical use for surveillance i.e. 0\u201310%.The activity monitoring operating characteristic (AMOC) curves The surveillance advantages of adjusting the ICD-9 codes used to identify ARI cases can be visualized by comparing the AMOC curves obtained using a \u201crespiratory\u201d code set used by a surveillance system of national scope Case detection that relied solely on text analyses of clinical notes resulted in outbreak detection performance roughly on par with that of the VA-adapted set of ICD-9 codes  Time series of background casecounts. 8-year background time series are provided for each of the CDA outlined in the (TXT)Click here for additional data file.Datafile S2(CDA 2) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S3(CDA 3) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S4(CDA 4) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S5(CDA 5) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S6(CDA 6) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S7(CDA 7) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S8(CDA 8) Time series of background casecounts.(TXT)Click here for additional data file."}
+{"text": "A subset of patients with autoimmune diseases including rheumatoid arthritis (RA) and lupus appear to be exposed continually to interferon (IFN) as evidenced by elevated expression of IFN induced genes in blood cells. In lupus, detection of endogenous chromatin complexes by the innate sensing machinery is the suspected driver for the IFN, but the actual mechanisms remain unknown in all of these diseases. We investigated in two randomized clinical trials the effects on RA patients of baminercept, a lymphotoxin-beta receptor-immunoglobulin fusion protein that blocks the lymphotoxin-\u03b1\u03b2/LIGHT axis. Administration of baminercept led to a reduced RNA IFN signature in the blood of patients with elevated baseline signatures. Both RA and SLE patients with a high IFN signature were lymphopenic and lymphocyte counts increased following baminercept treatment of RA patients. These data demonstrate a coupling between the lymphotoxin-LIGHT system and IFN production in rheumatoid arthritis. IFN induced retention of lymphocytes within lymphoid tissues is a likely component of the lymphopenia observed in many autoimmune diseases.NCT00664716.ClinicalTrials.gov  Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren\u2019s syndrome, systemic sclerosis, myositis and multiple sclerosis patients have circulating blood cells with elevated levels of RNA from IFN-induced genes, i.e. an \u2018IFN signature\u2019 We have investigated the effects of inhibition of the lymphotoxin-LIGHT system in RA using a soluble lymphotoxin-beta receptor  immunoglobulin fusion protein called baminercept. LTBR is a central component of a signaling system whereby lymphocytes instruct stromal cells to differentiate into specialized vasculature and certain reticular networks Unexpectedly, we found that baminercept reduced the IFN signature in RA patients. The reduced IFN signature in RA patients following baminercept treatment is the first time outside of high dose steroid therapy that an IFN signature was decreased by a pharmacological treatment not targeting IFN itself. Taken together with the known effects of LTBR inhibition, these studies not only link the LTBR axis to IFN production in man, but also provide potential insight into the nature of the IFN signature.Two randomized phase IIb controlled studies of the effects of baminercept in rheumatoid arthritis were conducted. One study enrolled patients with an inadequate response to disease-modifying antirheumatic drug therapy (DMARD-IR) and the other involved patients with an inadequate response to tumor necrosis factor inhibition (TNF-IR)  and an IFN score calculated  and type II IFN (IFN\u03b3) and, furthermore, each IFN is capable in many contexts of inducing the expression of the other IFN class Elevated levels of type I IFN or an IFN-like inducing activity can be found in the sera of a subset of the SLE patients with a transcriptional IFN signature; however, in RA the results range from not detectable to low levels relative to SLE sera SLE patients with a high IFN signature tend to be lymphopenic In rodents, blockade of the LTBR system leads to lymphocytosis within several weeks most likely due to loss of high endothelial venule addressin expression and reduced entry into the lymph nodes and mucosal environments In mice, lymphocytosis following LTBR blockade results from elevated T and B cells counts Given the emphasis on plasmacytoid DC as the source of the IFN signature in SLE, we examined RNA levels in the blood of two known pDC markers, CLEC4C (BDCA2) and LILRA4 (ILT7). LILRA4 levels increased following baminercept treatment, yet CLEC4C levels were unchanged  scoring system. Overall, baminercept was well tolerated  was a multicenter, phase IIb, double-blinded, placebo-controlled study of RA patients who lacked an adequate response to TNF-blocking therapy and had discontinued TNF blocking treatment for at least 90 days. The study dosed 114 patients with subcutaneous injections q2w of either placebo (38) or baminercept 200 mg (76). This study was terminated early due to poor efficacy in the DMARD-IR study; however, 81 patients completed the 3 months of dosing and another 15 patients received at least 2 months of treatment. Study was conducted between March 2007 and October 2008 at 40 sites in the United States, Canada, Belgium and United Kingdom.Investigators for both baminercept studies are listed in the supplemental materials in SLE data were from registry  representing a collection of 292 SLE patients from the Hopkins Lupus Center in the US. Patients were eligible if they were aged 18\u201375 years and met the American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematous. Baseline data were used in this study and patients were under standard clinical practice. Normal controls for RNA analyses were composed of healthy volunteer donors from Biogen Idec. Control group had equal numbers of males and females and was not exactly gender balanced with the predominantly female composition of both the RA and SLE cohorts.The RA studies were approved by the appropriate institutional review boards or ethics committees and all patients provided written informed consent Click here for additional data file.Checklist S1CONSORT Checklist.(PDF)Click here for additional data file.Protocol S1Trial Protocol.(PDF)Click here for additional data file.Protocol S2Trial Protocol.(PDF)Click here for additional data file."}
+{"text": "Preoperative quantitative assessment of coronary angiography (CAG) and real-time graft size and graft flow assessment using epigraftic ultrasonography in the operative field have been performed to ascertain the patency in the right coronary artery bypass grafting (CABG).This study aims to evaluate the efficacy of the quantitative coronary artery and graft assessment to increase the patency of the right CABG.CABG was performed in 200 patients from January 2010 to December 2014. Ninety-three patients underwent all of preoperative CAG, real-time graft assessment and postoperative CAG with a total of 93 grafts anastomosed to the right coronary artery. Severity of coronary artery stenosis was evaluated by CAG. The size of target right coronary artery was measured by ultrasonography in the operative field. Parameters about graft flow were obtained from flow velocity curve in all the graft. The grafts were divided into two groups: patent grafts  and failing grafts . All factors were compared in these two groups and evaluated by logistic analysis and receiver operating characteristic (ROC) curve analysis.The overall patency as measured by postoperative CAG was 94.6% (88/93). There were 7 failing grafts including 5 occlusion and 2 competitive slow flow. Logistic regression analysis revealed that the percentage of graft size measured by ultrasonography divided by the size of the right coronary artery (graft-RCA size mismatch) and the pulsatility index (PI) were independent predictors of early graft failure . ROC curve analysis revealed that graft-RCA size mismatch > 2.08 and PI > 4.55 were predictors of graft failure.In this series, epigraftic ultrasonography depicted graft flow clearly. Combination of preoperative quantitative coronary artery assessment and real time graft assessment was essential to predict graft failure during the CABG. This technique may increase the patency of the right coronary artery bypass grafting."}
+{"text": "The condition accounts for almost half of all nail issues yet continues to be largely under-reported and untreated. This study will investigate the antifungal efficacy of eucalyptus oil A longitudinal prospective study was used to monitor the changes in toenail mycotic infections over a four-month period, using undiluted eucalyptus oil as a topical antifungal agent. Data were collected from 22 participants (14 men and 8 women) aged between 40 and 84 with a total of 70 toenails, 35 with nail matrix infection and 35 without. To review the effect of eucalyptus oil on the clinical appearance of the fungal infected nail plates, toenails were monitored at four-weekly intervals for a period of four months. The participants\u2019 satisfaction with the therapy was assessed using the OnyCOE-t questionnaire.Of the 70 nails analysed, the patterns of infection were classified as proximal subungual onychomycosis (49%), distal lateral subungual onychomycosis (47%), white superficial onychomycosis (3%), and total dystrophic (1%). Almost half of all participants (45%) had onychomycosis affecting only one toenail. Only 23% of participants had previously treated the infection and the mean duration of infection was 10 years and 3 months.Nails with superficial onychomycosis (n=2) were found to have 86% clearance of infection after four months. One third of all nails (n=11) with distal lateral subungual onychomycosis and 50% (n=17) of nails with proximal subungual onychomycosis demonstrated a zone of clearance at the proximal nail plate tissue, suggesting a fungistatic effect of the eucalyptus oil.Topical eucalyptus oil is more effective as an antifungal treatment for fungal infected toenails without nail matrix infection. Eucalyptus oil may provide an acceptable and cheaper alternative to prescription topical antifungal agents, for people with white superficial onychomycosis or distal lateral subungual fungal nail infections."}
+{"text": "UGT1A1*28 was not questioned in our study.There is an error in the second sentence in the third paragraph of the \u201cGenetic differentiation and haplotype diversity for DMET Plus markers\u201d section of the Results. The correct sentence is: Although, the array captures many of the functional variants described for these genes, unfortunately The S5 TableMinor Allele Frequencies (MAF) for 1,647 genetic markers. The markers are those included in the DMET Plus array and for all populations: Europeans (Hapmap CEU), Africans (Hapmap YRI and LWK), Native Americans (Zapotecas), Brazilians and Mexican mestizos (Guanajuato (GUA); Guerrero (GUE); Sonora (SON); Veracruz (VER) and Yucatan (YUC)).(XLSX)Click here for additional data file."}
+{"text": "Systematic review and meta-analysis of published studies of alcohol use among young people (age 15\u201324 years) in eastern Africa to estimate prevalence of alcohol use and determine the extent of use of standardised screening questionnaires in alcohol studies.2 statistic (DerSimonian-Laird).Five databases  were searched for publications until 30th June 2013. Results were summarised using the guidelines on preferred reporting items for systematic reviews and meta-analyses (PRISMA) and on quality assessment using the modified quality assessment tool for systematic reviews of observational studies (QATSO). Heterogeneity was assessed using the IWe identified 2785 potentially relevant studies, of which 56 were eligible for inclusion. Only two studies (4%) used the standardised Alcohol Use Disorder Identification Test (AUDIT) questionnaire, and six studies (13%) used the Cut down, Annoyed, Guilt, Eye opener (CAGE) questionnaire. The reported median prevalence of alcohol use was ever-use 52% [interquartile range (IQR): 20\u201358%], use in the last month 28% (IQR: 17\u201337%), use in the last year 26% (IQR: 22\u201332%), and problem drinking as defined by CAGE or AUDIT 15% (IQR: 3\u201336%). We observed high heterogeneity between studies, with the highest prevalence of ever use of alcohol among university students  and female sex workers . Current use was most prevalent among male sex workers .Reported alcohol use and problem drinking were common among diverse groups of young people in eastern Africa, indicating the urgent need for alcohol-focused interventions in this population. Few studies have used standardised alcohol screening questionnaires. Epidemiological research to investigate alcohol-focused interventions in young people should aim to apply such questionnaires that should be validated for use in this population. Harmful alcohol use is a significant public health problem that often begins early in adult life. Globally, an estimated 2 billion people drink alcohol and 76 million have alcohol use disorders (AUD) WHO . The meaet al. et al. et al. et al. et al. et al. Factors associated with alcohol use include religion, personal income, education level, peer influence, having older sexual partners, stress and relatives and friends using alcohol  estimate the prevalence of alcohol use among specific groups of young people (15\u201324 years) in eastern Africa; (ii) determine the extent of use of standardised alcohol screening questionnaires [Alcohol Use Disorder Identification Test (AUDIT), Cut down, Annoyed, Guilt, Eye opener (CAGE) in identifying alcohol use and AUD in this region; (iii) assess the quality of research papers included in the review; and (iv) describe factors associated with initiation and persistence of alcohol use among young people in eastern Africa.).Five databases  were searched for publications to 30th June 2013. We used the following key terms:  AND (young people OR adolescent OR teenage OR youth) AND . , and consensus on potential eligibility reached. Studies were eligible if they were conducted in eastern Africa ; and included prevalence of alcohol use for young people aged 15\u201324 years.et al. et al. Guidelines on preferred reporting items for systematic reviews and meta-analyses (PRISMA) were used (Moher We used a data extraction form to collect the following information from each eligible article: (i) country; (ii) year the study was conducted; (iii) year of publication; (iv) study population ; (v) sample size; (vi) definition of alcohol use ; (vii) prevalence of alcohol use and AUD (problem drinking as classified by CAGE and AUDIT); (viii) factors associated with the initiation and persistence of alcohol use; (ix) alcohol use screening questionnaires applied; and (x) complications associated with alcohol use.et al. A descriptive quality assessment of the final papers included in the meta-analysis was conducted using the modified quality assessment tool for systematic reviews of observational studies (QATSO) (Wong 2 statistic (DerSimonian-Laird) and reported the prevalence for studies in four groups: (i) ever use of alcohol; (ii) alcohol use in the last year, (iii) alcohol use in the last month (current use) and (iv) problem drinking as defined by CAGE and AUDIT .We identified 4013 published study citations from five databases, of which 1228 were duplicates. Thus, 2785 abstracts were screened for initial eligibility to identify studies conducted in eastern Africa. We identified 696 relevant abstracts of studies conducted in eastern Africa. We conducted further screening for studies reporting on alcohol use and identified 285 abstracts for full article review. Of these 285 abstracts for full article assessment, we could not access six full articles, 11 were review articles and five were conference posters.Thus, we reviewed 263 full-text papers and identified 56 eligible for inclusion in the review. The main reason for exclusion was that the paper did not report information on alcohol use from the target population, that is, young people aged 15\u201324 years, or that young people were included but we could not separate the prevalence in this age group from that in older people , and two were case\u2013control studies. Almost all studies  were conducted in four countries: Ethiopia (n = 19), Kenya (n = 15), Tanzania (n = 10) and Uganda (n = 8); the remaining four studies were conducted in Rwanda (n = 2), Seychelles (n = 1) and Eritrea (n = 1). Most studies  reported current alcohol use, 17 studies reported ever use of alcohol, four studies reported alcohol use in the last year, and five studies reported problem drinking. Only two studies used the AUDIT alcohol use screening questionnaire  used probability-based sampling and had a response rate above 80% . However, 17 studies did not report the response rate  and street children (21% vs 11%) and high in male university students (53% vs 50%). There was significant heterogeneity based on I2 statistics in all subgroups, and therefore, we do not report pooled prevalence.Figure vs 17%).Four studies reported the prevalence of alcohol use in the last 12 months. These showed similar levels as found for reported current alcohol use. Three studies were from the general population  with a pooled prevalence of 30% (95%CI: 27\u201333%) and one from university students . One study reported gender-specific prevalence; it was high among males (34% vs. 9%(IQR: 9\u201320%) in the general population, 28% (IQR: 13\u201344%) vs 19%(IQR: 7\u201332%) among healthcare service attenders, 60% (IQR: 56\u201363%) vs. 41% (IQR: 24\u201358%) in secondary schools, and 43% vs. 28% in a university. There was no significant heterogeneity in studies conducted among university students except one study among female university students  among female bar workers and 47% (95%CI: 40\u201353%) among male sex workers. Median prevalence in the general population was 3% (IQR: 1\u201315%); two of the studies in the general population were from Ethiopia and showed low levels of problem drinking (1\u20133%), but a study from Tanzania reported a rather high median prevalence of 15% (95%CI: 10\u201320%).et al. et al. et al. In this review, eight studies reported problematic drinking, two studies applied AUDIT, and six (13%) used CAGE to screen for problem drinking; two of the studies that applied CAGE and one study that applied AUDIT did not report scores according to age groups  and female sex workers (66%) and lower among the general population and primary school students. Few studies reported alcohol use in the last year, and median prevalence in the general population was 29%. Reported current alcohol use was highest among male sex workers (69%), followed by the university students (33%), and was lowest in the general population and secondary school students with the exception of one study in the Seychelles that reported a high prevalence of 61%. Problem drinking was highest among groups known to engage in high-risk behaviours (such as bar workers and sex workers). Generally, reported alcohol use across all definitions of use was highest among groups known to engage in high-risk behaviours, followed by university students. Individuals attending healthcare services and general populations and secondary school students reported the lowest prevalence. Studies included in this review were of good quality; however, about two-thirds employed face-to-face interviewing approaches, an approach prone to social desirability bias that could lead to underreporting of alcohol use.vs. students vs. sex workers). We also attribute these variations to social influence and peer pressure ; it is, however, not widely used for the assessment of AUD among young people in general populations. In our review, only two studies used the internationally recommended AUDIT alcohol screening questionnaire (Mbatia et al. et al. The use of effective and validated instruments for the screening and assessment of alcohol use is essential to guide research and is important for the design and evaluation of interventions. AUDIT is validated and recommended by WHO for use at the primary healthcare settings and for the assessment of AUD in developing countries (Saunders Reported alcohol use among young people in eastern Africa is common and varies between different populations. The prevalence of AUD was highest among populations known to engage in high-risk sexual behaviours, but was also high among students in some of the studies. The studies reviewed lacked data about initiation and persistence of alcohol use, and little information was available about risk factors associated with alcohol use, and AUD. Notably, only few of the studies reviewed used internationally recommended and validated screening questionnaires such as AUDIT. Future epidemiological studies on alcohol use among young people should apply these questionnaires to facilitate comparison. However, such questionnaires have not been evaluated among young people in Africa, and studies closing this knowledge gap are therefore also required. Future studies should also determine factors responsible for initiation, persistence, and patterns of use in preparation for potential interventions. There is an urgent need of targeted interventions for groups of young people with a particularly high risk of alcohol use and AUD such as college students and young sex workers."}
+{"text": "Background Exposure to high levels of Aluminium (Al) leads to a neurodegenerative disorders , which may be mediated through over generation of free radicals. So in the present study we investigated the ability of both Quercetin and Omega 3 to ameliorate Al adverse effect on brain antioxidant through monitoring the main brain antioxidant enzymes on molecular and cellular levels.Forty male albino rats were used, they were divided into 4 groups; Control, Aluminum Chloride (AlCl3) supplemented group that orally supplemented with 100mg of AlCl3  per Kg b.w. for two months. Quercetin group treated as ALCl3 group and orally supplemented with 100 mg/kg b.w. Quercetin for two months according to Hui et al. [Our results indicate a significant increase in superoxide dismutase (SOD) activity and MDA level and a significant decrease in the activities of catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GPX) and levels of reduced glutathione (GSH) in brain tissues in AlCl3 supplemented group when compared with control or Quercetin and Omega 3 supplemented groups Table . At the Both Quercetin and Omega 3 has the ability to overcome the Al induced oxidative stress in brain, manifested by the significant reduction in free radicals concentration and induction of the activity and gene expression of the brain antioxidant enzymes."}
+{"text": "Patients with inflammatory bowel disease (IBD) demonstrate an inflammatory response which bears some similarities to that seen in ischaemic heart disease (IHD). The nature of the association of IBD with IHD is uncertain. We aimed to define the extent and direction of that association.This retrospective cohort study examined records from patients aged \u2265 15 years with IBD from 1987\u20132009 (n = 19163) who were age and gender matched with patients without IBD (n = 75735) using the General Practice Research Database. The primary outcome was the hazard ratio for IHD.A higher proportion of IBD patients had a recorded diagnosis of IHD ever, 2220 (11.6%) compared with 6504 (8.6%) of controls. However, the majority  developed IHD prior to IBD diagnosis (1404 (63.2%) of IBD cases and 3090 (47.5%) of controls). There was increased IHD incidence in the first year after IBD diagnosis. Mean age at IHD diagnosis was statistically similar across all IBD groups apart from for those with Ulcerative Colitis (UC) who were slightly younger at diagnosis of angina compared to controls  and coronary heart disease . Of those developing IHD following IBD diagnosis, UC patients were at higher risk of IHD (unadjusted HR 1.3 (95% CI 1.1\u20131.5), p<0.001) or MI (unadjusted HR 1.4 (95% CI 1.1\u20131.6), p = 0.004).Although IHD prevalence was higher in IBD patients, most IHD diagnoses predated the diagnosis of IBD. This implies a more complex relationship than previously proposed between the inflammatory responses associated with IHD and IBD, and alternative models should be considered. The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn\u2019s Disease (CD) are disorders of uncertain origin. In both UC and CD, an exaggerated immune response to unknown antigens is evident  and a nuThere is a well-described association between rheumatoid arthritis (RA) and increased cardiovascular mortality, mainly as a result of ischaemic heart disease (IHD)., 10 AtheThere are sufficient shared characteristics to the inflammatory responses seen in IBD and RA to hypothesise that the recognized association between RA and IHD might also exist for IBD and IHD. Previous cohort studies have examined the risk of IHD in patients with IBD and have variously found no effect, or a slihttp://www.cprd.com/home/) between 1987 and 2009. For each subject with IBD, a further 4 subjects were identified and matched for age and sex but without IBD. All cohort members were followed from the start date (i.e. the date their GPRD record began) until the earliest occurrence of one of the following endpoints: recorded code of IHD, death, date of exit from GPRD registered GP practice, or end of study period (31.12.2009). Patients with less than (1) 2 years up-to-standard enrolment with the GP or (2) 1 year of computerized prescription history or (3) no health contacts during their complete period of follow-up were excluded from the cohort. Patients whose date of death or date of transfer out of a GPRD-registered practice preceded date of IBD diagnosis were excluded from the cohort. Patients <15 years of age at entry were excluded.The study population for this retrospective cohort study consisted of around 2.1 million male and female patients with an active registration at practices contributing to the General Practice Research Database , or Crohn\u2019s Disease (CD), or inflammatory bowel disease (not otherwise specified) (IBD (nos)) recorded on the database since 1987; patients with ICD-10 Read Codes (K50-K51) records of both UC and IBD were coded as UC; CD plus IBD were coded as CD; individual records which included both UC and CD were included only in analyses of IBD (nos). Prevalent IBD cases on 01.01.1987 were excluded. The index date was defined as the date of first recording of IBD. Lifetime IBD severity was determined using an algorithm based on IBD drug-use  and surgical intervention (colectomy/stomata) developed by team members with clinical and research expertise in IBD.Age, sex and practice matched controls were allocated the same index date as their matched case. Because IHD has not been subjected to the same specific validation studies as IBD, our operational definition was developed using advice from clinicians with special interest in cardiovascular disease to include the following: Read Codes for IHD  Coronary Heart Disease (CHD) was considered for the purpose of this study to be synonymous with IHD and Read Codes for coronary heart disease (including coronary artery disease) were included.Data was accessed within limits set out by the Medical Research Council licence agreement for academic access with Medical Research Ethics Committee ethical approval. The proposal was approved by the Independent Scientific Advisory Committee of the GPRD (protocol number 10_003).a priori hypothesis, that IHD followed IBD, was conducted on a subset which included cases of IHD following IBD and their associated matched controls (COHORT B: n = 77540).Descriptive analysis of baseline characteristics and exploration of the direction of association between IBD and IHD was conducted using the whole cohort of patients aged over 15 years . Subsequent analysis of the The relative risks of ischaemic heart disease (IHD) and its sub-entities myocardial infarction (MI) and angina), as well as CHD were estimated as hazard ratios (HRs) for patients with IBD compared to non-IBD patients, using Cox proportional hazard models. Models were subsequently adjusted for age, gender, socio-economic status , comorbidity and concomitant drug use, IBD disease severity, and smoking status. We carried out both forward and backward stepwise covariate selection within the cox proportional hazard model. All covariates were initially included with entry testing based on the significance of the score statistic, and removal testing based on the probability of a likelihood-ratio statistic based on conditional parameter estimates. Models were tested for interactions between fitted variables. Precision of estimates is reported using 95% confidence intervals. Data management was performed using Stata 10IC. Cox regression proportional hazard computations and Kaplan-Meier survival analysis were conducted using SPSS 21.Data were examined from electronic primary care records from 221 general practices across the UK from patients with a first diagnosis of IBD recorded from 1st January 1987 to 31st December 2009 . FollowiOf 19163 IBD cases, a total of 2220 (11.6%) had an IHD diagnosis ever, compared with 6504 (8.6%) of those without IBD. Of these IHD diagnoses, 4494 (51.5%) occurred prior to IBD diagnosis (1404 (63.2%) of IBD cases and 3090 (47.5%) of controls) . AccordiA total of 17358 patients were excluded from subgroup analysis where IHD preceded IBD or, for controls, the matched IBD date  . Subset In order to examine the subset in a way that was consistent with previous research, the inciThis is the first study to fully examine both the strength and direction of association between development of ischaemic heart disease (IHD) and IBD. An increased incidence of IHD, angina, MI, and CHD diagnoses was seen in the first year after IBD diagnosis but the mean age of diagnosis comparing IBD cases with non IBD cases was not statistically different, apart from those with Ulcerative Colitis (UC) who were slightly younger at diagnosis of angina and coronary heart disease. Of those developing IHD following an IBD diagnosis, patients with UC were at slightly higher risk of a diagnosis of IHD or MI although results were not significant after adjustment for the role of covariates. Most notably, we found that although overall prevalence of IHD was higher in those with IBD, in the majority of cases the diagnosis of IHD actually predated that of IBD.This is the largest British cohort study to examine this issue. It used the General Practice Research Database which is an appropriate and reliable resource for IBD research, having been used for at least 19 studies published in peer-reviewed journals since 2000. The diagnostic reliability of IBD diagnosis and the year of IBD diagnosis in the GPRD has been confirmed in a recent validation study. Other GPAs others have highlighted , there iThe temporal relationship between IBD and IHD may be weakened by differences with which the diagnosis of each is recorded in the GPRD. IHD is a diagnosis made in the majority of cases fairly soon after the onset of symptoms, because of an event requiring admission to hospital . Nevertheless, among those with stable angina, nearly half have symptoms for 6 months or more before diagnosis. For IBD It is possible that IHD cases may have been missed or incorrectly coded within GPRD. Unrecorded diagnoses are increasingly unlikely within UK general practice due to policy and fiscal incentives to assess, monitor and treat cardiovascular disease, althoughThis is the first known study to examine the temporal relationship between IHD and IBD and we found that the majority of IHD cases predated IBD diagnosis. Previous research has predominantly focused attention on incident cases of IHD occurring at or after diagnosis of IBD. It is notable that the overall risk of prevalent (i.e. whole cohort) IHD was almost identical to a recent Danish study  at 2.1 IBy identifying and quantifying both the strength and direction of association between IBD and IHD, this study provides important insights into the burden of IHD in the IBD population. This is relevant for basic scientists exploring the temporal causal pathway, and clinicians who should be aware of the risks of IHD in patients with IBD and vice versa.S1 FigTotal number of patients showing time from IBD diagnosis (T0) to the first cardiovascular event  according to IBD type and age categories.(TIF)Click here for additional data file.S2 FigTotal number of patients showing time from IBD diagnosis (T0) to the first cardiovascular event  according to IBD type and gender categories.(TIF)Click here for additional data file.S3 FigTotal number of patients showing time from IBD diagnosis (T0) to the first Coronary Heart Disease (sub-group of CVD) event according to IBD type.(TIF)Click here for additional data file.S4 FigTotal number of patients showing time from IBD diagnosis (T0) to the first Ischaemic Heart Disease (sub-group of CVD) event according to IBD type.(TIF)Click here for additional data file.S5 FigTotal number of patients showing time from IBD diagnosis (T0) to the first Angina (sub-group of CVD) event according to IBD type.(TIF)Click here for additional data file.S6 FigTotal number of patients showing time from IBD diagnosis (T0) to the first Myocardial Infarction (sub-group of CVD) event according to IBD type.(TIF)Click here for additional data file.S7 FigTotal number of patients showing age at onset of Cardiovascular Disease  according to IBD type.(TIF)Click here for additional data file."}
+{"text": "Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility.While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 , rs1129038  and rs916977  are correlated (r BAP1, CDKN2A, or BRCA2 explain only about 3% of UM population-specific risk678310Uveal melanoma (UM) is the most common primary adult intraocular cancer142\u2009>\u20090.5), which were still significant following adjustment for multiple testing  established in recent GWASs for association with CM or related host phenotypes (including skin and eye pigmentation) , in a po testing : rs12913esting 12. As showOCA2, which codes for P protein involved in melanin synthesisHERC2, is a key pigmentation \u201cregulator allele\u201d that impacts the expression of OCA2 via a long range enhancer mechanismOCA2 expression resulting in darkly pigmented melanocytes. The C-allele conversely reduces expression of OCA2 producing lightly colored melanocytes3The locus at 15q13.1 determines pigmentation of eyes and skin by regulating the expression of 2\u2009=\u20090.48)  , that waIt is important to note that our study has limited power and hence may reduce the ability to detect associations exerting smaller risk effects. It is possible that there are other associations among the selected variants that are likely missed in this study due to relatively small size of our UM case population. The most significant associations at HERC2/OCA2 locus , as wellGNAQ mutation signatures were observed in posterior (choroid) versus anterior UM tumors , likely reflecting divergent UM pathways related to toxic pheomelanin synthesisAlso, the relatively small size of our case population did not allow for stratifying the associations by the primary location of tumors, and this will need to be explored in subsequent large consortia analyses. The molecular effect of pigmentation on different UM subtypes has recently been suggested, as different A limitation in this study is an inability to assess the effect of pigmentation phenotype information in our sample populations as the HERC2/OCA2 locus exerts a purifying selection effect in European ancestries21The identification of novel germline genetic loci involved in UM susceptibility in our study provides the first evidence of a link between the inherited genetics of pigmentation and UM risk. It has been established that lighter pigmentation and chronic sun exposure impact the development of choroid nevi, which occur in ~7% of the US population and are a known precursor for UMFor cases, the study originally employed 286 UM patients. Fourteen of these failed the genotyping or quality control, resulting in 272 UM cases available for association analysis. The vast majority of patients were ascertained from the ophthalmology, medical oncology or clinical cancer genetics clinics at Ohio State University. Four patients were referred to our research program from an outside institute. UM patients with family history of UM were excluded. The study was approved by The Ohio State University cancer institutional review board. DNA for patients and controls were extracted from peripheral blood lymphocytes by a simple salting out procedureOut of available specimens from 3500 participants currently ascertained by OSUMC Human Genetic Sample bank, for our analysis we selected 760 controls that were individually matched as closely as possible to cases by gender and age . The DNATo test the association of common genetic variants (MAF\u2009>\u20090.05) with the risk of UM, a total of 29 SNPs were selected through the comprehensive search of published GWAS data on melanoma risk, nevi-driven phenotypes, pigmentation, hair color, skin color and other melanoma risk etiologies. The selection criteria focused on variants with the most significant associations (in particular those surpassing GWAS level of significance) reported from each of these published GWAS. The complete list of selected variants with association information from prior studies is in For the genotyping of 29 selected variants, the highly multiplexed Sequenom MassARRAY system  was used according to the manufacturer\u2019s protocol. Quality control (QC) measures included duplicates (8 per each 384-well plate) and non-template controls (2 per plate) resulting in >99% observed concordance with no evidence of cross-contamination. Post-genotyping filtering criteria were as follows: exclusion of SNPs with minor allele frequency (MAF) <5%, exclusion of SNPs with a call rate <95%, exclusion of samples with a call rate <95%, and exclusion of SNPs with significant departure from Hardy-Weinberg equilibrium (p\u2009<\u20090.001). The filtering steps excluded one variant with MAF\u2009<\u20090.05, resulting in genotype information on 28 variants for 272 UM patients and 735 matched controls.2 tests (1 degree of freedom). All analyses were performed in PLINK2\u2009=\u20091) determined from European ancestries in the recent data release of 1000 Genomes Project Phase 3 (October 2014), as indicated in The association of UM risk with the selected 29 common genetic variants in the analysis of 272 cases and 1782 controls was estimated as odds ratios (OR) with 95% confidence intervals (95% CI), using unconditional logistic regression in an additive model where two copies of the minor allele have twice the effect of one copy. The genotype model (separate indicators for heterozygotes and rare homozygotes), dominant model (indicator for heterozygotes and rare homozygotes combined) and recessive model (indicator for homozygotes) were also assessed but not reported as they presented no significant additional information not captured by the additive model. All models were adjusted for continuous age at diagnosis (cases) or at the time of inclusion in the study (controls) and gender. Deviations of the genotype frequencies in the controls from those expected under Hardy-Weinberg equilibrium were evaluated by \u03c7IMPUTE2 was used for imputationThe imputed variants were tested for UM association using logistic regression implemented by the SNPTEST software under an additive model. Genotype uncertainties from imputation were accounted for in the model using genotype dosages. Notably, there were a number of variants comparably significant to our top genotyped associations . To asseHow to cite this article: Ferguson, R. et al. Genetic markers of pigmentation are novel risk loci for uveal melanoma. Sci. Rep.6, 31191; doi: 10.1038/srep31191 (2016)."}
+{"text": "In silico functional analysis revealed that many genes in these families might be associated with the regulation of responses to environmental stimuli via transcriptional regulation of the response genes. Moreover, these genes had diverse endogenous expression patterns in switchgrass during seed germination, vegetative growth, flower development, and seed formation. Interestingly, several members of the ERF and DREB families were found to be highly expressed in plant tissues where active lignification occurs. These results provide vital resources to select candidate genes to potentially impart tolerance to environmental stress as well as reduced recalcitrance. Overexpression of one of the ERF genes (PvERF001) in switchgrass was associated with increased biomass yield and sugar release efficiency in transgenic lines, exemplifying the potential of these TFs in the development of lignocellulosic feedstocks with improved biomass characteristics for biofuels.The APETALA2/ethylene response factor (AP2/ERF) superfamily of transcription factors (TFs) plays essential roles in the regulation of various growth and developmental programs including stress responses. Members of these TFs in other plant species have been implicated to play a role in the regulation of cell wall biosynthesis. Here, we identified a total of 207 AP2/ERF TF genes in the switchgrass genome and grouped into four gene families comprised of 25 AP2-, 121 ERF-, 55 DREB (dehydration responsive element binding)-, and 5 RAV (related to API3/VP) genes, as well as a singleton gene not fitting any of the above families. The ERF and DREB subfamilies comprised seven and four distinct groups, respectively. Analysis of exon/intron structures of switchgrass AP2/ERF genes showed high diversity in the distribution of introns in AP2 genes versus a single or no intron in most genes in the ERF and RAV families. The majority of the subfamilies or groups within it were characterized by the presence of one or more specific conserved protein motifs.  Panicum virgatum) is an outcrossing perennial C4 grass known for its vigorous growth and wide adaptability and, hence, is being developed as a candidate lignocellulosic biofuel feedstock  is a large group of regulatory protein families in plants that are characterized by the presence of one or two conserved AP2 DNA binding domains. AP2/ERF TFs are involved in the transcriptional regulation of various growth and developmental processes and responses to environmental stressors. The AP2 domain is a stretch of 60\u201370 conserved amino acid sequences that is essential for the activity of AP2/ERF TFs  have been suggested to be associated with the regulation of cell wall biosynthesis in some tissues Arabidopsis AP2/ERF TFs were excluded from our subsequent analysis.We used representative genes from appropriate rice gene families as the basis to search for orthologs in switchgrass. The amino acid sequences of AP2 domain-containing rice genes represented three families: AP2 (Os02g40070), ERF (Os06g40150), and RAV (Os01g04800). These proteins were used to query the derived amino acid sequences of all switchgrass AP2/ERF TFs using tblastn against the switchgrass EST database . The exon\u2013intron organizations in these genes were visualized by the gene structure display serverThe genomic and coding DNA sequences of the identified AP2/ERF TFs were retrieved from the Phytozome (The transcript data for the AP2/ERF superfamily TFs were extracted from the publicly available switchgrass gene expression atlas (PviGEA)Arabidopsis AtSHN2 (At5g11190) and rice OsSHN (Os06g40150) was identified by tblastn or blastp against the switchgrass EST database or draft genome (Phytozome v1.1 DOE-JGI) followed by cluster and multiple sequence alignment analysis to discriminate the most closely related gene for cloning. For construction of overexpression cassette, the open reading frame (ORF) of PvERF001 was isolated from cDNA obtained from ST1 clonal genotype of \u2018Alamo\u2019 switchgrass using gene-specific primers flanking the ORF of the gene and cloned into pANIC-10A expression vector by GATEWAY recombination  and watered three times per week, including weekly nutrient supplements with 100\u2009mg/L Peter\u2019s 20-20-20 fertilizer. Transgenic and non-transgenic control lines were propagated from a single tiller to produce three clonal replicates for measuring growth parameters  and quantitative [pyrolysis molecular beam mass spectrometry (py-MBMS)] analysis of lignin content was performed as previously described  particle size and sugar release efficiency was determined via NREL high-throughput sugar release assays on extractives- and starch-free samples  with least significant difference (LSD) procedure was used while PROC TTEST procedure was used to examine the statistical difference between the expression of target genes in transgenic vs non-transgenic lines using SAS version 9.3 . Pearson\u2019s correlation coefficient to determine the relationship between relative transcript levels and growth parameters was calculated by SAS.Arabidopsis along with the presence of conserved B3 domain suggest that these proteins might be categorized as putative AP2/ERF TFs. The characteristic features of these genes are summarized in Table S2 in Supplementary Material. The amino acid sequences of AP2/ERF TFs showed wide variation in size (ranging from 119 to 666 amino acids) and sequence composition. Twenty-two of these TFs contained two AP2 DNA-binding domains and hence were classified under AP2 family. Five of the AP2/ERF proteins had a B3 conserved domain at the C-terminus in addition to the common AP2 domain, and these genes were grouped into the RAV family. Three of the remaining 180 proteins, namely PvERF049, PvERF160, and PvERF177 with a single AP2 domain, which is more similar to the amino acid sequences of AP2 domains in the AP2 family TFs, were also grouped under the AP2 family. Moreover, one AP2/ERF protein showed a distinct AP2 domain different from all other switchgrass AP2/ERF proteins but with higher shared sequence similarity with the previously identified genes in rice and Arabidopsis. The remaining 176 proteins were grouped into ERF family, which was further subdivided into either one of two subfamilies (ERF and DREB) based on sequence similarity in the AP2 domain. The ERF subfamily members included 121 proteins while DREB had only 55 proteins .To confirm the classification and evaluate the sequence similarities between the switchgrass AP2/ERF TFs, a dendrogram was constructed by NJ method using the whole amino acid sequences of the proteins. The analysis showed distinct clustering of the proteins into specific groups and families as previously described in other species Figure . SpecifiTo complement the cluster analysis-based classification, the exon\u2013intron structures of AP2/ERF genes were evaluated. The schematic representations of protein and gene structures of switchgrass AP2/ERF superfamily are presented in Figure Analysis of amino acid sequence conservation in the whole proteins of AP2/ERF superfamily showed the presence of unique conserved motifs shared between proteins within families, subfamilies, or groups Figures . MoreoveGene ontology analysis of switchgrass AP2/ERF TFs, based on rice reference sequences, predicted candidate genes\u2019 molecular functions, putative roles in the regulation of diverse biological processes, and their cellular localization  containing expression data for about 78,000 unique transcripts in various tissues was recently developed  displayed increased expression level at radicle emergence whereas the other two (PvERF049 and PvERF203) showed increased expression at coleoptile emergence. The expression of the RAV genes and the singleton gene were apparently relatively less variable throughout the seed germination process  revealed apparent differential expression pattern between the organs and different stages of vegetative development . Moreover, the expression pattern of AP2/ERF genes during reproductive development also showed differential expression between the reproductive tissues from the initiation of inflorescence meristem to the maturation of the seeds .PvERF95, PvERF98, PvERF101, and PvERF102) and one gene in group II (PvERF148) of the DREB subfamily showed highest expression in vascular bundles and internode tissues followed by internode portions where active lignification is expected  and X  showed the highest expression in the vascular bundles followed by youngest internode sections , one gene in group VI-L (PvERF088), and three genes in group VII  had high expression in vascular bundles. Contrastingly, some genes in the ERF subfamily belonging to group V (PvERF001 and PvERF002) and VI (PvERF068) showed the highest expression in the basal fragments of the fourth internodes (E4) that is under less active lignification. Other genes including PvERF178 (VI); PvERF110 (VII), PvERF115 (VII), and PvERF164 (VII); and PvERF038 (IX) had notably high relative expression in roots than in other tissues. Compared to the ERF family genes, the expression of AP2 genes was highly diverse with some genes having high specificity to roots and vascular bundles. The expression of the two RAV genes analyzed was uniformly low throughout whereas the singleton gene was highly expressed in the LBs, LSH as well as the vascular bundles, and young internode sections  and rice OsERF057 (OsSHN) in ERF subfamily group V, for overexpression analysis in switchgrass. This gene was selected since the expression of its Arabidopsis homolog in transgenic rice resulted in modified cell wall composition  and the C-terminal motif (cm) specific to the Arabidopsis SHINE clade of TFs  and OsERF012 and OsERF057  and tiller height (R\u2009=\u20090.73 at P\u2009=\u20090.06)] . However, no tangible difference was observed in the rate of leaf chlorophyll leaching between transgenic and the control lines (data not shown). Subsequently, we analyzed whether the changes in leaf morphology might be accompanied by changes in the expression level of genes in the cutin and wax biosynthesis pathway, in which none were observed . Moreover, overexpression of PvERF001 in transgenic switchgrass showed relatively reduced expression of some lignin (PvC4H and PvPAL), hemicellulose (PvCSLS2), and cellulose (PvCESA4) biosynthetic genes, as well as some of the transcriptional regulators (PvMYB48/59 and PvNST1) of cell wall biosynthesis . The total lignin content in R1 tillers determined by Py-MBMS of cell wall residues and in leaves determined by phloroglucinol\u2013HCl staining did not show sizeable difference between the transgenic and non-transgenic control lines . Similarly, analysis of the S/G lignin monomer ratio in transgenic lines did not significantly change as compared to that of the non-transgenic control line . However, significant improvement in glucose release efficiency was observed in lines 7 (10%) and 8 (16%) relative to the non-transgenic control line  , and Populus (66). All three species along with switchgrass have a singleton in their genome. Consistent with the previous report in rice , also known as the cytokinin responsive factor (CRF) domain in Arabidopsis that is also shared by rice ERF genes belonging to same group in rice ERF subfamily  displayed LWSY conserved motif (M21) at the C-terminal and thus may play similar roles. No information is available in the literature on some of the conserved motifs identified here including M8, M13, M14, M15, M17, and M24 , which might potentially be specific to switchgrass.AP2/ERF TFs that function as repressors or activators of specific target genes are distinguished by the presence of conserved motifs called repression domains (RD) that are highly conserved, or by the presence of activation domains which are generally less conserved , DREB , and AP2 genes  during the initiation of seed germination as well as in vascular bundles and internode sections. Moreover, the observed robust expression of 14 DREB, 17 ERF, and 3 AP2 genes in tissues or organs undergoing active lignification  but less robust expression in less lignified tissues (leaves) also supports this assertion , reduced lignification, and enhanced carbohydrate content (cellulose) in the wood of transgenic lines hinting that these TFs may indeed interact with the transcriptional machinery regulating cell wall biosynthesis  (EjAP2-1) is an indirect transcriptional repressor of lignin biosynthesis via interaction with EjMYB1 TFs  gene resulted in improved enzymatic saccharification efficiency via increased level of starch  was expressed mainly in the abscission zone and functionally associated with the regulation of the pedicel abscission zone-specific transcription of genes including cell wall-hydrolytic enzymes  required for abscission  was proposed to have a native association with cell wall regulatory and biosynthetic pathways, yet this was not experimentally verified   exhibiting reduction in plant height but increase in the number of tillers (Zhou et al., PvERF001 showing increased plant height but no difference in number of tillers. This suggests that ERF genes might functionally be highly diversified and PvERF001 may be part of a different pathway than we anticipated such as regulation of responses to biotic stress or other abiotic stress or regulation of cell elongation or division in coordination with the cytokinin pathway, with the latter perhaps explaining the observed increase in biomass and vegetative growth in transgenic lines.A recent study involving overexpression of rice homolog of PvERF001 highlight the potential of these TFs for improvement of bioenergy feedstocks.In summary, the expression profiling of the switchgrass AP2/ERF genes provides baseline information as to the putative roles of these genes and thus a useful resource for future reverse genetic studies to characterize genes for economically important bioenergy crops. With the current advancements in switchgrass research and establishment of efficient transformation system, this inventory of genes along with the information provided here could facilitate our understanding regarding the functional roles of AP2/ERF TFs in plant growth and development. Furthermore, it would aid in the identification of potential target genes that may be used to improve stress adaptation, plant productivity, and sugar release efficiency in bioenergy feedstocks such as switchgrass. The increased biomass yield and sugar release efficiency from overexpressing WW designed and performed the experiments, analyzed the data, and wrote the manuscript. MM participated in experimental design and data analysis, assisted with revisions to the manuscript and coordination of the study. GT, RS, SD, and MD assisted with performing lignin and sugar release assays and contributed in revision of the manuscript. CS conceived the study and its design and coordination, and assisted with revisions to the manuscript. All authors read and consented to the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.http://journal.frontiersin.org/article/10.3389/fbioe.2015.00101The Supplementary Material for this article can be found online at Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file."}
+{"text": "XPD, XPB and TTD-A, code for subunits of Transcription Factor (TF)IIH. Interpreting XPD mutations in the context of available biochemical data led us to propose adverse effects on CDK-activating kinase (CAK) subunit of TFIIH and TFIIH-mediated functions as a relevant mechanism in preeclampsia. In order to gain deeper insight into the underlying biologic mechanisms involving TFIIH-mediated functions in placenta, we analyzed NER/transcription and global gene expression profiles of normal and preeclamptic placentas and studied gene regulatory networks.Preeclampsia is a significant cause of maternal and fetal mortality and morbidity worldwide. We previously reported associations between trichothiodystrophy (TTD) nucleotide excision repair (NER) and transcription gene mutations in the fetus and the risk of gestational complications including preeclampsia. TTD NER/transcription genes, XPD and XPB were consistently expressed from 14 to 40 weeks gestation while expression of TTD-A was strongly negatively correlated  with gestational age. Analysis of gene expression patterns of placentas from a case-control study of preeclampsia using Algorithm for Reconstruction of Accurate Cellular Networks (ARACNE) revealed GTF2E1, a component of TFIIE which modulates TFIIH, among major regulators of differentially-expressed genes in preeclampsia. The basal transcription pathway was among the largest dysregulated protein-protein interaction networks in this preeclampsia dataset. Within the basal transcription pathway, significantly down-regulated genes besides GTF2E1 included those coding for the CAK complex of TFIIH, namely CDK7, CCNH, and MNAT1. Analysis of other relevant gene expression and gene regulatory network data also underscored the involvement of transcription pathways and identified JUNB and JUND (components of transcription factor AP-1) as transcription regulators of the network involving the TTD genes, GTF2E1, and selected gene regulators implicated in preeclampsia.We found high expression of TTD NER/transcription genes in normal human placenta, above the mean of their expression in all organs. Our results indicate that TTD NER/transcription genes are expressed in placenta during gestational periods critical to preeclampsia development. Our overall findings suggest that impairment of TFIIH-mediated function in transcription in placenta is a likely mechanism leading to preeclampsia and provide etiologic clues which may be translated into therapeutic and preventive measures. Preeclampsia is a complex disorder affecting about 7% of all pregnancies and a major cause of severe intrauterine growth restriction (IUGR) and preterm birth . Preecla6) recessive disorder  and XPB  in placenta compared to skin and other tissues. XPD expression was also higher in placenta than skin and most other tissues but the difference did not reach statistical significance  with gestational age  . In our GTF2E1, which codes for a component of TFIIE, as the most interconnected gene in the network   revealed0588  revGTF2E1 with 120 significant interactions  and those coding for all three components of the CAK complex of TFIIH, namely CCNH , CDK7  and MNAT1 (which codes for MAT1)   are inferred to be the master regulator(s) in the network defined as gene(s) with the highest number of significant interactions with other genes within the network. In our analysis, the top gene in the network in terms of the largest number of interactions was -6) between GTF2E1 and FLT1 siRNA datasets suggesting similar consequences for inhibition of FLT1 tyrosine protein kinase and inhibition of transcription in the endothelial cells  transcriptome dataset GSE27871) [871 [27] We analyzed the reactome database  to identGTF2E1) and gene regulators   implica) Figure\u00a0. These a) Figure\u00a0, highligAlthough singular observations of certain pregnancy complications were noted in individual case reports of TTD patients (as illustrated in our recent genetic epidemiologic study ), gestata and three XP  The reactome dataset  was alsoIn order to infer potential common transcriptional regulatory networks of selected genes and gene regulators implicated in preeclampsia, analysis of the ENCODE Chip Seq derived regulatory network data  was condaReferences for most XPD mutations analyzed in our previous report can be found in Table four of Cleaver et al. [r et al. .The authors declare that they have no competing interests.RM and AD conceived the study and analyzed the data. XA and VN helped with data analysis and interpretation. AK helped with data preparation and analysis. All authors read and approved the final manuscript.2 scale) of three TTD NER/transcription genes in normal human tissue array including placenta in GSE 96 [NER/transcription gene expression profiles in normal human placenta. Panel a. Bar graph depicting expression (relative fluorescence intensity shown on logn GSE 96 . Red barn GSE 96 . CirclesClick here for file"}
+{"text": "Acromegaly is a rare endocrine disorder with excess growth hormone (GH) production. This disorder has important metabolic effects in insulin resistance and lipolysis. The objective of this study was to explore transcriptional changes induced by GH in adipose tissue.Patients with acromegaly (n=9) or non-functioning pituitary adenoma (n=11) were prospectively observed from March 2011 to June 2012. The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex-vivo for lipolysis and ceramide levels. Adipose tissue was analyzed by RNA sequencing (RNAseq).IGF1, IGFBP3) as well as several novel transcriptional changes, some of which may be important for GH signal regulation (PTPN3 and PTPN4) and the effect of GH on growth and proliferation. Several transcripts could potentially be important in GH-induced metabolic changes. Specifically, induction of LPL, ABHD5, ACVR1C could contribute to enhanced lipolysis and may explain the suggestive enhancement of adipose tissue lipolysis in acromegaly patients as reflected by glycerol release from the explants of the two groups of patients (p=0.09). Higher expression of SCD and TCF7L2 could contribute to insulin resistance. Expression of HSD11B1 was reduced and GR was increased, predicting modified glucocorticoid activity in acromegaly.There was evidence of reduced insulin sensitivity based on the increase in fasting glucose, insulin and HOMA-IR score. We observed several previously reported transcriptional changes (We identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly."}
+{"text": "Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion.in situ in Invading Glioma Cells (IGCs) compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT) processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC) xenograft model to explore gene expression changes  Glioblastoma (GBM), the most malignant glioma tumor, is highly invasive with a median survival of 16 months despite combined surgical resection, radiotherapy, and chemotherapy. Although the molecular signature of glioma has been investigated in detail The brain consists of numerous cell types forming tissue scaffolds that guide invasion Glioma stem cells (GSCs) are a subpopulation of cells in the tumor capable of self-renewal that can give rise to a heterogeneous tumor in vitro would affect cell physiology and gene expression. Traditional laser capture microdissection studies of glioma invasion focused on glioma specimens from human patients, dissecting neoplastic astrocytes as the invading cells at the rim of the tumor core Ideally, one would perform between\u2013group differential expression analysis for each cellular compartment. However, experimental methods for isolating the IGCs and their microenvironment cellular compartment are neither timely nor cost effective, and isolating them in situ. Subsequently, we found several genes in multiple pathways that may facilitate invasion which were validated at the protein level in xenografted GSCs and in clinical samples from GBM patients. Importantly, OLIG2, a proliferation regulator and glioma progenitor cell marker was upregulated in the IGCs relative to the tumor core. Inhibition of OLIG2 expression reduced migration and stemness and provided functional confirmation as a potential therapeutic target in glioma invasion. Overall, the novel approach in this study allowed us to construct and evaluate a more complete picture of multiple pathways within the area of glioma invasion than has been previously demonstrated.In the present study we used an innovative laser microdissection (LMD) enrichment strategy and gene expression analysis. Differentially expressed genes (DEGs) of IGCs and their microenvironment were simultaneously detected allowing us to deduce functional networks that characterize glioma invasion Following signed informed consent, tumor tissue was obtained from patients (aged \u226518 years) undergoing medically indicated resection of malignant gliomas at the National Institutes of Health as part of a clinical trial approved by the Institutional Review Board (NCI-02C0140). NCI Animal Care and Use Committee (ACUC) approved all animal experiments.Primary glioma stem cells were cultured in NBE medium as previously described GSCs migration was assessed by the xCELLigence RTCA DP device, according to the manufacturer instructions .An intracranial orthotopic model in SCID mice was utilized for the generation of infiltrative glioma xenograft tumors Raw data for this experiment has been deposited in the Gene Expression Omnibus (accession number GSE53717).The probe for each gene was designed and synthesized by NanoString nCounter technologies to match the Affymetrix probe target region . HousekeThe standard immunohistochemistry of paraffin sections and western blotting were performed as previously described in vitro cell migration assay (P\u22640.01). When laminin was used for chemotaxis, only 0923 cells showed significant migration (P\u22640.01). In haptotaxis conditions with fibronectin, only 1228A1 cells demonstrated significant migration (P\u22640.01). None of the GSCs migrated in chemotaxis with fibronectin. Intracranial tumors generated by 0923 and 1228A1 GSCs demonstrated an extensive infiltration into the surrounding cerebral cortex  in glioma invasion  enrichment analysis. GO terms that were overrepresented and had at least a 30% overlap with at least one other category were identified as significant  and 9 genes of cell polarity  were downregulated STAT3, which is downregulated, acts as a hub in the EMT network interacting with all other networks. On the other hand, majority of genes (13 out of 18) associated with neurophysiological process  and in the cell cycle  were upregulated CTNNB1), which plays a central role in the canonical Wnt pathway, acts as a major hub interconnecting with genes and gene products associated with tissue remodeling and wound repair  For every dataset, we focused on a subset of genes associated with significant cellular processes and canonical pathways  SEMA5A-Plxnb3, AQP4-Dag1, and FGF2-Sdc2) Further analysis identified 17 potential protein-protein binding interactions between the IGCs and the microenvironment residing host cells  and PDGFA proteins in the invasive glioma cells was confirmed (Pdgfra was only detected in host cells residing at the AOI (Shh) protein was only observed at the brain cortex and barely detected at the AOI or tumor core  transcription factor, is selectively expressed in a subgroup of glioma cells and required for glioma formation in a murine GBM model OLIG2 expression by the IGCs in situ may suggest their stemness, which supports their invasive capability in vivo. We thus investigated whether OLIG2 could serve as a therapeutic target in invading glioma cells. We examined the effect of OLIG2 knockdown (shOLIG2) on the differentiation state, self-renewal, proliferation, cell migration and in vivo invasion of GSCs. As demonstrated in NANOG, OCT4 and SOX2 in 0923 shOLIG2 GSCs were significantly decreased compared to the shControl cells. Immunofluorescence labeling  as previously demonstrated GFAP and TUJ1 in 0923 shOLIG2 cells in a more pronounced manner than in shControl cells  and SOX9. Our analysis revealed . These probes were designed to only capture human or mouse genes, and a significant (70\u201380%) proportion was indeed validated, and is in line with previous reports using pure samples Previous studies of global gene expression in GBM invasion used LCM of patient specimens did not distinguish changes in the microenvironment at the site of invasion CDK1, BUB1, FBX05, ADAM23 and PLXNA4, associated with cell cycle, cell adhesion or neurophysiological processes were found in both datasets. Though upregulated genes within the cell cycle functional category can imply activation of cellular proliferation, we observed the presence of inhibitory proteins of APC such as BUB1 and FBX05, which could promote cell cycle arrest PLXNA4, a semaphorin receptor required for guidance of newly differentiated neurons, was also common to both datasets Many of the DEGs common for both xenografted GSCs were at a low fold-change, but were nonetheless statistically significant. We then looked at the intersection of our DEGs with those previously reported in the invasive rim of 4 human GBMs in an attempt to correlate our xenograft data to a closely related one derived in a clinical setting EPHA2 and EPHA3 in maintaining the undifferentiated state of GSC has been reported EFNB3 enrichment at the AOI accompanied by EPHA4 expression in the IGCs. Cell contact-mediated bidirectional EFNB3/EPHA4 signaling and migration of interneurons during cerebral cortex development has been previously reported, suggesting the possible usage of this interaction during glioma invasion EFNB3 in the cerebral cortex may provide the switch between cell-cell adhesion and cell migration by A-Disintegrin-And-Metalloproteases (ADAM)-mediated shedding ADAM10, ADAM15 and ADAM19 at the AOI.Being exploratory and hypothesis generating, our analysis suggests some potential protein-protein interactions that have never been explored between glioma cells and host cells at the AOI. Recently the role of OLIG2 positive tumor cells within the AOI strongly suggests that the invasive niche contains GSCs OLIG2 in 0923 GSCs decreased the expression levels of their NSC markers , and reduced their self-renewal and proliferation abilities. Exposure of these cells to differentiation conditions reveals the potential of the shOLIG2 GSCs to differentiate more profoundly into distinct populations of glial and neuronal lineages than GSCs which express OLIG2. Moreover, OLIG2 knockdown inhibited their migration potential in vitro and in vivo. Recently, Siebzehnrubl et al. SOX2 and OLIG2 are induced by ZEB1-miR-200 feedback loop in GBM. Our data support their model, as non-invasive cells in the tumor mass express relatively low levels of OLIG2. Our in vitro data further show that OLIG2 can modulate TWIST and SNAI2 protein expression, the central regulators of EMT cancer invasion OLIG2, TWIST and SNAI2 expression within the AOI of xenografted 0923 GSCs.The presence of CHI3L1 (YKL40), CD44, and STAT3in situ contains both invasive and post-invasive (colonizing) glioma cell populations. We postulate that as cells exit the tumor mass and infiltrate brain parenchyma, OLIG2 expression is enhanced, and as they colonize brain parenchyma, expression of EMT markers is diminished.In epithelial cancer, EMT is evoked during tumor cell invasion and metastasis, leading to the generation of cancer cells with stem cell-like characteristics. Metastases are accompanied by a re-differentiation and a MET type transition, both of which are proposed to be a driving force of metastasis, suggesting that MET allows for growth and colonization of the invasive cell in situ. This study revealed several distinct glioma pathways as well as many previously characterized developmental and neurophysiological processes that had never been described in glioma. These multiple pathways serve as a rich reservoir for therapeutic targets that warrant further investigation. Firstly, our data shows that direct targeting of proteins such as CD44CHI3L1PARD3 may be ineffective at this stage of disease as they are already downregulated in glioma cells at the AOI. On the other hand, the identification of molecules selectively expressed by invasive glioma cells such as OLIG2 may allow the development of therapeutic strategies that specifically target this population of cells EFNB3 may be equally amenable to therapeutic targeting.While our approach of filtering out cross-hybridizing genes may have resulted in the loss of some differentially expressed genes, the exploratory nature of this study enabled us to capture for the first time multiple pathways that take place at the junction of tumor invasion and microenvironment Specific therapeutic targeting of glioma invasion is a field in its infancy. Within the tumor-bearing CNS, complex, dynamic and synchronized interactions between glioma tumor cells and tumor-microenvironment residing cells  may sustain glioma cell invasion. Recently, Sottoriva et al. detected the multiple coexisting cell lineages and expression subtypes at the individual GBM patient. They also suggested that these IGCs are a heterogeneous population of malignant cells that survived treatment Figure S1Migration in vitro and in vivo of 0827A2 GSCs. (A) Migration activity of 0827A2 GSCs was tested using the xCELLigence RTCA system. The bars represent the average cell indices at 13 h for the indicated conditions of at least 3 experiments. Asterisks indicate significant  differences in the migration of the cells compared to the control [cells in NBE medium in both upper and lower chambers (NBE/NBE) in uncoated well (\u2212/\u2212)] as determined by t-test. Error bars indicate standard error of the means. (B) Migratory nature of xenografted 0827A2 GSCs. H&E stained section depicting restricted infiltration of GBM cells. Inset depicts 10\u00d7 magnification, representative infiltration area.  Unsupervised hierarchal clustering in (C) human and (D) mouse arrays of 0827A2 GSCs xenografts shows that the regions are not completely segregated while a clean separation was observed in human and mouse arrays of both 0923 and 1228A1 GSCs xenografts (demonstrated in (TIF)Click here for additional data file.Figure S2Gene ontology and pathway analysis of host cells at the area of invasion (tumor microenvironment). (A) Gene ontology analysis of the microenvironment dataset. Please see legend of (TIF)Click here for additional data file.Figure S3Distinguishing invading human GSCs from mouse cells. Frozen section of xenograft glioma derived from intracranial injection of 1228A1 GSCs were stained with OLIG2 (red), hNuclei (green) and DAPI (blue). Invading GSCs were distinguished by either nuclear size or human-nuclear staining (white arrows). Magnification \u00d740.(TIF)Click here for additional data file.Figure S4OLIG2, PARD3 and Efnb3 expression in xenografted 1228A1 GSCs. Frozen sections of xenograft glioma derived from intracranial injection of 1228A1 GSC were stained with (A) OLIG2, (B) PARD3 or (C) Efnb3 . DNA was stained with DAPI (blue). At the left side of each panel: intracranial tumor histology  and when available a whole brain tile at same scale. Solid line box (tumor core) and dashed line box (area of invasion) identify magnified (\u00d740) images on right as indicated.(TIF)Click here for additional data file.Figure S5EPHA4, WISP1 and Shh expression in xenografted GSCs. Frozen sections of xenograft gliomas derived from intracranial injection of 0923 (Upper panel) or 1228A1 (Lower panel) GSCs were stained with (A) EPHA4, (B) WISP1 or (C) Shh . Please see legend of (TIF)Click here for additional data file.Figure S6Downregulated expression of EMT associated genes in invasive glioma cells of xenografted 1228A1 GSCs. Frozen sections of xenograft glioma derived from intracranial injection of 0923 GSC were stained with (A) CD44, (B) CHI3L1 or (C) ITGA6 . Please see legend of (TIF)Click here for additional data file.Figure S7PDGFA and mPdgfra expression in xenografted GSC. Frozen sections of xenograft glioma derived from intracranial injection of 0923 (Upper panel) or 1228A1 (Lower panel) GSC were stained with (A) PDGFA and (B) mPdgfra (both in red). Please see legend of (TIF)Click here for additional data file.Table S1NanoString Codeset Details.(XLS)Click here for additional data file.File S1Table S2: Pathway Maps in Invading GSCs and the Tumor Microenvironment. Table S3: Potential Protein-Protein Interactions between Invading GSCs and Their Microenvironment Residing Cells. Table S4: Differentially expressed genes in invading GSCs (array data). Table S5: Differentially expressed genes in the tumor microenvironment (array data). Table S6: Glioma invasion-related genes common with previously reported study by Kislin et al. (reference (DOC)Click here for additional data file."}
+{"text": "External quality assurance (EQA) systems are essential to ensure accurate diagnosis of TB and drug-resistant TB. The implementation of EQA through organising regular EQA rounds and identification of training needs is one of the key activities of the European TB reference laboratory network (ERLTB-Net). The aim of this study was to analyse the results of the EQA rounds in a systematic manner and to identify potential benefits as well as common problems encountered by the participants.The ERLTB-Net developed seven EQA modules to test laboratories\u2019 proficiency for TB detection and drug susceptibility testing using both conventional and rapid molecular tools. All National TB Reference laboratories in the European Union and European Economic Area (EU/EEA) Member States were invited to participate in the EQA scheme.A total of 32 National TB Reference laboratories participated in six EQA rounds conducted in 2010\u20132014. The participation rate ranged from 52.9% - 94.1% over different modules and rounds. Overall, laboratories demonstrated very good proficiency proving their ability to diagnose TB and drug-resistant TB with high accuracy in a timely manner. A small number of laboratories encountered problems with identification of specific Non-tuberculous Mycobacteria (NTMs) (N = 5) and drug susceptibility testing to Pyrazinamide, Amikacin, Capreomycin, and Ethambutol (N = 4).The European TB Reference laboratories showed a steady and high level of performance in the six EQA rounds. A network such as ERLTB-Net can be instrumental in developing and implementing EQA and in establishing collaboration between laboratories to improve the diagnosis of TB in the EU/EEA. Tuberculosis (TB) remains an important public health problem globally and within the European Union (EU) despite significant progress made in the past decade. In 2013, 64 844 TB cases were reported in 28 EU and two European Economic Area (EEA) countries, 6% less than in 2012 and reflecting a decrease in 19 countries [Timely and accurate diagnosis of active TB is a prerequisite for any successful TB control programme and an essential part of the action framework to eliminate TB in low-incidence countries . The labTo ensure compliance with existing international standards of laboratory diagnostics , all labThe introduction of new drug susceptibility testing methods, including rapid culture and molecular tools, and genotyping methodologies necessitated the development of novel as well as modification of existing EQA schemes (eg for rapid molecular tools). A series of recent reports revealed specific problems related to a lack of standardisation in second-line drug (SLD) susceptibility testing and multilocus MIRU-VNTR genotyping \u201315. The A situation analysis of national TB reference functions across the EU  formed tThe aim of this study was to systematically analyse the implementation of the EQA scheme across the network from 2010 to 2014, assess performance of the laboratories, identify common problems and discuss the potential benefits of the scheme for the participants.A total of six EQA rounds were conducted from 2010 to 2014 . All 34 The ERLTB-Net developed seven modules covering various types of laboratory techniques: (1) microscopy; (2) primary isolation; (3) identification; (4) drug susceptibility testing; (5) nucleic acid amplification testing (NAAT) for rapid detection of Mycobacteria; (6) molecular drug susceptibility testing using cultures; and (7) molecular drug susceptibility testing using crude DNA extracts .Mycobacterium species and drug susceptibility profiles) were used. Specimen panels included strains with varying DST profiles (M. tuberculosis suspensions treated with chloroform [M. tuberculosis complex (MTBC) strains  as well as non-tuberculous mycobacteria (NTM)  in various combinations.Artificial sputa (spiked with mycobacteria) were used for preparation of slides (for microscopy) and specimens for primary isolation and rapid NAAT-based detection; all specimens in the latter panels contained equal concentrations of Mycobacteria. For identification and DST, strains with validated characteristics  and  methods used for species identification (Module 3).Reports received from participating laboratories were analysed against reference results as determined by the EQA provider (NRL Germany and INSTAND e.V), and the percentage of correct results in each module was calculated by dividing the number of correct results by the total number of tests in the module. This provided the score for the given laboratory in the given module. If not all tests within a given module were performed , the overall score was adjusted accordingly. Laboratories scoring \u226580% were issued performance certificates for individual modules. Their individual performances were referred to as \u201cgood\u201d (scores 80.0\u202699.9%) and \u201cexcellent\u2019(100.0%) and overall performance of laboratories achieving 80% score was collectively termed \u201cgood\u201d. Scores under 80% were considered to indicate poor performance for the specific module(s) and no EQA certificate was issued .Error rates for specific methods were calculated as a proportion of incorrect results relative to a total number of individual tests performed by all laboratories across all rounds; for example in Modules 5 and 6 data was analysed by individual drugs. Proportions were compared using the chi-square test using GraphPad Prizm . A p-value < 0.05 was considered as significant.Mycobacterium species identification module in round 1 comprising 94.1% of laboratories within the network (The number of participating laboratories varied across EQA rounds and modules with the largest number of laboratories (N = 32) participating in the  network . These 3Performance characteristics of participating laboratories in the EQA rounds 1\u20136 are summarised in The proportion of laboratories using Ziehl-Neelsen (ZN) staining for smear microscopy (Module 1) varied from 46.0% to 58.0% with the remaining laboratories using primarily auramine fluorescent staining; a small number of laboratories (varying from 1 to 4 in different rounds) used the Kinyoun method.There were minor variations in the numbers of laboratories participating in the proficiency testing for microscopy in different rounds with the largest number (N = 27) taking part in round 5 and the smallest (N = 23) in rounds 2 and 4. In rounds 2\u20136, laboratories demonstrated good and excellent performance with only a small number  of laboratories failing to achieve the 80% threshold. The proportion of laboratories that were awarded certificates was 80.8% in round 1 and 96.2% in round 6. There were no significant differences in error rates and overall performance characteristics between laboratories using different smear staining methods  .M. tuberculosis complex from NTM and identify Mycobacteria species using a range of phenotypic and/or molecular tools. The number of participating laboratories varied from 23 (round 3) to 29 (round 1). Overall scores were good and excellent with only one laboratory in rounds 4 and 6 failing to achieve the 80% threshold. The proportion of laboratories reporting results of species identification varied from 64.3% to 95.7% in different years and largely depended on the composition of the EQA panels (MTBC or NTM) as not all laboratories identify the same spectrum of NTM species routinely on primary specimens. Common problems encountered by the laboratories included reporting the presence of mycobacteria in negative specimens , and inability to detect NTM in positive specimens (N = 2).Within module 2, laboratories were requested to detect the presence of mycobacteria in artificial spiked sputum specimens using bacteriological culture, and (if routinely performed) differentiate In module 3, participants performed species identification of mycobacterial cultures using phenotypic or molecular tools or a combination of both based on standard protocols adopted in those laboratories. The number of participating laboratories ranged from 21 (Rounds 2 and 5) to 32 (Round 1).M. tuberculosis complex  with M. bovis caprae and M. bovis BCG being the most problematic species.Within this module, performance varied considerably with a total of three laboratories across all rounds achieving low scores of 20\u201340%  and one laboratory misidentifying all specimens in round 5. The majority of participating laboratories, however, demonstrated either good or excellent performance. The proportion of laboratories that were awarded certificates varied from 85.2% (round 4) to 100% (round 6). Common problems experienced by the laboratories included misidentification of NTM and misidentification of species within the M. tuberculosis cultures for sensitivity to five first-line drugs (FLD)  and additionally to fluoroquinolones (FQ), capreomycin (CAP), amikacin (AMK), and kanamycin (KAN) (Modules 3\u20135) or FQ, CAP, and AMK (Modules 2 and 6) using any validated phenotypic method routinely used in the laboratory. All but one laboratory used automated liquid culture-based systems  for DST for second line drugs; for FLD including PZA methods varied and included Bactec MGIT960 as well as the proportion method on solid media and resistance ratio method on semi-solid and liquid media for PZA.In module 4, laboratories were requested to test five (modules 1\u20132 and 5\u20136) or ten (modules 3 and 4) The number of laboratories taking part in module 4 varied from 22 (Rounds 5 and 6) to 31 (Round 1) and overall performance was good with only two laboratories failing to achieve 80% in one round (round 2). Only susceptibility to rifampicin (RIF) and isoniazid (INH) was tested by all participating laboratories; other drugs were tested by a smaller number of laboratories in accordance with their routine practices. Importantly, the proportion of laboratories routinely testing for susceptibility to pyrazinamide (PZA), FQ and AMK increased over the five years from 65.0%, 56.6%, and 52.2% to 100.0%, 77.3%, and 77.3%, respectively, confirming the ability of many laboratories to detect extensively drug-resistant (XDR) strains.Error rates varied substantially between drugs . PZA wasThis module was designed to test proficiency of laboratories in rapidly detecting MTB complex bacteria in sputum specimens using nucleic acid amplification tests (NAAT). The number of participating laboratories ranged from 19 (Round 4) to 22 (remaining rounds) and performance was good with all but two laboratories (in Rounds 5 and 6) achieving scores >80%. The proportion of laboratories using GeneXpert  methodology for TB detection in primary specimens increased from 35.0% in 2011 to 65.2% in 2014. Other methods used for TB detection in primary specimens included BD ProbeTec DTB  used by up to 13.6% of laboratories in different years, and Cobas TaqMan  GT Mycobacteria Direct , and Artus PCR kit  .There were no differences in error rates and overall performance characteristics between GeneXpert and other NAAT methods for rapid MTB complex bacteria identification.In Module 6, proficiency of laboratories in rapidly detecting resistance to selected first  and second-line drugs  on cultures was tested. The number of participants remained relatively stable over five years and ranged from 18 (Round 1) to 22 (Round 2). Nearly all laboratories used line probe assays (LPAs) for molecular DST. A small number of laboratories (<10%) used in-house validated assays including targeted gene sequencing and pyrosequencing,Performance was good with only one laboratory in round 6 failing to achieve the 80% threshold score. The proportion of laboratories adopting technologies for rapid DST for second-line drugs increased from 66.7% (round 2) to 85.0% (round 6). Overall concordance with reference results was high, exceeding 99% for all drugs . Unlike M. tuberculosis strains, and therefore inactivated non-hazardous crude DNA extracts isolated from fully sensitive, poly- and multidrug-resistant strains were used. Module 7 panels were only included in rounds 3 and 4 and results were obtained from 26 and 24 laboratories, respectively.The primary aim of this module was to test the proficiency of the laboratories in rapid detection of highly drug-resistant Overall performance was good with a total of 8 errors reported . All laboratories achieved scores >80%. Errors were not confined to any specific drug and were lower for RIF (0.3%) and higher for INH (1.0%) . ConcordThe primary aim of this study was to systematically analyse the performance of national TB reference laboratories for detection, identification and drug susceptibility testing for TB diagnosis across the EU/EEA through a comprehensive series of EQA rounds, identify common problems and discuss the potential benefits of the EQA scheme developed within the EU-wide TB reference laboratory network.Overall, laboratories demonstrated good proficiency with scores consistently exceeding the 80% threshold in the vast majority of the laboratories. Steady high performance in both phenotypic and rapid molecular methods over five years with only 27 individual module result failures  shows an ability of national TB Reference laboratories to diagnose TB and drug resistance TB with high accuracy in a timely manner. The principal results of our study were in agreement with another report  demonstrChallenges with microscopy and species identification in rounds 1\u20133 have been addressed through corrective actions including additional training and laboratory visits. No major problems were detected in primary isolation (module 2). An in-depth analysis of laboratory performance for phenotypic DST has allowed us to identify methodological problems with specific anti-TB drugs including PZA, EMB and, interestingly, KAN and AMK. This is largely in agreement with earlier reports demonstrating a lack of standardised methodologies and drug concentrations for PZA (type of media) and KAN  ,19,20 anProficiency of laboratories in identification and DST using rapid molecular tools proved to be good and excellent. High scores were achieved by the laboratories in molecular DST on cultures and crude extracts and there was a significant increase in the number of laboratories adopting molecular techniques (particularly the GeneXpert system), which is critical for the timely detection of MDR strains and prevention of transmission ,5.Our study identified several common challenges in EQA schemes with relatively low participation rates being one of them. Significant variability of participation rates (52.9\u201394.1%) across modules and/or EQA rounds can be in part explained by the fact that not all laboratories perform all the tests routinely ; data collected outside the current study suggests that up to 25% of NRLs are not routinely engaged in primary laboratory work (unpublished data). A small number of laboratories encountered challenges in sending the results within the agreed timeframe or were unable to take part due to financial constraints . This highlights the importance of adequate management and careful financial planning including allocation of funds for participation in EQA schemes. Other problems encountered in individual laboratories preventing them achieving the 80% threshold included clerical errors (mislabelling etc), incorrect interpretation of molecular and phenotypic tests results, as well as cross-contamination issues. These problems may be indicative of more general problems in the laboratory practice and should be taken into account in the laboratory quality management.Laboratory services play a crucial role in improving the delivery of health care and reducing the prevalence of TB and drug-resistant TB in particular. Quality assessment through proficiency testing is a fundamental tool used to ensure accuracy of test results by comparing quality between laboratories, evaluating performance and detecting errors so that corrective actions, including additional training and support visits, can be taken in a timely manner to restore the high quality of services.M.tuberculosis genotyping [Overall, results of our study and earlier reports on proficiency testing and EQA schemes for notyping ,14 demonParticipating laboratories benefited from the developed EQA program in a number of ways including free of charge EQA and performance certificates essential for their accreditation by relevant national bodies, availability of training for their staff members as well as targeted actions including direct consultations with the EQA providers and support visits from scientists within the network who were able to provide additional expertise and help to NRLs where needed. Steadily high performance during the implementation period suggests that aforementioned network activities addressing the challenges identified through the analysis of EQA results were effective. Sustainability of EQA and training activities at EU/EEA level as well as their further development through inclusion of novel validated methodologies (eg Next Generation Sequencing) are crucial for ensuring timely and high-quality laboratory diagnosis of TB in the EU/EEA.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "Cerebral near-infrared spectroscopy (NIRS) represents an exciting prospect for the non-invasive monitoring of cerebral tissue oxygenation in traumatic brain injury (TBI). Earlier attempts at clinical application of cerebral NIRS demonstrated that further work was needed . The bas\u00ae computational light modelling software (developed at the University of Birmingham) [The optimal depth for grey matter target tissue (grey-white matter junction) was ascertained by reviewing a series of brain CT scans of patients who had sustained a TBI. Set (average) measurements were derived from these identifying the target depth of the grey matter strip from the point of probe placement. Currently there are five commercially available cerebral NIRS systems. Table mingham) . The novWe reviewed 32 trauma series CT brain images and the average depth to grey matter was derived as 21.37 mm  from the surface (Figure Based on the computational modelling of our work, the FORE-SIGHT NIRS device by CAS Medical source detector layout provides the greatest sensitivity at depth for the purposes of cortical monitoring in trauma. Variations in the layout have a significant impact on the quality of signal detected."}
+{"text": "IL1RAPL1, PIR, GABRQ, GPRASP2, SYTL4) with cadherin, protocadherin and ankyrin repeat gene families most commonly altered . Other genes related to neurogenesis and neuronal migration , were also identified.Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism  from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters . We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disorders. Seventy-eight genes identified met selection criteria ranging from 1 to 9 filtered variants per female. Five females presented with functional variants of X-linked genes ( PTEN tumor suppressor gene ; d1 = peak height of digested DNA from the first allele and u1 = peak height of undigested DNA from the first allele; d2 = peak height of digested DNA from the second allele and u2 = peak height of undigested DNA from the second allele. Highly skewed XCI is defined as >80% calculated ratio for either one of the AR gene alleles in the digested DNA sample. To ensure the reproducibility of XCI results and equal amplification of both alleles, the digestion, PCR amplification, and genotyping were repeated up to three times in several samples.The digestion process preferentially degrades activated (unmethylated) over inactivated (methylated) DNA. Undigested DNA is preferentially amplified and produces larger peak heights. The peak height values for digested DNA is normalized using peak height values for the undigested DNA for each subject. The percentage of XCI for each XCI status for each subject was assigned to one of the three mutually exclusive categories: (i) randomly selected inactivation of either allele from each X chromosome (XCI = 50%:50% to 64%:36%); (ii) moderately skewed inactivation favoring 1 allele of one of the X chromosomes (XCI = 65%:35% to 80%:20%); and (iii) highly skewed inactivation of a single allele representing one X chromosome (XCI > 80%:20%). The relative frequency of random, moderate, and highly skewed XCI categories was determined for the females with autism. The binomial frequency distribution of X-linked gene variants (present or absent) among females with autism spectrum disorder exhibiting moderate and high levels of XCI skewness were approximated using Yates\u2019 chi-squire test and odds ratios were calculated with 95% confidence intervals.The top genes chosen were based on the final selection criteria identified for each female and evaluated for biologic function and whether each gene was previously reported as a clinically relevant candidate or known gene for autism . The X cCCDC64 in subject HI0605) and some novel ] in 77% of the remaining females. In most females, we found more than one gene that could contribute to the causation of autism. This compares with a recent report of molecular findings among 2000 consecutive patients (primarily pediatric age) referred for clinical whole exome sequencing for evaluation of suspected genetic disorders at a large USA medical center in which 25% received a molecular diagnosis. About 60% of the diagnostic mutations were not previously reported [In summary, we shared our experience using a descriptive next generation whole exome sequencing case study approach examining 30 well-characterized Caucasian females with autism between 5 and 16 years of age recruited from multiplex families enrolled at the AGRE for research purposes. Interpretation of DNA findings are limited due to an inability to study other affected and non-affected family members to determine whether the gene variants were de-novo or inherited in origin for correlation with clinical phenotypes and lack of Sanger sequencing confirmation. Using strict selection criteria, four females (13%) were found to possess single gene variants of known candidate genes for ASD with a high likelihood of causality. We also identified multiple plausible candidate genes [some known (e.g., reported . By phen"}
+{"text": "Left ventricular ejection fraction (LVEF) is the primary risk stratification tool used for therapeutic decision making related to device therapy. However, an influence of right ventricular dysfunction on cardiovascular events is becoming apparent. The incremental prognostic value of right ventricular ejection fraction (RVEF) on future arrhythmic events among those being considered for device therapy has not been well examined. In this study we evaluate the significance of MRI-based measurement of RVEF versus other clinical and MRI-based variables for their ability to predict Sudden Cardiac Death (SCD) or Appropriate ICD therapy.Consecutive patients with cardiomyopathy were evaluated for device candidacy. All patients underwent a standard Late Gadolinium Enhancement (LGE) MRI protocol followed by a blinded core-laboratory based quantification of left ventricle (LV) and right ventricle (RV) volumes, ejection fraction (EF) and total hyperenhancement (HE). Patients were stratified according to the presence or absence of significant RV systolic dysfunction, defined as an RVEF \u226445%. All patients were followed for the occurrence of SCD or appropriate ICD therapy. The secondary outcome was heart failure admission or non-sudden cardiac death. All clinical and MRI-based variables were evaluated for associations with the primary and secondary outcomes with Cox proportional multivariable regression analysis also performed.A total of 318 patients  were followed over a median of 467 days. At the end of follow-up 49 patients (15.4%) suffered a primary outcome (10 SCD and 39 appropriate therapies). Baseline clinical characteristics were similar among those with and without the primary outcome with the exception of prior history of ventricular arrhythmia and ischemic etiology (p < 0.05). Following adjustment for etiology, LVEF, LVEDV, and Total HE, those with an RVEF\u226445% were more likely to experience the primary outcome  and the secondary outcome  of interest.Patients with right ventricular dysfunction, defined as RVEF\u226445% by cardiac MRI, are at an increased risk of future arrhythmic events. Similarly, these individuals are at an elevated risk of heart failure admission and non-sudden cardiac death.This research was supported by the Imaging in Cardiovascular Therapeutic grant from the Ontario Research Fund and the Canada Foundation of Innovation."}
+{"text": "In order to improve the tracking accuracy, model estimation accuracy and quick response of multiple model maneuvering target tracking, the interacting multiple models five degree cubature Kalman filter (IMM5CKF) is proposed in this paper. In the proposed algorithm, the interacting multiple models (IMM) algorithm processes all the models through a Markov Chain to simultaneously enhance the model tracking accuracy of target tracking. Then a five degree cubature Kalman filter (5CKF) evaluates the surface integral by a higher but deterministic odd ordered spherical cubature rule to improve the tracking accuracy and the model switch sensitivity of the IMM algorithm. Finally, the simulation results demonstrate that the proposed algorithm exhibits quick and smooth switching when disposing different maneuver models, and it also performs better than the interacting multiple models cubature Kalman filter (IMMCKF), interacting multiple models unscented Kalman filter (IMMUKF), 5CKF and the optimal mode transition matrix IMM (OMTM-IMM). Bayes filtering algorithms have been broadly used in target tracking systems ,2,3,4, wBlom and Shalom have proposed the interacting multiple model (IMM) algorithm based on a generalized pseudo-random algorithm to decrease the error of single model algorithm, which will improve the quick response and accuracy of target tracking . The IMMIn this paper, the interacting multiple models five degree cubature Kalman filter (IMM5CKF) based on a five degree cubature Kalman filter and IMM algorithm is proposed to improve the tracking accuracy, model estimation accuracy and quick response of target tracking algorithms. The negative weights of 5CKF go to 0 when the system dimensions go to \u221e, so 5CKF is more stable than UKF . The simThe five degree cubature Kalman filter is proposed to improve the accuracy of the traditional Cubature Kalman Filter . It choox, P is the covariance of x. The five degree Cubature Kalman Filter includes two steps, time update and measurement update.Supposing state variables (1) FactorizeThe Cholesky decomposition of (2) Evaluate the cubature points:(3) Evaluate the propagated cubature pointsThe sample points are obtained by propagating the cubature points through the state equation as:(4) Estimate the predicted pointsState prediction (5) Estimate the predicted error covariance:(1) Factorize:(2) Evaluate the cubature points:(3) Evaluate the propagated cubature pointsThe sample points are obtained by propagating the cubature points through the observation equation:(4) Estimate the predicted measurement:(5) Estimate the innovation covariance matrix:(6) Estimate the cross-covariance matrix:(7) Estimate the Kalman gain:(8) Estimate the updated state:(9) Estimate the corresponding error covariance:In the paper, the proposed IMM5CKF includes the merits of the 5CKF algorithm and IMM algorithm. The main character of IMM5CKF is that it calculates the state distribution and error covariance matrix by choosing an odd number of special cubature points with equal weights, and the negative weights go to 0 when the dimension of the system goes to The mixed initial value and measure value  of position and velocity are used to contrast the performance of the filtering algorithms. The RMSE defined in state vector The RMSEs of the IMM5CKF, IMMCKF, IMMUKF, 5CKF and OMTM-IMM are shown in In this paper, IMM5CKF is proposed to enhance the tracking accuracy, model estimation accuracy and response sensitivity of nonlinear maneuvering target tracking problems. The algorithm introduces a five degree cubature Kalman filter into interacting multiple models which simultaneously disposes of all the models through a Markov Chain. A classical target tracking problem is utilized to demonstrate that the IMM5CKF can indeed improve the quick response sensitivity of target tracking algorithm, and it exhibits more accurate than IMMCKF, IMMUKF, CKF and OMTM-IMM. In our future research, the study may focus on multisensor navigation and positioning systems. The proposed algorithm should be suitable for the complex real environments according to the analysis."}
+{"text": "Left ventricular late gadolinium enhancement (LV-LGE) is a known incidental cardiac magnetic resonance (CMR) finding in atrial fibrillation (AF) patients and has recently been associated with increased mortality . While LA 1:2 observational case-control study was conducted with a dataset of cases with new onset ischemic stroke after 1st CMR scan and controls matched by age and sex. Cases and controls were selected from a database of 762 AF patients without any prior history of MI who underwent cardiac MRI exams between June 2006 and January 2013. We manually reviewed the electronic medical records of all patients with CMR and sequentially selected the first identified age and sex matched controls (subjects without stroke event after their CMR scan). Two experienced readers scrutinized the CMR scans of cases and controls for presence of left ventricular delayed enhancement. We then collected all comorbidities and conducted univariate (Chi-square test/t-test as appropriate) and multivariate analyses to examine the association between LV-LGE and occurrence of stroke.Out of 762 patients, we identified 14 cases (1.8%) with new onset ischemic stroke after the first MRI scan. Of these cases, 2 (14%) were found to have LV-LGE. We age and sex matched these 14 cases with 28 controls in a 1:2 fashion. Description of demographic variables and univariate measures of association are presented in Table In this case-control study of AF patients without a history of MI, an incidental finding of LV-LGE is shown to predict the risk of stroke, especially in the case of patients with a higher CHADS2 score.Not applicable."}
+{"text": "Furthermore, our study indicates that the structure of CsA during dissociation from the protein possesses a distribution of conformations different from those in solution under equilibrium condition.The immunosuppressive drug cyclosporin A (CsA) binds to its receptor protein cyclophilin 18 (Cyp18) in two distinct kinetic phases, while the mechanism remains elusive. Stopped-flow measurements coupled with titration and competition experiments were used to investigate the puzzling two-phase process of CsA and Cyp18 interaction. This study leads to the dissection of different conformational fractions of either direct fast binding or slow binding with rate-limiting conformational inter-conversion and the real-time measurement of  Berkeley Modenna method[-1 (The slow binding conformer may need to convert to the active conformer before binding to Cyp18 (Model II). Thus, the rate of slow binding represents the apparent converting rate. When the concentration of CsA is lower than that of Cyp18, the slow binding conformers will bind to Cyp18 once they convert to the active conformation with the rate of kna method was usedethod[-1 . This reOur work provides the evidence that the two-phase binding kinetics of CsA to Cyp18 is caused by the ligand conformational heterogeneity. This leads to the dissection of different conformational fractions of either direct fast binding or slow binding with rate-limiting conformational inter-conversion. Moreover, the competition experiment described in S1 FigTime courses of Cyp18 intrinsic fluorescence intensity upon to the adding of THF(A) or LiCl/THF(B). (A) Time courses of Cyp18 intrinsic fluorescence with (Red) or without (Black) subtraction of reference curve (only THF). The arrows show the procedures of the experiments and the curves before and after subtraction of reference curve. (B) Time courses of Cyp18 intrinsic fluorescence with (Red) or without (Black) subtraction of reference curve (only LiCl/THF). The arrows show the procedures of the experiments and the curves before and after subtraction of reference curve.(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig\u22123 s-1.The values shown in the inset represent the different ratios of CsA to CypA. The k value was 8.25 \u00b1 0.03 x 10(PDF)Click here for additional data file.S4 FigBlack curves are plotted by the data converted from (PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Tables-f and kf-s used for fitting was board (highlight), whereas the fitting showed closed value to the predicted, this indicated the conformational selection model was the most dominant process of CsA binding to Cyp18 in aqueous solution.The range of k(PDF)Click here for additional data file."}
+{"text": "The aim of our investigation was to determine effect of the internal carotid arteries (ICAs) tortuosity (S-shape), kinking and coiling on the arterial blood flow by magnetic resonance imaging and ultrasound (US).50 healthy volunteers (control group) and 43 patients with carotid abnormalities (CAs) were examined on 1.5T MR-scanner using routine MR protocol and quantitative MR angiography (qMRA) for estimate of the arterial blood flow velocity and cross sectional area of the ICA. We observed the cross sectional area and the values of peak velocity, mean velocity, flux velocity of arterial blood flow at one cardiac cycle at cervical and intracranial segments of the ICA ."}
+{"text": "Immune reconstitution inflammatory syndrome (IRIS) is a common cause of death and even more common cause of morbidity in patients started on highly active antiretroviral therapy (HAART). At present, very limited data is available about IRIS in the local population so the present study was conducted to determine the incidence, clinical manifestations, risk factors and outcomes of IRIS in south Indian HIV/AIDS patients.Study was a prospective surveillance method to identify IRIS from two ART centers in Mysore city, India for a period of two years. HIV patients who are initiated with HAART were included for the study and were followed up for a period of six months. Data were analyzed using SPSS version 21.s (11%) and other opportunistic infections (27%). The major manifestation of IRIS were fever (44%) followed by lymphadenitis (36%). Statistically important predictors for occurrence of IRIS were male gender and low CD4 count. Two deaths were attributable to IRIS and 54% of them required hospitalization.Out of 798 people followed 82 patients had experienced IRIS with an incidence rate of 10%. Among them 48% were unmasking and rest were paradoxical worsening. Diagnosis included tuberculosis (44%), herpes zoster (18%), cryptococcal meningitiPatients with advanced immunodeficiency at HAART initiation are at greatest risk of developing IRIS and should be appropriately screened and monitored. Educational programs on recognizing and treating these conditions should be initiated in ART access programs."}
+{"text": "Infaunal communities of benthic macro-organisms (\u2265 1mm length) were studied from 81 samples collected across nine sites to the north and south of the Orange River in the Benguela upwelling ecosystem in 2003, with a view to describing communities and understanding the drivers of regional community structure, as well as to document diversity and to examine geographic affinities. Although the fauna was dominated by polychaetes and peracarid crustaceans, patterns in community structure could only weakly be explained by the measured environment (~35%). This is attributed to the generalist nature of the species recovered, which were widely distributed amongst different sediments, water-depths and latitudes. The fauna is dominated by species that enjoy a widespread regional and global distribution and is characterised by relatively low diversity, which is discussed. Coastal-upwelling ecosystems are amongst the most productive in the world, where pelagic systems are characterised by short diatom-based food chains leading to industrial scale fisheries . Biomass2 l-1), and sometimes high levels of hydrogen sulphide in the pore water [sensu [cf 8]. Macrofaunal diversity within OMZs is also low, and communities show a remarkable homogeneity in composition across wide spatial scales; a fact that is attributed to the lack of biogenic structures and large burrowers ).The results of this study suggest that the fauna of the soft-sediment environment off southern Namibia and off Namqualand is characterised by relatively low diversity and by species with a generalist habit and wide distribution. Further work on measuring a wider suite of environmental variables is desirable, and studies into the detailed taxonomic identity of all material collected is encouraged.S1 Fig(TIF)Click here for additional data file.S2 FigNumber  of identified species recovered in one or more of the nine regions (a) or sediment textural groups (b) sampled off southern Namibia and off Namaqualand during 2003.(PPTX)Click here for additional data file.S1 TableList of the identified species recovered from the samples collected off southern Namibia and off Namaqualand during 2003, with an indication of their presence (1) or absence (0) in on-line distributional databases . Information from other sources also indicated, where appropriate. A summary of the known distribution of each species is also indicated.(DOCX)Click here for additional data file.S2 TableList of additional genera, not included in (DOCX)Click here for additional data file.S3 TableMean abundance and standard error (per sample) of the top ten most commonly represented families at each of the sites sampled off southwestern Africa during 2003.(DOCX)Click here for additional data file.S4 TableAverage (root-root) abundance per sample of those macro-infaunal taxa identified by the SIMPER routine in PRIMER 6 as being responsible for 90% of the identity of each of the water-depth zones . The weighted mean water-depth (m) occupied by each of the identified species is also shown.(DOCX)Click here for additional data file.S5 TableAverage (root-root) abundance per sample of those macro-infaunal taxa identified by the SIMPER routine in PRIMER 6 as being responsible for 90% of the identity of each of the sediment textural groups identified by Folk (1954) sampled off southwestern Africa during 2003. The weighted mean sediment particle size (\u03bcm) occupied by each of the identified species is also shown.(DOCX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file."}
+{"text": "Focal left atrial tachycardia (FLAT) although a common cause of supraventricular tachycardia(SVT) among children, the one's arising from left atrial appendage (LAA) present a unique challenge for successful ablation because of anatomical location. We present two children with FLAT arising from the epicardial LAA, successfully mapped and ablated through percutaneuous epicardial approach. The LAA is one of the major sources of FLATs in children . HoweverA 12 year old girl presented with history of recurrent episodes of palpitations and fatigue. She had left ventricular dysfunction secondary to (TIC). Tachycardia was refractory to multiple antiarrhythmic drugs and was referred for RFA. Patient was in incessant atrial tachycardia and baseline 12 lead electrocardiogram (ECG) revealed negative P waves in leads I and avL, positive P wave in leads V1, III and avF and isoelectric P wave in lead II . ActivatThe second case was a 6 year old boy presented to us with incessant atrial tachycardia at the rate of 190 per minute with 1:1 AV conduction and TIC. The 12 lead ECG showed negative P waves in leads I and avL and positive P waves in the inferior leads and in lead V1 . He had There have been several case series of successful catheter ablation of an LAA tachycardia using different approaches -6. To thThus, the epicardial catheter ablation may be an alternative approach to endocardial catheter ablation in atrial tachycardias with an LAA origin without the need for subjecting these patients to surgical ablation."}
+{"text": "Recent reports suggest that within the heterogeneous population that constitutes a melanoma, certain cell types exhibit molecular and functional features similar to stem cells. These melanoma-initiating cells (MICs) have the ability of unlimited self-renewal, multilineage differentiation and the potential to initiate and maintain tumor growth . FurtherMICs were enriched by Fluorescence Activated Cell Sorting using the metabolic marker Aldehyde Dehydrogenase (ALDH) and by establishing melanoma spheres in non-adherent culture conditions from 20 human melanomas. Expression of SOX2 and of HH pathway components was determined by real time PCR and Western blot analysis. Modulation of the HH signaling was performed by stable expression of lentiviral vectors encoding short-interference RNAs specific for SMO or GLI1 (to inhibit HH), and PTCH1 (to activate HH). Functional analysis of SOX2 was performed by stable overexpression and silencing using lentiviral vectors.SOX2 promoter in melanoma cells. Functionally, we show that SOX2 is required for HH-induced melanoma cell growth and MIC self-renewal. We present evidence that SOX2 is highly expressed in a population enriched for cancer stem cells in patient-derived melanomas. Knock-down of SOX2 sharply decreases self-renewal of melanoma spheres and of ALDHhigh melanoma stem cells. Consistently, ectopic expression of SOX2 in melanoma cells is sufficient to enhance stemness in vitro. SOX2 silencing also inhibits cell growth and induces apoptosis in melanoma cells. Most importantly, depletion of SOX2 drastically impairs tumorigenicity of ALDHhigh MICs in orthotopic xenografts.We find that the HH signaling regulates the expression of SOX2 and the downstream effectors of the HH signaling, the transcription factors GLI1 and GLI2, bind to Our data identify SOX2 as a novel mediator of the HH signaling in melanoma cells and indicate that SOX2 is a critical factor for the survival of MICs. These findings could provide the basis for novel therapeutic strategies based on the inhibition of SOX2 for the treatment of human melanomas."}
+{"text": "Reprogramming of metabolic pathways and abnormal acetylation of DNA are two common features of cancer, including prostate cancer (PCa).CWR22Rv1 cells (a castrate-resistant human PCa cell line) were treated with a polyherbal mixture of botanicals (PHBs) consisting of 10 herbal extracts [de novo lipid biosynthesis through the phosphorylation of acetyl-CoA carboxylase and by inhibiting the expression of fatty acid synthase and SREBP1c. Also via AMPK, the PHBs inhibit the activity of mTORC1 complex by phosphorylating raptor, decreasing the activity of S6K. These effects can be mimicked by treatment of AICAR (activator of AMPK) and over-expression of AMPKalpha, and attenuated by compound C (AMPK inhibitor) and siRNA silencing of AMPK. Furthermore, the PHBs increase the cellular pools of acetyl CoA via mechanisms that may include ATP-citrate lyase. Coordinately, there are increases in acetylation of histone 3 and expression of the tumor suppressor proteins p21 and p27, a mechanism that most likely involves the down regulation of class I and II histone deacetylases and up regulation of histone acetyl transferase  via ERK1/2 signaling. The inhibitory effects on cell proliferation can be attributed in part to the synergistic activity of some of the individual components in the PHBs as determined by the Chou-Talalay method [in vitro.Our results show that the PHBs can modify lipogenesis in CWR22Rv1 cells by enhancing the activation of AMPK, with concomitant decreases of Bioactive nutrients derived from multiple herbs inhibit the growth of androgen-deprived castrate resistant PCa cells via multiple mechanisms, one of which involves up regulation of AMPK signaling."}
+{"text": "P. falciparum resistance mechanism to ACT has become a global research goal. The selective pressure of ACT and the possibility that some specific Pfcrt and Pfmdr1 alleles are associated with treatment failures was assessed in a clinical trial comparing ASAQ to AL in Nanoro. Dried blood spots collected on Day 0 and on the day of recurrent parasitaemia during the 28-day follow-up were analyzed using the restriction fragments length polymorphism (PCR-RFLP) method to detect single nucleotide polymorphisms (SNPs) in Pfcrt (codon76) and Pfmdr1  genes. Multivariate analysis of the relationship between the presence of Pfcrt and Pfmdr1 alleles and treatment outcome was performed. AL and ASAQ exerted opposite trends in selecting Pfcrt K76T and Pfmdr1-N86Y alleles, raising the potential beneficial effect of using diverse ACT at the same time as first line treatments to reduce the selective pressure by each treatment regimen. No clear association between the presence of Pfcrt and Pfmdr1 alleles carried at baseline and treatment failure was observed.The adoption of Artemisinin based combination therapies (ACT) constitutes a basic strategy for malaria control in sub-Saharan Africa. Moreover, since cases of ACT resistance have been reported in South-East Asia, the need to understand  Plasmodium falciparum resistance to antimalarial drugs is the main challenge for malaria control in endemic countries. To overcome resistance to chloroquine (CQ), artemisinin-based combination therapies (ACT) have been recommended by the World Health Organization (WHO) for the treatment of uncomplicated malaria  to distinguish between recrudescence and new infections constitutes another limit of this study and could partially explain why no significant difference was observed between the two groups (recrudescence and new infections). In this study the prevalence of mutation in Pfmdr1-D1246Y was extremely low and it was difficult to correlate the presence of this mutation and treatment outcomes. No samples carried mutation in Pfmdr1-S1034C and Pfmdr1-N1042D as reported by several studies throughout Africa [Our findings suggest also no association between the presence of s report . The Pfmfantrine . Therefos report . Furthert Africa , 30.Pfcrt K76T and Pfmdr1-N86Y alleles, raising the potential beneficial effect of using diverse ACT at the same time as first line treatments to reduce the selecting pressure by each treatment regimen. No association between the presence of Pfcrt and Pfmdr1 alleles carried at baseline and ASAQ treatment failure was observed.AL and ASAQ exerted opposite trends in selecting S1 Fig(XLSX)Click here for additional data file."}
+{"text": "Quantitative real-time reverse transcription-polymerase (qRT-PCR) is a widely used technique to characterize changes in gene expression in complex cellular and tissue processes, such as the cytoprotection or inflammation. The selection of an adequate internal reference gene for accurate and consistent analysis of gene expression is of major importance. Carbon monoxide (CO) affects several metabolic pathways and de novo protein synthesis is crucial in the cellular responses to the gasotransmitter. Herein a selection of commonly used reference genes was analyzed to identify the most suitable internal control genes to evaluate the effect of the CO on gene expression in cultured cortical astrocytes. The cells were exposed to CO by incubation with CORM-A1 (CO releasing molecule A1) and four different algorithms  were applied to better evaluate the stability of eight putative reference genes. Our results indicate that Gapdh  and Ppia (peptidylpropyl isomerase A) is the most suitable gene pair for normalization of qRT-PCR results under the experimental conditions used. Pgk1 (phosphoglycerate kinase 1), Hprt1 (hypoxanthine guanine phosphoribosyl transferase I), Sdha , Tbp (TATA box binding protein), Actg1 (actin gamma 1) and Rn18s (18S rRNA) genes presented less stable expression profiles in cultured cortical astrocytes exposed to CORM-1 for up to 60 min. Analysis of the effects of CO on the expression of Bdnf and bcl-2 gave different results depending on the reference genes used. A significant increase in the expression of both genes was found when the results were normalized with Gapdh and Ppia, in contrast with the results obtained when the other genes were used as reference. This study highlights the need for proper and accurate usage of reference genes in quantification of qRT-PCR results in studies on the effect of CO in gene expression."}
+{"text": "Permanent neonatal diabetes mellitus (PNDM) is a rare disease which is defined as the onset of diabetes before the age of 6 months with persistence through life. Patients with KCNJ11 or ABCC8 gene mutations have the opportunity to switch to oral sulfonylurea therapy. There were limited studies about the genetic analysis and long term follow-up of PNDM.Report four cases of PNDM, including their genetic mutations, treatments and long-time follow-ups. All of the patients and their parents got gene analysis include INS, KCNJ11 or ABCC8 gene.None of the patients and their parents suffered from any genetic mutations of these three common genes. One of the children got continuous subcutaneous insulin infusion (CSII) and the others got multiple injections of insulin (MII). The PNDM patients had persisted after 35 months to 60 months of follow-up, 3 patients maintained almost stable blood sugar level, and 1 patient had poor sugar control.All of PNDM patients are suggested undergo genetic evaluation. For patients without KCNJ11 and ABCC8 gene mutation, oral sulfonylurea might not be considered. CSII is a useful tool for overcoming the difficulties of diabetes, and can also improve quality of life."}
+{"text": "Liocarcinus depurator we assessed the contribution of historical and contemporary processes on population connectivity patterns across three main oceanographic discontinuities along the Atlantic-Mediterranean transition: Gibraltar Strait, Almeria-Oran Front and Ibiza Channel. A partial fragment of the cytochrome oxidase I gene was sequenced in 366 individuals collected from localities at both sides of each discontinuity during three time periods. Although localities showed genetic fluctuations through time, a significant gradient was detected along the coast for all sampling periods. Significant inter-annual differences identified within the Alicante area, north of the Almeria-Oran Front, were associated with shifts in the relative contribution of Atlantic and Mediterranean water masses. The persistence of a clinal pattern in the Atlantic-Mediterranean transition area together with local fluctuations suggests a complex balance of dispersal and selection.Spatial genetic studies often require sampling broadly separated areas, difficult to access simultaneously. Although comparing localities surveyed at different time periods might result in spurious genetic differentiation, there is a general believe on the stability of genetic structure through time, particularly if sampled localities are isolated or very distant. By analysing spatial and temporal genetic differentiation of the portunid crab  Spatial genetic studies have increased in the last decades in many taxa while temporal genetic studies, despite being essential to understand biodiversity distribution, are still scarce. Landscape genetics and phylogeography are both concerned with understanding the distribution of genetic variation across natural environments1358The large population sizes of marine organisms generally result in little genetic differentiation despite restricted gene flow, and molecular markers show practical limitations in making inferences for recent timescales and single time point samples111314Three oceanographic discontinuities along the Atlantic-Mediterranean transition in the south and eastern Iberian Peninsula  have been shown to restrict gene flow in several marine species. The connection of the Mediterranean Sea and the Atlantic Ocean through the Gibraltar Strait is characterized by the inflow of surface Atlantic water and outflow of deeper Mediterranean water1791419121423182512Liocarcinus depurator showed that the Almeria-Oran front did not represent a significant barrier to gene flow, whereas Ibiza Channel acted as the main genetic barrierL. depurator across the three main oceanographic discontinuities along the Atlantic-Mediterranean transition. A partial region of the mitochondrial DNA cytochrome oxidase subunit I (COI) was analysed in 366 individuals from five areas situated at both sides of each discontinuity  and sampled during three time periods , and another including haplotypes mostly found in the Mediterranean (Ldep02 and related haplotypes) and were thus referred as the Atlantic (ATL) and the Mediterranean (MED) haplogroups, respectively  the present study evidences that contemporary processes impact local genetic diversity and modify connectivity between populations. Temporal variability of oceanographic discontinuities should not be overlooked when defining connectivity patterns because this could mislead conservation decisions (e.g. when designing networks of marine protected areas)28Liocarcinus depurator populations under strong influence from Atlantic waters and decaying diversity going into the Mediterranean, suggests an Atlantic origin of the species. Many phylogeographic studies identify genetically differentiated units that can be attributed to vicariance or selection reducing gene flowCOI haplotypes for L. depurator can be related to an abrupt decline of sea temperature in north Atlantic waters around 38\u201340 kya14L. depurator probably diverged due to vicariance events and posterior range expansions, as observed in other species influenced by climatic fluctuations during the Quaternary3435Changes in environmental conditions  and historical shifts of species distributions can shape genetic variation, as shown by spatially-explicit demographic modelling of genetic differentiationLiocarcinus depurator epipelagic larvae could drive genetic connectivity of this species by moving along with surface currents4et al.The greater diversity observed in samples under stronger Atlantic influence  using microsatellite loci suggesting genetic exchange from the west side of the Almeria-Oran front towards the east and northet al.The largest fluctuations in haplotype frequency across time were found in ALAC located between two main oceanographic discontinuities, the Almeria-Oran front in the south and the Ibiza Channel in the north. The ALAC07 sample showed a relatively high frequency of individuals from the Atlantic (ATL) haplogroup, whereas ALAC09 and ALAC13 were clearly dominated by haplotypes from the Mediterranean (MED) haplogroup. A strong genetic break between Almeria-Oran front and Ibiza Channel and higher proportion of Atlantic genotypes was also observed in the comber  pointed to the effect of variable reproductive success, and highlighted the unpredictable nature of connectivity in coral reef fishes43Clupea arenguset al.et al.Liocarcinus depurator as well as in other species with high dispersal capabilities  gene fragment was amplified using the universal primers LCO1490 and HCO2198et al.2 (25\u2009mM), 0.5\u2009\u03bcl dNTP\u2019s (1\u2009mM) and 0.4\u2009\u03bcl (10\u2009\u03bcM) of each primer. PCR products of 2013 samples were cleaned with ExoSAP (1.2\u2009U Exonuclease and 1.2\u2009U Shrimp Phosphatase per \u03bcl) at a proportion of 1:2 (ExoSAP:PCR product) and sequenced at the Scientific and Technical Services of the University of Barcelona (Spain) or at Macrogen Inc. .Muscle tissue from each individual was preserved in pure ethanol on board of the vessel. Total DNA extraction was performed for 2009 and 2010 samples using Chelex 10% as in Estoup ST values and their significance assessed performing 1000 permutations with Arlequin v. 3.5P-values were corrected for multiple comparisons using the false discovery rate (FDR) as in NarumST pairwise distances with GenAlEx v6.5et al.Sequences were visually inspected, aligned and trimmed, to obtain a final alignment of 527\u2009bp, with BioEdit v7.2.5Liocarcinus depurator haplotypes were estimated by Bayesian Inference (BI) using MrBayes v 3.2L. depurator COI sequences was reconstructed using the median joining methodThe phylogenetic relationships between http://www.socib.eu/) and buoys located within the different sampling areas  salinity data as a proxy for identifying Atlantic and Mediterranean water masses ."}
+{"text": "Classical methods for determining malignant disease prognosis are based upon characterizing the morphology and location of tumor cells. While this analysis provides important information about a patient's disease it fails to capture the biological complexity of the tumor microenvironment and the contribution of the anti-tumor immune response. Basic histological quantification of T lymphocyte density, cytotoxicity, and memory by CD3, CD8, and CD45RO, respectively, has demonstrated that increased infiltration of T lymphocytes is associated with statistically significant improvement in patients' disease-free survival (DFS) and overall survival (OS) in colorectal carcinoma (CRC). Delineating the location of T lymphocytes into two areas within the primary tumor, the center and the invading margin is termed Immunoscore.In this study we examined whether tumor genotype could predict the clinical outcome of patients with CRC and if combining Immunoscore with analysis of the tumor genotype could further enhance the accuracy of predicting clinical outcome. We analyzed 200 primary colorectal tumor samples for mutations in 50 common driver genes, including those implicated in models of colon carcinogenesis . Each mutation was then assessed for prediction of DFS. Patients presented with a mean of 4 \u00b1 2 mutations. The most common mutations were in KRAS (58%), TP53 (49%) and APC (37%). Neither, a single mutation or the number of mutations significantly predicted clinical outcome.We examined whether mutations in the primary tumor were associated with presence of metastasis. Mutational profiles were remarkably similar between primary tumors from patients whether or not they had metastatic progression at the time of surgery. None of the 50 major cancer genes was more frequently mutated in patients with metastasis. However, using integrative analysis we found that tumors from patients with metastatic disease downregulated adaptive immune genes including those involved in co-stimulation, proliferation and positive regulation of T cells. Furthermore when analyzing the ability to predict patients' OS using Immunoscore in these late stage tumors, high Immunoscore still distinguished patients with better clinical prognosis. These data suggest immune contexture accurately predicts clinical outcome regardless of tumor stage. Further analysis of pre-existing immunity together with the analysis of tumor genotype may provide better understanding of tumor progression and invasion."}
+{"text": "Nigeria is expected to be the nation with the 11th highest population of older persons by 2015. This demographic transition will have implications for the medical care services. Currently, there is no geriatric social health insurance policy nor comprehensive geriatric healthcare services in the country. The minimal health system response may be due to lack of comprehensive knowledge of geriatric disease burden, pattern and healthcare needs. This paper aims to describe the trend and pattern of geriatric health research publications, and to review the current geriatric health policies in Nigeria.A systematic review of published reports in PubMed was performed for the period of January 1990 to April 2014. The review of current geriatric health policies was conducted by document analyses of an annotated national bibliography on digitized health policies and guidelines.A total of 38 policies and guidelines of the Federal Ministry of Health were reviewed and none of them targeted geriatric health. The systematic review identified 52 eligible studies out of 3519 studies. Twenty-five studies (48%) were community-based studies, twenty (38%) were conducted in hospital settings, while only one was carried out in an old people\u2019s home and four were narrative literature reviews. Twelve studies (23%) were done in a rural area, 24 (46%) in an urban area and 11 (21%) report findings from both locations.One study reported the health of the elderly and economic policies (1), elderly destitution (1), health implication of ageing (1), attitude to ageing (2), care for the elderly (3), quality of life and life satisfaction (3), nutrition (2) and physical activity (1). The morbidity pattern reported from the reviewed articles were as follows: medical morbidities (8), geriatric emergencies and admissions (2), dental problems (5), surgical morbidities (1), nosocomial infection (1), mental health morbidities (6), orthopaedic (2), otorhinolaryngology (3), urology (1) and visual morbidities (5).The findings underscore a geriatric health research and policy needs. It is recommended that resources be invested into collaborative research for the development and implementation of evidence based geriatric health policies."}
+{"text": "Cervical spine arthritis is a well-recognized complication of juvenile idiopathic arthritis (JIA). It is usually present in patients with more severe disease.To evaluate the prevalence of symptomatic cervical spine involvement and their association with MRI findings in children with JIA.The study was a retrospective study of all patients with JIA followed at University Children's Hospital Ljubljana from September 2010 to January 2013. We reviewed the charts of 206 patients with JIA diagnosed according to the ILAR criteria. Clinical, laboratory data and MRI of cervical spine where available were collected and reviewed.206 patients, 143 girls (69%) and 63 boys (31%) with JIA were followed at University Children's Hospital Ljubljana from September 2010 to January 2013. Twenty-two out of 206 (11%) patients had pain in the neck and/or limited range of motion of cervical spine. Twelve out of 206 (6%) patients had persistent cervical spine symptoms, MRI of the cervical spine with application of paramagnetic contrast was performed in those. The results revealed inflammation of atlantoaxial (AA) joint without subluxation in 6/206 (3%) patients. Among 6 patients with AA joint inflammation were 5 girls and one boy. Three of them had RF negative polyarthritis, two persistent oligoarthritis and one girl had juvenile psoriatic arthritis. Five out of six (83%) patients were ANA positive and none of them had positive HLA B-27 antigen. In four out of six patients (66%) with AA joint inflammation, the neck pain was an initial manifestation of JIA. Five out of six patients (83%) were treated with anti-TNF alpha agents and demonstrated good clinical recovery.The prevalence of AA joint inflammation in our cohort of patients with JIA was 3%. Cervical spine involvement could present as an initial manifestation of JIA and in 83% of our cases demonstrated good clinical response on treatment with anti-TNF alpha agents.None declared."}
+{"text": "Borrelia burgdorferi sensu lato. The most important for human pathogenicity are B.garinii, B.afzelii and B.burgdorferi sensu stricto. Indirect laboratory diagnostics of LB is based on serological methods such as Enzyme-Linked ImmunoSorbent Assay (ELISA) and Western Blot Assay (WB) that detect specific antibodies. Another method in the diagnostics of LB is a new test LymeSpot. This test is based on Enzyme-Linked ImmunoSpot Assay (ELISPOT). We present our first experience with the test LymeSpot.Lyme borreliosis (LB) is multisystem infectious disease with various clinical manifestations. In Europe, LB is caused by gram-negative spirochetal bacteria of the complex B. burgdorferi sl.From November 2013 to June 2014 we performed LymeSpot on the group of 42 patients who were tested for suspicion of LB presence. LymeSpot is based on specific cell immune response of T-lymphocytes after stimulation by Borrelia antigens. The result is a number of antigen specific effector T-cells producing IFN-\u03b3 in the form of spots. We compared the results of LymeSpot test with the level of specific IgM and IgG antibodies detected by ELISA and WB with using recombinant antigens From the number of 42 patients we detected positive LymeSpot test only in 4 of them , a cutoff value in 3 patients . From the group of 42 patients were simultaneously performed ELISA and WB in 26 persons. In this group we found positive LymeSpot in 4 patients and cutoff value in 2 patients. In the group of 4 patients with positive LymeSpot was detected higher level of IgM antibodies in 3 patients and only IgG antibodies in 1 patient. They were patients with clinical manifestations of LB who were treated with antibiotics afterwards. Among 20 patients with negative results of LymeSpot these findings correlated with antibody response in 8 patients (40%). In this group we detected seronegative finding (IgM-IgG-) or finding of passing through LB (IgM-IgG+). In other 12 patients with negative LymeSpot test we detected serological finding of beginning (IgM+IgG-) or running LB (IgM+IgG+). They were mostly patients without clear symptoms of LB, patients with long-term positivity of IgM antibodies without clinical manifestations of LB or patients after antibiotic therapy.Our first experience shows that results of LymeSpot test better correlate with clinical findings and LB activity as well as can be effective marker of success of antibiotic therapy."}
+{"text": "The majority of distal radius fractures are associated with an ulnar styloid fracture -3. ThereBecause of its close association with the Triangular Fibrocartilage Complex (TFCC), fractures of the ulnar styloid might indicate possible TFCC disruption with subsequent DRUJ instability ,8,9. StuBone fragments resulting from non-union could also provoke irritation and pain ,10 due tAs the results of treatment of chronic instability of DRUJ following a distal radius fracture are more unpredictable , it is a"}
+{"text": "Breast cancer is the second most lethal cancer in women. Further, death rates for African American women are the highest for any racial/ethnic group. Hormone receptor status is one of the major prognostic factors and a determinant of treatment options for breast cancer, thus suggesting the importance of molecular level characterization for precision treatments. In this study, we have identified transcriptome level differences correlating to receptor specific molecular subtypes of breast cancer in African American women.http://cancergenome.nih.gov/), yielding transcriptome level analysis between four specific subtypes of breast cancer (Table Clinical and gene expression data from 18 African American women samples were obtained from The Cancer Genome Atlas (TCGA: The samples were analyzed using One-way ANOVA with Welch's correction for unequal sample sizes with type 3 sum of squares. Genes with ANOVA p-value < 0.01 and with relative expression fold change > |2.0| were considered significantly altered; this yielded 90 differentially expressed genes between cancer subtypes in our dataset (Figure BRCA1, SMAD3, SMAD4, EGFR and MDC1 genes[MDC1 showed altered expression for all subtypes of breast cancer and a significant p-value for the Luminal A subtype compared to the Triple negative subtype. The MDC1 protein has been previously implicated in the DNA damage response[The biological interaction network included important DNA repair sub-networks consisting of  response and signIn conclusion, our results highlight a significant difference in the transcriptome levels of critical DNA repair proteins among the different breast cancer subtypes in African American women. The differentials that were observed stress the importance of molecular level characterizations to understand this disease. Understanding the protein interactions involved in this network will have a major role in predicting best courses of action and aid in precision medicine-based approaches to treating breast cancer."}
+{"text": "We report on the derivation of a diploid 46(XX) human embryonic stem cell (HESC) line that is homozygous for the common deletion associated with Spinal muscular atrophy type 1 (SMA) from a pathenogenetic embryo. By characterizing the methylation status of three different imprinted loci , monitoring the expression of two parentally imprinted genes (SNRPN and H19) and carrying out genome-wide SNP analysis, we provide evidence that this cell line was established from the activation of a mutant oocyte by diploidization of the entire genome. Therefore, our SMA parthenogenetic HESC (pHESC) line provides a proof-of-principle for the establishment of diseased HESC lines without the need for gene manipulation. As mutant oocytes are easily obtained and readily available during preimplantation genetic diagnosis (PGD) cycles, this approach should provide a powerful tool for disease modelling and is especially advantageous since it can be used to induce large or complex mutations in HESCs, including gross DNA alterations and chromosomal rearrangements, which are otherwise hard to achieve. Parthenogenesis is the process by which an oocyte is stimulated to divide and develop into an embryo without being fertilized. It can be artificially induced by triggering unfertilized eggs to resume meiosis without undergoing cell division, or achieved spontaneously following failed fertilization. The resulting embryos, which contain only maternal chromosomes, are unviable due to poor development of extra embryonic tissues \u20137. Yet, This study was approved by the Ethics Committee at Shaare Zedek Medical Center (IRB 87/07) for the derivation of HESC lines from genetically affected PGD derived embryos, in compliance with protocols approved by the National Ethics committee.The SMA HESC line was established from a PGD derived embryo that developed into a fully grown hatched blastocyst by day 7 following fertilization. At this stage the inner cell mass (ICM) was mechanically isolated by manual cutting with an ultra-sharp splitting blade (Bioniche). The intact ICM clump was placed on a feeder cell layer of mitomycin C-inactivated mouse embryonic fibroblasts and cultured in HESC media . Outgrowths of proliferating cells were manually propagated using the cut-and-paste method. Following 5\u20137 passages, the newly established HESC line was further propagated by collagenase type IV (Gibco) and then frozen for future use as described in ..31]. In S1 FigDifferential expression of SNRPN  but not H19  in SZ-SMA5, is different from wild-type HESC control (WT) and corresponds to the maternal only origin of SZ-SMA5 cell line.(TIF)Click here for additional data file.S2 FigSequencing results (shaded) of 4 randomly selected probes from the SNP array  were used to validate the CytoScan 750K array data obtained for SZ-SMA5. For each probe heterozygosity rate , allele variations, and SNP array result are indicated, illustrating high accuracy of the assay for whole genome homozygosity detection.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file."}
+{"text": "Several classes of antimicrobial nanoparticles (NPs) and nanosized carriers for antibiotics delivery have proved their effectiveness as alternative agents to combat the antimicrobial resistance experienced with conventional drugs. Gold nanostructures find extensive applications in nano electronics and nanomedicine.The present study involved the synthesis of gold nanoparticles using a sodium cholate, as both reducing and capping agent and characterization by UV- Visible spectroscopy and High ResolutionTransmission Electron Microscopy (HRTEM). The antibacterial activity on significant bacterial species was evaluated by micro broth dilution method. The mechanism for antibacterial action of the gold nanoparticles were studied by reactive oxygen species (ROS) generation that causes oxidative stress to microbial cells and release of intracellular enzyme lactate dehydrogenase into extracellular medium (LDH assay) indicative of loss of cell membrane integrity.80) of the nanoparticles on E. coli, S. typhi, P. aeruginosa, K. pneumoniae, ranged from 20 to 40\u00b5g/mL. The ROS generation was directly dependent on the concentration of the nanoparticles and no detectable enzyme leakage was recorded.The synthesized gold nanoparticles showed characteristic peak at 541 nm by UV- Visible spectroscopy with particle size of 10nm as confirmed by HRTEM. The minimum inhibitory concentration (MICThe results showed appreciable antibacterial activity of gold nanoparticles against the tested species and the possible mechanism of antibacterial activity may be due to increased intracellular ROS generation causing oxidative stress to the bacterial cells while LDH assay indicated that nanoparticles caused no damage to the cell membrane integrity."}
+{"text": "Within the focal point of focused ultrasound (FUS), high pressure fluctuations cause shear stress on cells and tissues with energy dissipation leading to heating of the targeted tissue. The extent of the mechanical and thermal effects strongly depends on the ultrasound parameters and also potentially the acoustic properties of the tumor. High temperatures lead to coagulative necrosis with little immunogenic response as tumor antigens most likely denature during the ablation. As antigen presentation by activated dendritic cells (DCs) is necessary to activate T cells during an anti-tumor immune response, we hypothesize that non-ablative FUS treatment can be used to increase tumor immunogenicity by activating molecules that enhance intratumor dendritic cell (DC) infiltration and T cell activation. One of the first steps in this process is an activated stress response, including surface calreticulin (CRT), high mobility group protein B1 (HMGB1) release, ATP secretion and heat shock protein 70 (HSP70) surface expression and release. Using non-ablative FUS, antigen release can be stimulated by mechanical stress, thermal stress, or both. Here, we examine the stress response following non-ablative FUS treatment in three murine tumor models with varying consistencies and determine the causative agent  of the stress.in vivo in three subcutaneous tumor models in C57BL/6 mice, varying the mechanical and thermal energies to determine which protocol results in the greatest anti-tumor immunity. We investigated CRT surface expression, ATP release and both intra and extracellular expression/release of HMGB1 and HSP70. Since the effect of FUS treatment may vary depending on the cancer cell type, we investigated three different mouse cancer cell lines varying in consistency from solid to fluid . Animals were sacrificed 24 hours post-treatment and tumors were excised for stress response analysis by flow cytometry. Plasma was also obtained for analysis of soluble proteins by ELISA. Stress response was compared to non-treated tumors (control) as well as to in vitro treatment of a cell pellet with the same FUS parameters. For all FUS treatment a Philips Therapy and Imaging Probe System  was used.We tested a range of non-ablative FUS treatment protocols in vivo model of 3LL 24 hours following FUS treatment that delivers high thermal energy when compared to other treatment settings and no treatment  in surface expression of HSP70 in an"}
+{"text": "ADG) of growing animals. The objective of this study was to identify commercial single nucleotide polymorphism (SNP) panels that could improve the predictability of days on feed (DOF) to reach a target United States Department of Agriculture (USDA) grade given animal, diet, and environmental information under feedyard conditions. The data for this study was comprised of crossbred heifers (n = 681) and steers (n = 836) from commercial feedyards. Eleven molecular breeding value (MBV) scores derived from SNP panels of candidate gene polymorphisms and two-leptin gene SNP (UASMS2 and E2FB) were evaluated. The empty body fat (EBF) and the shrunk body weight (SBW) at 28% EBF (AFSBW) were computed by the Cattle Value Discovery System (CVDS) model using hip height (EBFHH and AFSBWHH) or carcass traits (EBFCT and AFSBWCT) of the animals. The DOFHH was calculated when AFSBWHH and ADGHH were used and DOFCT was calculated when AFSBWCT and ADGCT were used. The CVDS estimates dry matter required (DMR) by individuals fed in groups when observed ADG and AFSBW are provided. The AFSBWCT was assumed more accurate than the AFSBWHH because it was computed using carcass traits. The difference between AFSBWCT and AFSBWHH, DOFCT and DOFHH, and DMR and dry matter intake (DMI) were regressed on the MBV scores and leptin gene SNP to explain the variation. Our results indicate quite a large range of correlations among MBV scores and model input and output variables, but MBV ribeye area was the most strongly correlated with the differences in DOF, AFSBW, and DMI by explaining 8, 13.2 and 6.5%, respectively, of the variation. This suggests that specific MBV scores might explain additional variation of input and output variables used by nutritional models in predicting individual animal performance.Cattle body composition is difficult to model because several factors affect the composition of the average daily gain ( USDA) Choice or Canadian AAA graded meat versus lower quality grade meat  CT was asAn analysis  indicateIn conclusion, our analysis indicates that it is possible (and desirable) to incorporate genomic information into mathematical nutrition models to enhance their predictability by accounting for individual makeup  differences. This incorporation, however, may require profound modifications of nutrition models to accommodate new concepts, such as genome wide associated studies , 55, to S1 File(ZIP)Click here for additional data file."}
+{"text": "In 2008 the Paediatric Rheumathology European Society (PReS) promoted an International Project for the study of Autoinflammatory Diseases (AID) named Eurofever whose main purpose is to create a web-based registry for the collection of clinical, laboratory and response to treatment information in patients with AID.To implement the Registry with the new recently described AID and genes and modify the web-system to make it suitable for the collection of longitudinal data.With the technical help of Paediatric Rheumatology INternational Trial Organization (PRINTO) web-masters, we were able to revise the electronic case report forms bringing 2 main novelties: i) inclusion of the more recently described AID  and the relative clinical manifestation ii) modification of drug layout. In this process information on safety and efficacy has been included. Very soon Centres will be asked to update on a yearly base the information regarding each patient with particular focus on modification of the clinical picture, onset of complication/sequelae, treatment, adverse events if present, laboratory and instrumental findings.At present baseline demographic information from 3089 (M:F=1513:1576) patients from 101 centers in 38 countries are available. In 77% complete clinical information from disease onset to diagnosis and response to treatment is also available. For each disease the number of enrolled patients is: FMF 894 pts ; TRAPS 268 pts (226 complete); CAPS 284 pts (208 complete); MKD 189 pts (165 complete); Blau's disease 71 pts (22 complete); PAPA 27 pts (22 complete); NLRP-12 mediated periodic fever 14 pts (9 complete); DIRA 3 pts ; CANDLE 2 pts (1 complete), Schnitzler 1 pt and Majeed 2 pts (both complete). Among multifactorial autoinflammatory diseases: PFAPA 612 pts (380 complete); CRMO 417 pts (394 complete); pediatric Bechet disease 92 pts (72 complete) and 217 patients with undefined periodic fever (182 complete). Longitudinal electronic data capture is now ready and online for authorized PRINTO members.A common registry for collection of patients with AID is available and the enrollment is ongoing. This project represents the first attempt of a common registry for different autoinflammatory syndromes. The longitudinal collection and analysis of data coming from the Registry will improve our knowledge in the field of autoinflammation both on the natural history of the single disease and the efficacy and safety of the treatment commonly used in the clinical practice with particular regards to biologics."}
+{"text": "Pompe disease (OMIM 232300) is an AR glycogenosis due to deficiency of the lysosomal enzyme alpha-glucosidase (GAA). As a result, glycogen storage occurs in muscles and patients present a wide clinical spectrum ranging from early onset severe cardiomyopathy (EOPD) to adult onset forms (LOPD). Severe loss of GAA activity correlates with early onset and severe phenotypes. Residual enzyme activity warrants later onset and a slowly progressive course, although a strict correlation is not always observed. Patients with Classic infantile Pompe disease show hypotonia, macroglossia, respiratory insufficiency and early death for cardiorespiratory failure.The availability of enzyme replacement therapy (ERT) with alglucosidase alfa ( human recombinant GAA) has changed the natural history of the disease allowing most children with EOPD a longer survival and a longer preserved muscle performance with increased quality of life in LOPD.The experience of the Regional referral Center for Metabolic Diseases, University of Catania, concerns 11 patients ( 9 months to 65 years at the time of the diagnosis). Their clinical and laboratory follow-up included eye tracking and Muscle MRI.EOPD, with a severe clinical picture since the first weeks of life and cardiomyopathy was observed in a newborn who died at age 4 months, despite early started and high dosage ERT. Another girl with EOPD is on ERT since the age of 9 months and, today, after 7 years of treatment shows only mild signs of muscle weakness and no cardiac involvement.Five more LOPD patients on ERT had a significant improvement of blood parameters including transaminases, LDH and CPK. No progression of muscle impairment was seen after 5 to 8 years of treatment, except for one 35 years old man, who was already severely compromised and did not show any benefit in terms of respiratory ventilation.In a recently performed Italian survey of classical Pompe disease treated with ERT, a substantial improvement in cardiac parameters and gross motor function was observed, even if residual muscle weakness still exist and gross motor function remain below age-appropriate levels.The different response to ERT depends on several factors mainly on timing of treatment (worse outcome if started later than 5 months of age) and cross reactive immune material (CRIM-negative status associated with less good response to ERT).Although some residual mild weakness is present in treated patients, ERT has demonstrated its effects on respiration, lowering nocturnal apneas and allowing patients a better quality of life."}
+{"text": "Road traffic injury (RTI) has assumed major public health importance world-wide and the burden is heavier on the health-care infrastructure of countries in Sub-Saharan Africa. In Nigeria, RTI is the leading cause of trauma related morbidity and mortality. While there are some published epidemiological reports on RTI in the region, studies on the mechanism of causation of road traffic crashes (RTC) are not available.Over a 9-month period, we prospectively captured the 571 victims of RTC presenting to a single tertiary health care center in Nigeria. Data collected include demographic data, Mechanism of causation of RTC, Injuries sustained and outcomes.Over three-quarters of the victims are young people and half were either traders (27.5%) or students (20%). Pedestrians, motorcycle riders and open truck occupants (people sitting at the rear loading compartment of trucks) often had fatal injuries. Analysis of collision patterns showed that lone crashes were the most frequent though car-to-motorcycle crashes caused a quarter of the deaths. Host factors  were responsible for four-fifths of the crashes while vehicular and environmental factors accounted for the remaining. On binary regression analysis, head injured victims had higher odds of dying than the non-head injured (Odds ratio = 6.5).This paper elucidates the mechanisms of causation of and types of injuries sustained following RTC in Nigeria and thus provide opportunities for prevention and control of this unacceptable situation. Worldwide, Road Traffic Injury (RTI) has assumed major public health concern as it is responsible for an increasing number of morbidity and mortality. The World Health Organization (WHO) has attributed this increase to rapid urbanization and motorization and has aptly identified RTI as the price humanity must pay for modernization . The cosAll RTI victims who presented to University of Ilorin Teaching Hospital between October 2006 and June 2007 were prospectively captured. Biodata of victims, details of how the RTI occurred (mechanism of causation), the location of the victim during the incident (host status), the types of injuries sustained and eventual outcome was documented. Age categorization: The age of the victims were categorized into three groups  for statistical analysis. Host status: The host status was also categorized as riders of motorcycles (two wheeler vehicles); drivers of cars, buses or trucks (four wheeler vehicles); passengers of motorcycles; passengers of four wheeler vehicles; pedestrians and open truck occupants . Crash mThere were 571 patients over the nine month period consisting of 427 males and 144 females (M:F ratio = 3:1). There was no statistical significant difference in outcome between the sexes (p = 0.439). Median age was 30 years (range 6 months to 84 years). Over three-quarters of victims were young people, with another one-fifth being middle-aged and only 0.5% were elderly. There was however no significant statistical difference in outcomes between the age categories (p = 0.168). Majority of victims were either engaged in business or trading (27.5%) or were students (20%). The least involved group was the professional (2%). There were a total of 388 crashes consisting of 310 single patient and 78 mass (>1 victim) involvements (single: mass crash ratio = 4:1). Two crashes which involved 15 and 11 casualties constituted the highest mass crash casualty.Pedestrians, motorcycle riders and open truck occupants  represenOf the various collision patterns, lone crashes (Solitary crash involving only one vehicle with no collision with another vehicle or pedestrian) were the most frequent on our roads accounting for about 29% of 388 crashes and were responsible for the highest casualty of 199 patients (35%) . Car-to-Soft tissue injuries constituted the largest (35%) injuries . Head inThe African region has been identified to carry the highest road traffic death rate of all continents , 4. SoutAbout 43% of victims in this study were passengers of 4 wheeled vehicles, 28.4% were on motorcycles (rider and passengers), and 14.5% were pedestrians. These three groups of road users are particularly prone to RTI in the developing countries . The motEighty percent of crashes were due to host factors and accounted for 74% of morbidity and about 84% of mortality. Over-speeding/inappropriate speed constituted the major host problem (80%). Odero's presentation also identified human error as leading cause with over-speeding topping the list in Kenya, Uganda, South Africa, Ghana, Zimbabwe, Ethiopia and Tanzania . AlcoholThe following recommendations are suggested to policy makers to reduce the occurrence of and injuries from RTI: 1) Enforcement of helmet use by motorcyclists, seat belts by drivers and passengers of 4 wheeled vehicles and a law against travelling on the back of trucks and Lorries. 2) Strict regulation and enforcement of speed limit. The Federal Road Safety Corps should be equipped with speed detectors in their patrol cars and our roads must have speed detectors at strategic points with camera facilities. 3) Appropriate road engineering with road signs and conspicuously displayed speed limits to guide road users. Provision of road shoulders and service lanes will prevent broken down vehicles from being impediments to traffic. 4) Construction of new roads to open new network of roads so as to decongest the major roads. 5) Regular road maintenance to eliminate potholes. 6) House to house waste collection coordinated by the local government authority should be introduced to replace the current practice of refuse tanks dumped on major roads. 7) Use of \u201cTokunbo\u201d tires must be banned urgently.This paper has elucidated the mechanisms involved in causation of RTIs, the injury spectrum seen in involved victims and the relationships of these variables to outcome of clinical management of the victims. Several opportunities for control are also put forward based on the findings in the study."}
+{"text": "Nature Communications7: Article number: 10578 10.1038/ncomms10578 (2016); Published 02232016; Updated 03212016The original version of this article contained an error in the spelling of the author Eugen Buehler, which was incorrectly given as Eugen Beuhler. This has now been corrected in both the PDF and HTML versions of the article."}
+{"text": "Active JIA of the knee can lead to bony overgrowth and leg length discrepancies in children with JIA. Fixed flexion deformities of the knee result in loss of inner range quadriceps strength, abnormal gait and reduced independent function and participation in sports and activities.Our objective was to review the use of stretch and cast procedures alongside Intra-articular steroid injections (IAI) for active JIA of the knee resulting in fixed flexion deformities (FFD) of greater than 15 degrees.A retrospective review was undertaken of all patients presenting to Great Ormond Street Hospital NHS Foundation Trust between 2005-2013 with active JIA of the knee resulting in FFD and loss of knee extension range of movement (ROM) greater than -15 degrees extension and underwent a stretch and cast procedure alongside IAI for treatment of their disease. ROM was assessed pre and post procedure. Patients received their IAI under general anaesthetic, and then the physiotherapists carried out a stretch and cast procedure.The stretch and cast procedure included patella mobilisations, gentle and prolonged knee extension passive stretching, and casting with a fibre-glass cast for 72 hours. All patients then received 2 weeks of intensive physiotherapy strengthening. ROM and inner range quadriceps strength were measured at the end of these 2 weeks post procedure.30 patients  had a FFD of between -15 and -90 degrees (mean -30) extension at the affected knee(s). A total of 35 joints were injected and underwent the stretch and cast procedure plus physiotherapy strengthening. Post intensive rehab the patients all had improved or normal ROM (mean -7 degrees) and improved muscle strength  in order to maintain this improvement. This was maintained at 4-6 month follow up in 94% of patients. The 2 patients who did not maintain range of movement had poor compliance to their physiotherapy home exercise programme.ROM improved following procedure in all patients, indicating that stretch and cast treatment is an effective intervention for the management of fixed flexion deformities secondary to active JIA. Ongoing strengthening of inner range quadriceps is vital to maintain this improved range of movement and restoration of function and normal gait.None declared."}
+{"text": "Rare diseases; clinical practice guidelines; recommendationshttp://www.rarebestpractices.eu) is a 4-year project (2013-2016) funded by the EC FP7. The project aims at improving clinical management of patients with rare diseases (RD) and at narrowing the existing gap in quality of healthcare among countries.RARE-Bestpractices (http://www.rarebestpractices.eu) involves 9 EU countries, including 15 partners from academic institutions, governmental bodies, patient organizations and networks, which will exploit the added value of integrating different contributions and viewpoints.RARE-Bestpractices  and systematic reviews.http://rarejournal.org)Project expected outputs include: 1) identification of challenges to be considered in deriving high quality standards for CPG on RD; 2) transparent procedures and criteria for the evaluation of CPG and their collection in a publicly searchable database; 3) identification of notation criteria to improve user understandability and implementation of CPG; 4) production of mechanisms to assess RD clinical research needs; 5) development of training activities targeted to key stakeholders to disseminate process and tools for developing and evaluating CPG; 6) the publication of a new scientific journal  for RD; in fact, one main criterion for ERNs should be the competence to produce CPG and actively disseminate them among Centers of Expertise."}
+{"text": "Asthma is the most prevalent of all childhood diseases and accounts for the majority of hospitalizations and school absences in children . Current1262 children enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study with complete skin prick test and wheeze data at one year were grouped into four clinically relevant phenotypes: atopy + wheeze, atopy only, wheeze only, and control. Bacterial 16S rDNA from 3-month and 1-year stool samples of 319 children in these four phenotypes was extracted, amplified, and subjected to high throughput Illumina sequencing. Quantitative polymerase chain reaction (qPCR) and short chain fatty acid (SCFA) analysis were also conducted on 44 children in the two extreme phenotypes (atopy + wheeze vs. control).16S sequence analysis of our sample cohort (319 subjects) identified bacterial populations that differed in abundance in the atopy + wheeze group at 3-months of age but not at 1-year of age. Additionally, significant changes in the abundance of certain bacterial genera were found in the atopy + wheeze group when compared to controls by qPCR at 3-months of age only. Changes in stool short chain fatty acid production between the atopy + wheeze group and the control group were also observed at 3-months of age only.Shifts in the relative abundance of certain gut bacterial populations and differences in the levels of stool SCFAs before 3-months of age are associated with atopy and wheeze at one year of age."}
+{"text": "Suppressor of cytokine signaling (SOCS) proteins are the negative regulators in cellular signal transduction system. SOCS family proteins consisting of 8 proteins (CIS and SOCS1-7) inhibit JAK/STAT protein activity to maintain proper cytokine functions. Initially identified for the negative feed-back function of cytokine signal transduction, suppressors of cytokine signaling (SOCS) have emerged as multi-functional protein involved in the regulation of development, apoptosis and oncogenesis. Recent reports showed that SOCS can be also affected by cytokine and other cell signaling factors to regulate cancer development and progression as well as cell death. The present study was aimed to investigate various effects of SOCS1 protein on the tumor suppressive function. We have found that SOCS1 promotes radiation-induced apoptosis of colon cancer cells through cell cycle arrest at G1 involving activation of p53 and p21 induction. SOCS1 also exhibits radiosensitization effects on the growth of implanted colon tumor cells in nude mice. As a mechanism of anti-tumor action of SOCS, we now present the data on the suppressive effects of SOCS1 on tumor cell migration and invasion. Notably SOCS1 over-expression and knock-out inversely regulates the expression of EMT markers such as E-cadherin and vimentin along with modest morphological change of cells from epithelial to fibroblast shape, representing EMT process. Data on the invasion and EMT signaling pathways suggest that SOCS1 potentially regulates tumor cell invasion and metastasis in vitro and in vivo in colon cancer models. SOCS1 may be not only a useful predictive factor for radiation response but also a possible drugable target for human colon cancer."}
+{"text": "Evaluation of segmental instability in DLS is essential for spinal surgery to make the decision \"fusion or not fusion.\" Some previous studies have shown radiographic data regarding segmental instability in DLS. However, little is known about segmental motion of wedging segments in DLS. To evaluate the segmental instability of wedging segments using dynamic films and the impact of osteophyte formation on segmental motion in degenerative lumbar scoliosis (DLS).A total of 101 patients complaining of neurogenic claudication owing to lumbar spinal canal stenosis (LCS) were enrolled and divided into 2 groups based on their coronal spinal deformity; Cobb angle of >10 degree (DLS group) or <10 degree (LCS group). The following parameters were measured on anteroposterior films: lateral translation, degree of osteophyte formation, and range of motion (ROM) in lateral bending films. The facet joint space discrepancy was measured on computed tomography images. The radiographic parameters were compared between 85 wedging segments (>5 degrees) in DLS group and 150 nonwedging segments in LCS group.Mean lateral translation was significantly greater in the DLS group (P<0.01 for each level). Average joint space discrepancy was significantly greater in the DLS group . ROM was significantly greater in the DLS group with the same degree osteophyte formation. Degree of osteophyte formation was inversely correlated with ROM in the DLS group (R(2)=0.5696).The present study indicated that wedging segments in DLS had greater motion than nonwedging segments in LCS. However, the osteophyte formation provided restabilization for the wedging segments in DLS, suggesting that evaluation of osteophyte formation is an important factor in surgical decision making for DLS."}
+{"text": "The new tendency in rehabilitation involves non-invasive tools that, if applied early after stroke, promote neurorecovery. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation may correct the disruption of cortical excitability and effectively contribute to the restoration of movement and speech. The present paper analyses the results of non-invasive brain stimulation (NIBS) trials, highlighting different aspects related to the repetitive transcranial magnetic stimulation frequency, transcranial direct current stimulation polarity, the period and stimulation places in acute and subacute ischemic strokes. The risk of adverse events, the association with motor or language recovery specific training, and the cumulative positive effect evaluation are also discussed.Abbreviations: AAT = Aachen Aphasia Test, BDNF = brain-derived neurotrophic factor, IFG = inferior frontal gyrus, M1 = primary motor cortex, MRI = magnetic resonance imaging, NIBS = non-invasive brain stimulation, PET = positron emission tomography, rTMS = repetitive transcranial magnetic stimulation, SLT = speech and language therapy, STG = superior temporal gyrus, tDCS = transcranial direct current stimulation, NIHSS = National Institutes of Health Stroke Scale After an injury, there are changes in motor and sensitive cortical somatotopies, both in the damaged region and the remote areas from ipsi- and contralateral hemisphere. An increased activation in contralesional primary motor cortex (M1), bilateral ventral premotor cortex and supplementary motor area are commonly found in stroke patients [3]. While the healthy subjects show greater activity in the contralateral hemisphere to the moving hand, stroke patients assume a bilateral pattern in general [4]. Due to its intrinsic plasticity, the brain has the capacity to restructure its neural networks and to reconfigure its activity after an ischemic or haemorrhagic stroke. The metabolic and functional cerebral alteration can be observed by functional imaging studies (positron emission tomography (PET) scan and functional magnetic resonance imaging (fMRI), and also by transcranial magnetic stimulation mapping of the motor area [5]. These mechanisms are activated differently depending on stroke size and location. Small ischemic or haemorrhagic lesions may be compensated by the recruitment of residual language areas and the increase in perilesional activity. By contrast, the larger lesions in the language regions are followed by the recruitment of homotopic non-dominant areas [6]. In the recovery of aphasia, three models of neuroplasticity were framed by prior research: (1) activation of perilesional language areas in the dominant hemisphere, (2) recruitment of homologue area in the non-dominant hemisphere, and (3) improper recruitment of different regions in the non-dominant hemisphere  [5]. Secondary to the decrease of transcallosal inhibition, some right hemispheric areas may deploy an inhibitory effect over the residual perilesional areas in the left hemisphere, interfering with the language recovery. Based on these data, a new model for the recovery of aphasia was proposed based on the suppression of non-dominant hemisphere activity and the stimulation of the perilesional areas in dominant hemisphere [5]. However, the role of right language homologues in the early recovery after stroke seems to be transient, to an extent perilesional neuronal recruitment occurs [4]. Transcranial direct current stimulation (tDCS) of the brain is an electrophysiological method which may be used to modulate the neocortical excitability. A direct current generator is connected to two patch electrodes (an active and a reference one) positioned over the scalp, to stimulate the subjacent tissue with low amplitudes currents (0.5 - 2.0 mA) and to modify the threshold for discharge of cortical neurons. The modulation of cortical excitability is polarity-dependent: \u201canodal stimulation\u201d (increased in network excitability) \u2013 when the active electrode generates a positive potential compared to the reference electrode; \u201ccathodal stimulation\u201d (decreased in network excitability) \u2013 when the active electrode generates a negative potential . Repetitive transcranial magnetic stimulation (rTMS) is another therapeutic tool that can contribute to the modulation and reconfiguration of different cortical areas. In contrast to tDCS, rTMS results in the induction of action potentials and depolarization of the neuronal membrane. The principle of transcranial magnetic stimulation is to produce a perpendicular magnetic field, by a stimulating coil, which induces an electric field, which, in contact with the cerebral tissue, is transmitted as an electric current, parallel to the generating coil. The depth of the stimulation depends on the type of coil and the intensity of the stimulation. The excitatory or inhibitory effect is correlated with the frequency of rTMS: high frequencies (\u2265 5 Hz) are excitatory, while low frequencies (\u2264 1 Hz) are inhibitory . By modulating cortical excitability with respect to neural plasticity, these two non-invasive brain stimulation (NIBS) techniques represent potential therapeutic tools in recovery after stroke [10-14]. This model suggests that the balance between the left and the right hemisphere of stroke patients is altered by an increased interhemispheric inhibition from the unaffected hemisphere to the affected hemisphere. Accordingly, a therapeutic effect may be obtained either by increasing the excitability of the affected hemisphere, or by decreasing the excitability of the unaffected hemisphere [10]. The mechanism of excitability enhancement in the motor cortex underlies the motor learning and the use-dependent plasticity, which are impaired in the affected hemisphere. Other positive effects of the NIBS are the enhancement of neural coupling between the primary and secondary motor areas in the affected hemisphere, the reduction of the hyperactivity in the primary and secondary motor areas in the unaffected hemisphere, and the excitability modulation in both hemispheres [10].There are two main directions of NIBS treatment in neurorehabilitation: the motor deficit and the speech disorders. The improvement of motor and language performances is based on interhemispheric competition theory [15]. The major disadvantage is the deterioration of bimanual movement due to the reduction of transcallosal inhibition that controls that kind of movement. This possible consequence may be prevented by applying a low frequency rTMS concomitant with anodal tDCS over the affected hemisphere [16]. The neural modulation induced by NIBS and the improvement of motor and speech deficits can be sustained by subsequent motor training and speech therapies .The advantages of inhibitory NIBS over the intact hemisphere are the uniform response and the lower risk of potential epileptic seizures, which are more probably to appear after rTMS in the infarcted area . The genetic polymorphism can be involved and may explain the different response of stroke patients to this therapy. BDNF is one of the factors strongly involved in synaptic plasticity of the human motor cortex [9]. The consequence of BDNF val66met, a common single nucleotide polymorphism, is the reduced secretion of BDNF [19]. This is clinically expressed by a poorer retention in short-term motor learning and slower cognitive and motor recovery . Therewith, the individual variation in response to rTMS may be explained by the difference in BDNF concentration [20]. Although it was demonstrated that the early rehabilitation facilitates motor recovery after stroke, the application of NIBS in acute stages is controversial [21]. In this respect, a recent Cochrane meta-analysis evaluated the efficacy and safety of rTMS in recovery after stroke regardless of the duration of illness [22]. Nineteen randomized controlled trials (RCTs) with a total of 588 patients were included. Even if the rTMS treatment was not associated with a significant improvement in activities of daily living, or a significant improvement of motor function, a positive trend was noted, larger and homogeneous RCTs being needed in order to confirm the results [22]. The majority of the clinical studies evaluating the role of rTMS in rehabilitation were performed in subacute and chronic stroke patients, few data being available for acute stroke [22]. Also, epileptiform discharge on EEG and seizures, can be noted especially after high-frequency rTMS (10 Hz) [11].The most encountered adverse events reported in clinical trials evaluating rTMS are transient or mild headache (2.4%), anxiety (0.3%), neurocardiogenic syncope after initial exposure to rTMS (0.6%), exacerbation of pre-existing insomnia (0.3%) and local discomfort at the site of the stimulation [23]. In 2005, Khedr and colab. applied 3 Hz, in 10 daily stimulation sessions on the affected side in 26 patients with acute cortical stroke and in 26 patients with acute subcortical stroke (recruited between the fifth and tenth day post-stroke). The evaluation of motor recovery showed an improved function in the paretic hand in both groups [24]. Liepert and colab. showed that one session of 1 Hz rTMS therapy  on the contralesional hemisphere in 12 patients with acute subcortical stroke (mean 7 days), disclosed an enhancement in the hand functioning at Nine Hole Peg Test (a transient improved dexterity of the affected hand), but no change in the grip strength [25]. In 2010 Khedr and colab. published another study on 48 acute stroke patients  which supported 3 Hz, 130% resting motor threshold intensity, or 10 Hz, 100% resting motor threshold intensity, in 5 daily stimulation sessions on the ipsilateral hemisphere. The improved hand function persisted for 12 months after rTMS treatment [26]. Participants  were divided in two groups \u2013 the study group (5 patients) \u2013 stimulated in the right pars triangularis, and the control group (5 patients) \u2013 stimulated in vertex (sham stimulation). The results pointed out an improvement of Aachen Aphasia Test (AAT) scores in patients from the study group, but not in those with sham stimulation. Compared with baseline, a larger activation index was observed on PET scan in the right hemisphere in the control group compared with the study group, 2 weeks after rTMS, suggesting that inhibitory magnetic stimulation of the right-hemispheric Broca homologue followed by SLT might be a feasible and effective complementary therapy for post stroke aphasia [26]. Weiduschat studied the effect of 1 Hz rTMS stimulation together with subsequent speech and language therapy (SLT) in 10 right-handed patients at 16 weeks after stroke [27]. The patients were included between 2-12 weeks after the onset. This group was compared with a sham stimulation group . The assessment included Computerized Picture Naming Test, Boston Diagnostic Aphasia Examination and Aphasia Severity Rating Scale. After a follow-up period of 15 weeks, no differences in naming accuracy between the two groups were noted, but reaction time was slightly faster in real rTMS group [27].Waldowski and collab. studied the effects of 1 Hz rTMS  over pars triangularis and pars opercularis from the right inferior frontal gyrus (IFG), followed by 45 min/ day SLT, in 13 right-handed patients with aphasia [18]. Forty patients received 3 weeks of motor training on the paretic upper limb (45 minutes daily) preceded by 30 minutes of 1 Hz rTMS (stimulated group) or by 30 minutes of sham rTMS over the contralesional M1 (control group). The functional assessment of the paretic hand (by Wolf Motor Function Test and NIHSS) performed before, immediately after and at the 3 months follow-up revealed no statistically significant differences between the two groups [18]. In a randomized, sham-controlled, double-blind study, Seni\u00f3w and colab. evaluated the association of low-frequency rTMS of the contralesional M1 area with physiotherapy [13]. In 2013, Heiss et al. analyzed for the first time the consequences of the inhibitory NIBS over the contralesional IFG in left-handed aphasic patients. They reported the results of a randomized controlled trial comparing the effect of combined rTMS/ SLT in 29 right-handed patients with left hemisphere infarcts and 2 left-handed patients with right hemisphere infarcts. The start of treatment was between 25 and 93 days after stroke onset. Fifteen right-handed patients  received 10 sessions of inhibitory 1 Hz rTMS over the triangular part of the right IFG (20 min each) followed by 10 sessions of SLT, while 14 right-handers with heterogeneous aphasia forms  received 10 sessions of 20 min rTMS over the midline at the vertex (sham stimulation). Two left-handers  were treated according to the same protocol with real rTMS over the left hemisphere. The speech performance was evaluated by AAT, and the language activation patterns were assessed with PET scan prior to and after the treatment. The results showed better recovery of language function in right-handed patients after real rTMS than in sham-treated right-handers. Furthermore, a shift of network activity towards the left, ipsilesional hemisphere was observed in treated right-handers, while the sham group maintained the activation in the contralesional hemisphere. Both left-handed volunteers also improved, the PET scan showing a very small interhemispheric shift (less than in rTMS-treated right-handers) and a consolidation of active networks in both hemispheres [12]. In both groups, the inhibitory NIBS was followed by SLT 45 min/ day. The global AAT and naming subtests disclosed better scores, which correlated with a PET activation in the left hemisphere in rTMS group post-treatment compared to the sham group [12]. Another RCT compared the effect of 1 Hz real rTMS versus sham stimulation  over the right pars triangularis, in 24 patients suffering of subacute stroke [28]. The tDCS was initiated 4 to 8 weeks after stroke onset. Each of the 6 daily stimulation sessions was followed by a robot-assisted arm training. Motor arm function was assessed with the Fugl-Meyer motor score and language impairment with the AAT. The motor function improved in all patients (in a significant manner in 3 cases), and aphasia improved in 4 patients [28]. Hesse and colab. evaluated the role of anodal tDCS on the ipsilesional side in the recovery after stroke in 10 patients [29]. In all patients, the reference electrode was placed on the contralateral supraorbital region, the sessions of stimulation lasted 30 min/ day for 10 days and were completed by online SLT. The application of Korean-Western Aphasia Battery evidenced a significant improvement in auditory verbal comprehension after right cathodal tDCS compared to sham and left anodal tDCS, with an overall improvement in Aphasia Quontient and spontaneous speech across groups [29]. In 2011, You and collab. evaluated the role of tDCS in 21 aphasic patients with subacute stroke divided in 3 equal groups: the patients in the first group received anodal tDCS on the left Wernicke\u2019s area , the subjects from the second group received cathodal tDCS on the right Wernicke\u2019s area and the other 7 participants were sham stimulated [NIBS could be a useful therapeutic tool in the early rehabilitation after stroke. Both methods may enhance the neuroplasticity in the injured area and reestablish the balance between different regions of the brain. The association with specific motor tasks and SLT reinforces the effect of NIBS and partially restores the damaged neural networks.Larger RCTs are needed in order to confirm the effectiveness of NIBS, but the small clinical studies published so far showed encouraging results in motor and speech recovery."}
+{"text": "Previous studies reported that patients in end-of-life (EOL) care may still receive aggressive treatment in the Intensive Care Unit (ICU). Despite To characterize factors associated with death in the ICU in patients accompanied by a palliative care team (PCT) in a tertiary private hospital in Brazil.Retrospective analysis of prospectively collected data based on a standardized questionnaire of PCT. All 628 questionnaires from June 2008 to December 2013 were included. Two groups were compared: patients that eventually died in the ICU versus patients that died outside the ICU.Out of 443  patients who died; 76 12.1%) died in ICU and 367 (58.4%) outside the ICU setting. a comparison between groups is shown in Table 2.1% diedNon-cancer patients died more frequently in the ICU (p = 0.03). We observed the presence of conflicts among patients who died in ICU: conflicts between family members (family-family conflicts) and between family and the attending physician (family-physician conflicts) were equally common, but there were a significant number of conflicts originating between family and nurse staff Figure .Figure 1Explicit directives of EOL care were more commonly explicitly written in non-ICU patients . As expected, we also observed that a remarkable percentage of ICU patients received advanced life support until death (42%). There were no association between death in the ICU and age, late PCT consultation (less than 3 days before death) and prolonged hospitalization .Circumstances associated with death in the ICU of patients assisted by PCT included a non-cancer diagnosis, conflicts as reason to referral, being in the ICU or receiving life support at the time of the initiation of PCT consultation, and the lack of written advanced directives of EOL care. Further studies are needed to evaluate whether modifying these circumstances may be related to a different EOL care."}
+{"text": "World leaders remain committed to globally-coordinated oral poliovirus vaccine (OPV) cessation following successful eradication of wild polioviruses, but the best timing and strategy for implementation depend on existing and emerging conditions.Using an existing integrated global poliovirus risk management model, we explore alternatives to the current timing plan of coordinated cessation of each OPV serotype . We assume the current timing plan involves OPV2 cessation in 2016 followed by OPV1 and OPV3 cessation in 2019 and we compare this to alternative timing options, including cessation of all three serotypes in 2018 or 2019, and cessation of both OPV2 and OPV3 in 2017 followed by OPV1 in 2019.If Supplemtal Immunization Activity frequency remains sufficiently high through cessation of the last OPV serotype, then all OPV cessation timing options prevent circulating vaccine-derived poliovirus (cVDPV) outbreaks after OPV cessation of any serotype. The various OPV cessation timing options result in relatively modest differences in expected vaccine-associated paralytic poliomyelitis cases and expected total of approximately 10\u201313 billion polio vaccine doses used. However, the expected amounts of vaccine of different OPV formulations needed changes dramatically with each OPV cessation timing option. Overall health economic impacts remain limited for timing options that only change the OPV formulation but preserve the currently planned year for cessation of the last OPV serotype and the global introduction of inactivated poliovirus vaccine (IPV) introduction. Earlier cessation of the last OPV serotype or later global IPV introduction yield approximately $1 billion in incremental net benefits due to saved vaccination costs, although the logistics of implementation of OPV cessation remain uncertain and challenging.All countries should maintain the highest possible levels of population immunity to transmission for each poliovirus serotype prior to the coordinated cessation of the OPV serotype to manage cVDPV risks. If OPV2 cessation gets delayed, then global health leaders should consider other OPV cessation timing options. The Global Polio Eradication Initiative (GPEI) continues to make progress toward the primary goal of interrupting all global transmission of the three wild poliovirus (WPV) serotypes . After aOPV comes in different formulations. Trivalent OPV (tOPV) protects against all three serotypes and represents the current vaccine of choice for OPV RI and the vaccine used for SIAs up until 2004. In 2005, the GPEI began using serotype 1 monovalent OPV (mOPV1) and later some serotype 3 (mOPV3) for some SIAs, because of their higher seroconversion  for the mOPV serotype than achieved by the same serotype component of tOPV, particularly for the first dose , 16. In The inactivated poliovirus vaccine (IPV) currently represents the only vaccine alternative to OPV. While the killed, injectable IPV provides very good individual protection from paralytic poliomyelitis and boosts intestinal immunity in individuals with immunity from a prior live poliovirus infection , it does not protect as well against asymptomatic participation in poliovirus transmission\u00a0as OPV, particularly in settings with more intense fecal-oral transmission, and it does not spread beyond the vaccine recipient \u201328. ConsRecognizing the risks associated with OPV2 cessation, the GPEI established 6 prerequisites for OPV2 cessation, including the need to validate the elimination of persistent cVDPV2s , which rWe use an integrated global model of long-term poliovirus risk management options  described in detail elsewhere . Brieflystatus quo of OPV use in most countries to characterize incremental cost-effectiveness ratios (ICERs) and incremental net benefits (INBs) using 2013 United States dollars ($). The global model estimates financial costs associated with RI and SIAs, including any outbreak response SIAs (oSIAs) before and after OPV cessation [The global model  estimateessation . The gloessation  and the essation , includiessation  and emphTo model the global population and poliovirus transmission, the global model  assumes Table\u00a0status quo) option assumes OPV2 cessation on April 1, 2016, consistent with the current target date [All options assume tOPV intensification from January 1, 2015 characterized by an increased proportion of planned, preventive SIAs  using tOPV instead of bOPV , 39. Theget date , and OPVget date . For theget date , 39 untiget date , 39, whiget date  and the Due to the assumed sufficiently high frequency of SIAs leading up to OPV cessation of any serotype for all OPV cessation options, none of the options lead to any subsequent cVDPV cases. With only a small number of paralytic cases from WPV1 remaining in the model during the first year of the time horizon , VAPP cases represent the main source of paralytic poliomyelitis in the model for 2015\u20132019. Table\u00a0With respect to vaccine dose estimates, our results include the entire world , assume relatively high effective wastage, and assume sustained high SIA frequency up until cessation of the last OPV serotype . Most scTable\u00a0The INBs represent a more informative metric for this analysis. OPV23 cessation in 2017, OPV123 cessation in 2019, and OPV123 cessation in 2019 with tOPV-only from 2017 all result in the same expected financial costs for vaccination as the current timing plan because they involve different OPV formulations without affecting the overall duration of OPV or IPV use in any of the income levels. Thus, for these alternative OPV cessation timing options the incremental costs reflect only treatment costs (or savings) associated with additional incurred (or prevented) paralytic cases. Given the relatively small number of paralytic cases involved in any of these options, their INBs remain close to 0. The INB estimate of approximately -$4.5 million for OPV123 cessation in 2019 (with or without tOPV-only from 2017) suggests that if the excluded logistical costs of coordinating OPV cessation once instead of twice amount to more than $4 million , then some economic justification exists for this original path of coordinated OPV cessation of all three OPV serotypes. OPV123 cessation in 2019 with tOPV-only from 2017 yields almost the same INBs as OPV123 cessation in 2019, which involves some continued bOPV SIAs , because the cases would occur for all OPV cessation timing options. However, longer transmission of WPV1 and/or cVDPV2 will affect the feasibility of some of the options and expected SIA frequency and costs. Some reduction in SIA frequency may remain sufficient to keep population immunity high enough to avoid cVDPVs after OPV cessation, although too much reduction or inconsistency in SIA quality would result in cVDPVs , and insOur analysis leads to the realization that flexibility in national vaccine licensing for the transition period may prove helpful. While under the current plan the GPEI continues to encourage countries to pursue licenses of bOPV for RI use after OPV2 cessation, our analysis suggests potential value in simultaneously pursuing national licenses for RI use of bOPV or mOPV1, and potentially also securing licenses now to use any mOPV serotype for outbreak response if ever needed. In addition, given uncertainty about the status of population immunity for serotype 2, our results underscore the importance of developing contingencies with manufacturers to continue tOPV production past the current planned OPV2 cessation target of April 2016.All countries should maintain the highest possible levels of population immunity to transmission for each poliovirus serotype prior to the coordinated cessation of the OPV serotype. If OPV2 cessation gets delayed, then global health leaders should consider other OPV cessation timing options."}
+{"text": "The fat signal can lead to misinterpretation and poor visualization of epicardial enhancement. In previous work fat was suppressed by using two appropriately timed fat-selective RF pulses which re-invert and invert fat signal  but this technique was sensitive to off-resonance and heart rate variations. The goal of the present work is to make two improvements to fat-saturated LGE: (1) increase robustness against B0 and B1 variations by using asymmetric adiabatic RF pulses, and (2) increase robustness against heart rate variations through dynamic timing of fat-selective RF pulses.Late Gadolinium Enhancement (LGE) allows imaging of infarction and cardiomyopathies by measuring the accumulation of contrast agent within the myocardium. The shortened T1 (10\u03bcT) and pulse duration (40 ms). Mz magnetization depends on the repetition time of the IR pulse and therefore in cardiac gated sequences depends on the patient heart rate. Heart rate variation leads to a shifting of the inversion time (TIfat) at which the fat signal is nulled. Therefore a heart rate independent nulling of fat signal was developed by measuring the length of each R-R interval during the examination and time-shifting the fat-selective inversion pulse accordingly  and 3.0T (300 ms). With appropriate TI selection the technique led to nulling of signal from healthy myocardium and from fat. The cases without contrast injection had poor blood-myocardium contrast due to the lack of Gd  but fatBenefits of fat-saturated LGE imaging include avoiding image wrapping of subcutaneous fat and therefore reduced possible misdiagnosis Figure ), and in"}
+{"text": "It was more effective following vaccination with live than killed vaccines. In conclusion, application of synbiotic Biomin Imbo, as a feed-additive adjuvant promotes acquired humoral immune responses of broiler chickens. Increased susceptibility of birds to avian pathogens in intensive husbandry system has emphasized on necessity of improvement of innate and specific immune responses of birds by the fast establishment of a beneficial microflora and immune stimulator factors to guarantee healthy and low-price products. During this study, 192 one-day-old broiler chicks (Ross-380) in four groups with three replicates per group were used to investigate effectiveness of synbiotic Biomin Imbo on immune responses of the chickens following routine vaccination against Newcastle disease (ND), avian influenza (AI), infectious bronchitis (IB) and infectious bursal disease (IBD). The results of this study indicated that supplementation of Biomin Imbo in diet enhanced humoral immune responses significantly in the case of ND, IB, IBD ( Finding novel antigens as well as adjuvants is the most beneficial methods to induce an optimal protective immunity against human1 and poultry diseases including avian infectious bronchitis (IB), infectious bursal disease (IBD), Newcastle disease (ND) and avian influenza (AI) which cause significant economic losses in poultry industry worldwide.2,3 Interest in the dietary use of prebiotics and probiotics blossomed in the late 1800s/ early 1900 and the growing enthusiasm on the beneficial effects of pre-, pro- and synbiotics was motivated near the turn of the 20th century.4 Ban of antibiotic growth promoters (AGPs) due to increased bacterial resistance and drug residues in poultry production together with consumer's demand for \"natural\" products have encouraged findings of alternatives for AGP. In order to preserve gut microbiota and to promote host innate defenses, administration of synbiotic  as alternative approach for promoting of performance and immune responses in modern poultry husbandry widely accepted.5,6 Probiotics affect the intestinal microbial balance and subsequently improve performance and reduce mortality in broiler chickens.7,8 Probiotics also protect chickens against avian pathogens,9,10 activate immunocytes and stimulate systemic immune responses11 including promoting the endogenous host defense mechanisms12 and enhancement of production natural antibodies13 as well as specific antibodies.14 On the other hand, prebiotics may control or manipulate microbial composition and/or activity, therefore combination of probiotics and prebiotics improve the survival rate of probiotics in digestive tract contributing to the stabilisation and/or enhancement of the probiotic effects.15,16 Under the present circumstances, improvement of post-vaccination immune responses against the most economically important poultry diseases, in particular IB, IBD, ND and AI is topic for research. Ideologically, synbiotics would have more beneficial effects than these elements alone.17-20 Therefore, the present project was undertaken to study the immuno-modulatory effects of the synbiotic Biomin Imbo on antibody responses during a routine vaccination of broiler chickens against IB, IBD, ND and AI as well as to compare its immunomodulatory effectiveness in vaccination with live and killed vaccines.In the 21Chickens and experimental design. One hundred and ninety-two one-day-old broiler  chicks (Ross-308 strain) were randomly allocated into four groups: (A) vaccinated + diet containing Biomin Imbo, (B) vaccinated + diet not-containing Biomin Imbo, (C) environmental control (unvaccinated + diet without Biomin Imbo), and (D) Biomin control (unvaccinated + diet containing Biomin Imbo). Three replicates were considered for each group (16 chicks per replicate). After leg labeling, the chicks of each replicate were housed in separated boxes and nutritional requirements , ambient temperature, lighting, ventilation as well as other environmental conditions fully met the requirements laid down in the technical instructions of Ross-308 broiler management.21 Vaccinated groups (A and B) and unvaccinated groups (C and D) were kept in separated houses.Enterococcus facium IMB 52; 5 \u00d7 1011 CFU per kg), cell wall fragments of useful micro-organisms, prebiotic (fructo-oligosaccharides) and phycophytics  was used as recommended by manufacturer . Synbiotic Biomin Imbo containing of probiotic  level (below log2-3), chickens of the groups A and B were vaccinated  and  on 11-days and second vaccination (only live vaccine) was carried out on 21-days of age using clone 30 strain of ND virus by eye-drop route as a recommended route inducing higher antibody titer with the closest-rang.22 In the case of AI, one vaccination is carried out on 11-days-old using killed (H9N2) vaccine by subcutaneous injection as a routine vaccination for broilers in the region. In the case of IBD, optimal time for first vaccination was estimated3 and D78 vaccine was used on day 16 and repeated on day 24 of age (based on MDA of the chicks). In the case of IB, as protection significantly (p < 0.05) correlated with levels of local respiratory antibody and not with serum antibody23 therefore, regardless to the potential negative effects of MDA against IB virus, Ma5 vaccine was used via eye-drop for vaccination of one-day-old chicks against IB on day 1 and is repeated on day 18 of age using the same vaccine.2,24Sampling. As level of MDA titer is very important for determination of the best timing of vaccination against IBD as well as ND. On day 1 (one-day-old chicks), blood samples were collected from half the chicks of each replicate as previously described.25,26 On day 7 and then at weekly intervals  until 42 days of age, blood samples were collected from jugular veins and brachial vein, respectively as previously described.27,Serum antibody titers assessment. Antibody level was determined using weekly serum samples of each bird separately in each replicate and treatment. Hemagglutination inhibition test (HI) was used for evaluation of antibody titers against ND and AI, as it has been reported that HI test is an excellent indicator of the immune status and disease resistance of a flock especially to assess protective response following vaccination,27,28 while the indirect enzyme-linked immunosorbent assay  was used for evaluation of antibody titers as recommended for IB29 and IBD.3,29,30Statistical analysis. SPSS software  was used for analyzing of the results under completely randomized design employing one-way ANOVA analysis of variance and the means of different treatments were compared with Bonferroni, Duncan multiple range and repeated measure tests. Significance differences were taken at p < 0.05 level. Newcastle disease antibody titer. Antibody titers against ND of the chickens of different groups are shown in Avian influenza antibody titer. Antibody titers of the chickens against AI are shown in p = 0.160).Infectious bronchitis antibody titer. Status of MDA and acquired antibody titer against avian infectious bronchitis are shown in nd vaccination and peaked around 42 day of age. In comparison to groups A and B (vaccinated groups), antibody titers of chickens treated with Biomin Imbo (group A) differed significantly (p = 0.020) from those of group B during day 28 to end of experiment  antibody titer than those of vaccinated but not treated with Biomin Imbo diet. 31,32 but also leads to immuno-modulation of humoral immune responses as well as cellular immune responses,33 however debates on their potential side effects (cytotoxic and moderate genotoxic effects) is open.34 Comparison of a growth promoters, prebiotics, probiotics as well as synbiotics on their preventive effects in colonization of salmonella in poultry revealed that antimicrobial agents allowed higher colonization as compared to prebiotics and probiotics,9 but Biomin controls the intestinal colonization of Salmonella enteritidis in chickens.35In general, dietary supplementation of synbiotic Biomin Imbo not only ameliorate performance of poultryEnterococcus faecium) of Biomin Imbo enhances humoral immune responses against sheep red blood cells (SRBC).36 Biomin Imbo also increases most parameters of blood profile including total protein37 and higher protein promotes induction of specific antibody titer against avian pathogens. Dietary inclusion of synbiotic Biomin Imbo increased growth performance and improved intestinal morphology, nutrient absorption38 and resistance of birds to pathogens or diseases.37 Comparison of the synbiotic with another probiotic indicated that the synbiotic had much more beneficial effects than probiotic alone5 as well as prebiotics alone39 or AGP alone.40 Enhanced effects of Biomin Imbo on antibody titers of the chickens against ND, AI, IB and IBD were observed during this study and is in agreement with previous reports that the serum antibody responses to oral and systemic administration of antigens were significantly enhanced by probiotics supplementation.41 Due to the immunomuadulatory effects of vitamin E, future synbiotics may include vitamin E as well.42With regards to immunomodulatory effects of Biomin Imbo, there are some reports that probiotic (nd vaccination). Analyzing of the results, as shown in p = 0.100) until 21 day of age; b) From day 21 up to end of the experiment, difference between vaccinated  and unvaccinated  groups due to vaccination was significant (p = 0.010); c) Comparison between antibody titers of chickens of group A (vaccinated and treated with Biomin Imbo) and those of chickens of group B (vaccinated but not treated with Biomin Imbo) was significant on the day 35 (p = 0.049) and on the day 42 (p = 0.048) of age. Continuously reduction of ND antibody titer of chickens of unvaccinated groups (C and D) and its remaining at undetectable level during experimental period confirmed that neither environmental nor cross contamination had occurred. Antibody titers of vaccinated chickens (groups A and B) increased following first vaccination (live + killed) and reached the highest level on day 35 of age  is the highest available titer that could be induced by vaccinations (two live + one killed vaccines) as mean titers 4 to 6 log2 for single live and at least log2-8 for live plus killed vaccine was reported by OIE.43 Higher ND titers of chickens treated by Biomin Imbo is observed in our study is also in agreement with those of log2-7.2 and mean titer of log2-7.5 was reported for mentofin treated chickens.44 The beneficial effects of Biomin Imbo could be more evident in undesirable circumstances due to intensive husbandry systems. However, the enhancement effects of Biomin Imbo on humoral immune responses against ND observed during this study is also been reported for an another probiotics14 as well as other synbiotics.The results obtained during this study  is in agp = 0.150) until 21 day of age; b) From day 21 up to end of the experiment, difference between vaccinated  and unvaccinated  groups due to vaccination was significant (p = 0.020); c) Difference between group A (vaccinated and treated with Biomin Imbo) and group B (vaccinated but not treated with Biomin Imbo) was not significant (p = 0.160). Regarding lack of significant increasing effects of Biomin in the case of AI, it may be attributed to the mechanism of this product on providing a better condition for multiplication of live vaccines whereas a killed vaccine was used in the case of AI. High antibody titers observed during this study (-5.6) of chicken group A could be attributed to enhancement effects of Biomin Imbo on antibody titers of the chickens as it has been reported that optimal nutritional status may enhance immune function indicated by increased vaccine response following vaccination against influenza.37,45As shown in is study  for chic24 As shown in p < 0.05).33 As maternal IBV antibodies are in low concentrations in the tear secretions than in sera, therefore, the interference between MDA and virus of vaccine may happen in a very low level. However, in the eye-drop or spray routes, invasion of the gland by virus of vaccine without the involvement of blood borne circulation after infection by the conjunctival and intranasal routes, would explain why the high levels of MDA of one-day-old chicks did not impair immunization.46 Lack of rising of antibody titers of unvaccinated chickens (groups C and D) during experimental period indicated that there was neither environmental nor cross contamination. Late rising of antibody titer (28 days post-1st vaccination and 10 days post-2nd vaccination) of the vaccinated chickens (groups A and B) and reaching the highest level at six weeks age were observed during this study is in agreement with the studies reporting that antibody peaked around 45 day of age following vaccination on day 1 and on day 25. Our observation on enhancement effects of Biomin Imbo on humoral response against IB is in agreement with the results reported for an another synbiotic.33 Recent studies indicate that supplementation of vitamin E may also enhances higher immune responses against IB.42Humoral immunity has a key role in protection of chickens against IB.3 Maternally-derived antibody transferring rate (up to 73.00%) from breeders to yolk/chicks not only varied among different chickens' line but also MDA varied among one-day-old chicks even from same broiler breeder flock47 and depending on the range of MDA, finding optimal timing of primary vaccination would be too difficult. Although there are several methods for predicting the timing of initial vaccination,30,48 in routine vaccination program for intensive poultry husbandry system, primary vaccination against IBD may equalized MDA of the chicks and good immune response may be obtained following booster dose. Generally, infectious bursal disease with clinical signs occurs around three to six weeks of age3 and the birds are most susceptible at 30 to 35 days old. Therefore, an ideal vaccination program must induce protective antibody titer at this age as occurred during this study  Differences among the groups  were not significant (p = 0.100) until day 28 of age; b) From day 28 up to end of the experiment, difference between vaccinated  and unvaccinated  groups due to vaccination was significant (p = 0.020); c) Difference between group A (vaccinated and treated with Biomin Imbo) and group B (vaccinated but not treated with Biomin Imbo) was significant (p = 0.036) only on day 42 of age. Humoral antibody plays a key role in protection against IBD.is study  and IBD In conclusion, Application of synbiotic Biomin Imbo enhances antibody responses following vaccination against ND, AI, IB and IBD but it is more effective in live than killed vaccines and could be used as a feed-additive adjuvant for improving innate and acquired immune responses in chickens."}
+{"text": "We also update the information about the inhibition properties of single pgip gene products against microbial PGs and the results, including field tests, showing the capacity of PGIP to protect crop plants against fungal, oomycetes and bacterial pathogens.Polygalacturonase inhibiting proteins (PGIPs) are cell wall proteins that inhibit the pectin-depolymerizing activity of polygalacturonases secreted by microbial pathogens and insects. These ubiquitous inhibitors have a leucine-rich repeat structure that is strongly conserved in monocot and dicot plants. Previous reviews have summarized the importance of PGIP in plant defense and the structural basis of PG-PGIP interaction; here we update the current knowledge about PGIPs with the recent findings on the composition and evolution of  To this end, pathogens produce a wide array of plant cell wall degrading enzymes (CWDEs), among which endo-polygalacturonases  are secreted at very early stages of the infection process . Most of these genes have been identified as pgip genes on the basis of sequence identity but only a few of them have been shown to encode proteins with PG-inhibitory activity.Early characterization of a polygalacturonase-inhibiting activity was reported in 1970s . These proteins do not interact in vitro, although VvPGIP1 reduces symptoms caused by BcPG2 upon co-infiltration in leaves. The number and sources of PGs tested is also limited; only a few studies have been carried out against PGs of bacteria and insects  possessing non functional pgip genes . Recently, a wheat gene with some sequence similarity to pgip genes has been reported and was shown to be involved in the defense response against Fusarium graminearum  forms with PG from A. niger (AnPGII), F. phyllophilum (FpPG) and C. lupini (ClPG). Site-directed mutagenesis has shown that the residues involved in the interaction are located in the concave surface of the inhibitor  suggesting that the protein is highly versatile in recognizing different epitopes of various PGs  Bnpgip1 or Bnpgip2. Arabidopsis plants overexpressing Atpgip1 or Atpgip2 showed a significant reduction of disease symptoms caused by B. cinerea  PGIP (PcPGIP) capable of inhibiting the PGs secreted by B. cinerea, showed a reduction of disease lesions caused by this fungus both on ripening fruit (15% reduction) and leaves (about 25% reduction). The initial establishment of infection was not affected in the transgenic plants but the later colonization of the host tissue was significantly reduced , Vvpgip1 (from V. vinifera), Capgip1 [from pepper (Capsicum annum)] and Brpgip2 (from B. rapa) have been obtained in transgenic tobacco. Plants expressing PvPGIP2 showed about 35% reduction of symptoms caused by B. cinerea  that are highly resistant to blue mold disease. These transgenic plants expressing PvPGIP2 represented the first example of PGIP-expressing plants subjected to field trails. Recently, transgenic rice expressing OsPGIP1 showed also improved resistance against Rhizoctonia solani in field experiments  caused by Solanum tuberosum) plants expressing the gene StPGIP1 from S. torvum showed a 50% reduction of wilt disease symptoms caused by Verticillium dahliae and a normal plant growth  plants constitutively expressing the pear PcPGIP gene represent an interesting example of the potential of PGIP for protection against pathogens other than fungi and oomycetes. These plants show a delayed development of the Pierce's disease (PD) caused by bacterial pathogen Xylella fastidiosa  of the symptoms as compared to wild-type plants  plants overexpressing BrPGIP2 showed higher resistance against P. carotovorum and produced normal looking pods-like structures with no viable seeds. Combination of crossing with non-transgenic plants did not restore fertility of the transgenic plants, suggesting that mechanisms such as ploidy changes occurring during the tissue culture stage or changes in cell-wall architecture of sexual organs are responsible for the abnormality , transformed with Ripgip from raspberry (Rubus idaeus L.)  and apple  transformed with pear PcPGIP  transformed with bean Pvpgip2  transformed with bean Pvpgip1  to transform both durum and bread wheat by particle bombardment. PvPGIP2 was correctly targeted to the apoplast and the transgenic plants did not show any major morphological and growth defects. Transgenic wheat showed a significant reduction (46\u201350%) of foliar spot blotch symptoms caused by the hemibiotrophic fungal pathogen Bipolaris sorokiniana and improved resistance (25\u201330%) against the hemibiotrophic fungal pathogen F. graminearum  E3 ligase that is involved in several stress responses, including Pi starvation, and flowering (Sato and Miura, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Different reports of shared manifestations for malignancy and rheumatic diseases in children since 1970s indicate the presentation of malignancies, particularly ALL, with musculoskeletal (MS) symptoms.To evaluate the rate and the characteristics of hematological malignancies in Iranian children with joint manifestations based on two different scopes of data collection since 1981.In this retrospective review, we considered two different aspects of evaluation within two pediatric tertiary centers in Iran: 1- Children's Hematology/Oncology Research Center, 2- Pediatric Rheumatology Center.Here we report the results of 3 studies  conducted through 1981-2006, followed by current (IV) study performed since 2006. Findings of four different studies are mentioned in detail, in Table The relative increase in the rate of malignancy in this review (period of 1981-2012) could be an alarm to perform BM aspiration in children with joint manifestations harboring the following as \"Red Flags\": (i) Boys at the age of 5-7, (ii) Large joint involvement  and (iii) Arthralgia at presentation. According to recent recommendations by ACR for early aggressive treatments in JIA patients, this precautionary measure may minimize the potential dangers and consequences of misdiagnosis prior to initiation of any treatment.None declared."}
+{"text": "Glycine max) because of ruptured cell walls. Using RNA-Seq, we examined the seed coat transcriptome from three stages of immature seed development in two pairs of isolines with normal or defective seed coat phenotypes due to the net pattern. The genome-wide comparative study of the transcript profiles of these isolines revealed 364 differentially expressed genes in common between the two varieties that were further divided into different broad functional categories. Genes related to cell wall processes accounted for 19% of the differentially expressed genes in the middle developmental stage of 100\u2013200 mg seed weight. Within this class, the cell wall proline-rich and glycine-rich protein genes were highly differentially expressed in both genetic backgrounds. Other genes that showed significant expression changes in each of the isoline pairs at the 100\u2013200 mg seed weight stage were xylem serine proteinase, fasciclin-related genes, auxin and stress response related genes, TRANSPARENT TESTA 1 (TT1) and other transcription factors. The mutant appears to shift the timing of either the increase or decrease in the levels of some of the transcripts. The analysis of these data sets reveals the physiological changes that the seed coat undergoes during the formation of the breaks in the cell wall.The plant cell wall performs a number of essential functions including providing shape to many different cell types and serving as a defense against potential pathogens. The net pattern mutation creates breaks in the seed coat of soybean ( Plant cells are surrounded by cell walls which provide tensile strength, mechanical support, protection from insects and pathogens, prevention of water loss, and that participate in cell to cell communication Glycine max) has been well characterized, and contains features in common with the majority of the legumes: an epidermal layer of palisade cells, or macrosclereids, a sub-epidermal layer of hourglass cells, or osteosclereids, a few layers of parenchyma, and an aleurone layer The seed coat, or testa, of the mature soybean  of the cell wall leading to higher levels of this transcript in the defective seed coats at the middle weight range of 100\u2013200 mg seed weight The effect on PRP1 transcript levels was assumed to be a downstream effect of the net pattern mutation. In this report, we present the global gene expression analysis of the net pattern cell wall mutant in soybean using transcriptome analyses of three different stages of seed development at 50\u2013100 mg, 100\u2013200 mg, and 400\u2013500 mg. By comparing RNA-Seq data from the two lines containing the defective seed coat trait compared to their standard counterpart isolines using Bowtie alignments The isolines in the background of cultivar Clark are referred to as Clark standard (CS) which exhibits an intact seed coat and Clark defective (CD) that contains the defective seed coat mutation that had been backcrossed into the Clark standard line. Likewise, Harosoy standard (HS) is compared to the Harosoy defective (HD) isoline that contains the defective seed coat mutation. The genotypes and phenotypes of these two isoline pairs is presented in Next-generation high throughput sequencing of the transcriptome (RNA-Seq) was used and the cDNA libraries were constructed from seed coats from 50\u2013100 mg, 100\u2013200 mg and 400\u2013500 mg seed weight stages in standard and mutant isolines of Clark and Harosoy cultivars. Each library was sequenced on the Illumina GAII or HiSeq 2000 platforms. The number of raw sequence reads obtained from all four isolines, at different seed weight stages are presented in As presented in As shown in A selection of 29 of the 364 differentially expressed genes at the 100\u2013200 mg seed weight stage are shown in As presented in The expression levels of PRP1 and PRP2 at different seed weight stages were previously demonstrated by The graphical representations of the expression levels of the other differentially expressed genes shown in It is clear from the 68 graphs of the gene expression patterns shown in There were 21 hormone regulated genes that were differentially expressed in the seed coat of wild type and defective isolines of both Clark and Harosoy background  includinThe expression pattern of two other hormone regulated genes in ie., if expression of a particular gene was higher in the standard isoline of Clark, then it was lower in the standard isoline of Harosoy)  .Two zinc finger domain (C2H2 type) containing protein genes that had TT1 (TRANSPARENT TESTA1) annotations were approximately 6-fold and 15-fold more highly expressed in the defective seed coats of the Clark and Harosoy lines, respectively, at the 100\u2013200 mg seed weight stage  & 4. TheAlong with the two TT1 gene models, there were 14 total transcription factor genes that showed differential expression in seed coats of standard and defective isolines in both of the Clark and Harosoy backgrounds at the 100\u2013200 mg stage . The mosWe provide an overview of the genes that are affected by the \u201cnet pattern\u201d mutation which affects the structural integrity of the soybean seed coat. As shown in Allergens, thaumatin-like proteins, and cysteine-rich domain containing proteins have also been reported to play important roles in various functions related to the cell wall While we have concentrated on the 51 cell wall related genes that were significantly differentially expressed in both varieties, we note that there are 920 additional cell wall related genes that did not show differential expression in the seed coats of either of the two isoline pairs. Thus, there are many processes related to the cell wall that are not affected at the transcript level by the net-pattern mutation.Auxin is a plant growth regulator that is required for cell expansion, division and differentiation. Auxin pathway related genes have been reported to regulate several cell wall related genes in Arabidopsis Glycine maxThe proline-rich proteins are composed of small tandem repeats such as PPVYK or PPVEK, where the second proline is often hydroxyproline I alleles), as compared to black Clark isolines   . LikewisOur RNA-Seq data  show excet al., WRKY transcription factors are involved in regulation of downstream genes encoding the NAM, ATAF1/2, and CUC2 (NAC) and CCCH type (C3H) zinc finger TFs that activate secondary wall synthesis Arabidopsis thaliana, these were expressed in specific cell types of roots, stems and seeds that undergo suberization Transcription factors are important players for controlling the flow of genetic information from DNA to RNA and ultimately affecting the growth and physiology of the plant. In this study, there were approximately 240 differentially expressed transcription factor genes at different seed weight stages \u2013S4. ThesIt is likely that the defective seed coat mutation in soybean sets in motion changes in many pathways related to the cell wall. Some of the differential expression may be a temporal shift in developmental appearances of transcripts. Notably, in the case of the TT1 homolog, it appears that the decline in its transcript levels was delayed in the defective seed coats relative to the standard seed coats , thus leGlycine max. There were approximately 1300 significantly differentially expressed genes affected by this mutation in each isoline pair with 364 in common between the two isolines of different genetic backgrounds. The cell wall structural protein genes including proline-rich proteins (PRP1 and PRP2) and glycine-rich proteins were among the transcripts affected by the mutation as well as a number of transcription factors. Some of the transcript patterns indicate that a developmental shift in timing of gene expression underpins the differential gene expression changes at mid-maturation as shown by graphical presentation of expression patterns for 82 out of 364 genes that were significantly differentially expressed in both the Clark and Harosoy backgrounds. In summary, the mutation appears to set in motion a complex series of events, many manifested at the transcript level, that lead to changes in physiology and ultimately structure of the cell wall. The information on potential candidate genes for this mutation and the regulated genes will not only be helpful in understanding cell wall physiology in soybean, but could also provide a platform for improvement in bioenergy crops like sorghum, maize and Miscanthus.We present an overview of genes whose expression was affected by the \u201cnet pattern\u201d mutation in soybean. Two isolines of different genetic backgrounds were used to understand physiology related to this mutation that causes defective cracks in the seed coats. Twelve samples representing three stages of seed coat development from each of the four lines were subjected to the power of next-generation sequencing to obtain millions of transcript reads that were mapped to all 78,773 high and low confidence gene models of Glycine max used in this study were a black seeded Clark line, Clark defective seed coat, Harosoy standard and Harosoy defective seed coat. The defective seed coat mutation was originally found in two PI (plant introduction) lines, PI 339.994 and PI423.730B and these lines were backcrossed to the black seeded Clark line (UC9) to create an isoline UC412 containing this mutation. The same mutation was also backcrossed into the Harosoy line to create an isoline UC508. The L or PI numbers represent the official USDA isoline or plant introduction numbers, respectively. The UC number is an internal number used by our laboratory. Detailed information on these lines is presented in The isolines of For RNA extraction, immature seeds were harvested over the course of several weeks. The individual seeds were pooled and sorted by weight. Following this, each seed was dissected, separating the cotyledon and embryo from the seed coat, and placed in separate 15-ml polypropylene centrifuge tubes . All tissue was then frozen in liquid nitrogen and placed in storage at \u221280\u00b0C until it could be lyophilized. RNA of seed coats of seeds from the 50\u2013100 mg, 100\u2013200 mg and 400\u2013500 mg seed weight stages of each isoline was extracted separately using the RNA for 5 ml volumes from \u223c30 mg (50\u2013100 mg and 100\u2013200 mg seed weight stage) and \u223c70 mg (400\u2013500 mg seed weight stage) dry weight. The modified protocol used here is based on the protocols of McCarty The 75 bp and 100bp reads were mapped to the 78,773 Glyma cDNA gene models (JGI/Phytozome) using Bowtie et al. Coding region gene models were collected from the masked soybean genome from Phytozome version 6.0 and the soybean genome version 1.0 GFF file of the soybean genome DESeq (available via Bioconductor) is an R package to analyze count data from high-throughput sequencing data such as RNA-Seq and test for differential expression 32P]dATP by random primer reaction method Total RNA was extracted from the frozen tissue including 4\u20135 day old soybean hypocotyls minus their cotyledons and seed coats of 100\u2013200 mg seeds from four lines using a standard phenol chloroform method with lithium chloride precipitation The data have been entered into Gene Expression Omnibus at that National Center for Biotechnology Information as Accession Series GSE54903.Figure S1The Distribution of Expression Levels in RPKMs of Differentially Expressed Genes in the Clark Isoline Pair at Three Different Seed Weight Stages. (A) 50\u2013100 mg in Clark Standard (B) 50\u2013100 mg in Clark Defective (C) 100\u2013200 mg in Clark Standard (D) 100\u2013200 mg in Clark Defective (E) 400\u2013500 mg Clark Standard (F) 400\u2013500 mg Clark Defective.(TIFF)Click here for additional data file.Figure S2The Distribution of Expression Levels of Differentially Expressed Genes in the Harosoy Isoline Pair at Three Different Seed Weight Stages. (A) 50\u2013100 mg in Harosy Standard (B) 50\u2013100 mg in Harosoy Defective (C) 100\u2013200 mg in Harosoy Standard (D) 100\u2013200 mg in Harosoy Defective (E) 400\u2013500 mg Harosoy Standard (F) 400\u2013500 mg Harosoy Defective.(TIFF)Click here for additional data file.Figure S3Williams (Phytozome) and Wayne (NCBI) cultivars showed 100% sequence homology.The Nucleotide and Amino Acid Sequence Alignment for PRP1. (A) Alignment of PRP1 nucleotide sequence from NCBI (J02746) and PRP1 sequence (Glyma09g12200.1) from Phytozome database (B) Alignment of PRP1 amino acid sequence from NCBI with PRP1 amino acid sequence from Phytozome database. The nucleotide and amino acid sequence from (TIFF)Click here for additional data file.Figure S4The Nucleotide and Amino Acid Sequence Alignment of the PRP2 Gene. (A) Alignment of PRP2 nucleotide sequence from NCBI (J05208) and PRP2 sequence from Phytozome database (Glyma09g12260.1) (B) Alignment of PRP2 amino acid sequence from NCBI with PRP2 amino acid sequence from Phytozome database. There is difference of one tandem repeat in the amino acid sequence. The PRP2 protein is shorter in Williams (Phytozome) as compared to Wayne (NCBI) cultivar.(TIFF)Click here for additional data file.Figure S5The Genome Organization of PRP1 and PRP2. As in the Phytozome database, PRP1 and PRP2 are on chromosome 9 and the distance between these genes is \u223c146 kb.(TIFF)Click here for additional data file.Figure S6The Expression Pattern of 13 Selected Differentially Expressed Genes in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Backgrounds. The genes over expressed in the defective isolines . CS: Cla(TIF)Click here for additional data file.Figure S7The Expression Pattern of 16 Selected Differentially Expressed Genes in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Background. The genes overexpressed in the Standard isolines . CS: Cla(TIF)Click here for additional data file.Figure S8The Expression Pattern of 11 Fasciclin-like Arabinogalactan Gene in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Background. These genes showed higher expression in defective isoline as compare to wildtype isoline . CS: Cla(TIF)Click here for additional data file.Figure S9The Expression Pattern of Cell Wall Genes Overexpressed in the Seed Coats of Defective Isolines in Both Clark and Harosoy Background. These graphs present data for 25 additional cell wall related genes not previously shown in (TIF)Click here for additional data file.Figure S10The Expression Pattern of Cell Wall Genes Overexpressed in the Standard Seed Coats of Both Clark and Harosoy Background. These graphs present data for 3 additional cell wall related genes not previously shown in (TIFF)Click here for additional data file.Figure S11The Distribution of Differentially Expressed Genes in the Seed Coats of Either (A) Clark or (B) Harosoy Backgrounds at the 50\u2013100 mg Seed Weight Stage. The number of differentially expressed genes  was (A) 720 genes in Clark isolines and (B) 48 genes in Harosoy isolines. In both backgrounds, there were major categories related to the cell wall.(TIFF)Click here for additional data file.Figure S12The Distribution of Differentially Expressed Genes in Seed Coats of Either (A) Clark or (B) Harosoy Backgrounds at the 100\u2013200 mg Seed Weight Stage. The number of differentially expressed genes  was (A) 173 genes in Clark isolines and (B) 156 genes in Harosoy isolines at 100\u2013200 mg seed weight stage. In both backgrounds, one of the major categories was related to the cell wall.(TIFF)Click here for additional data file.Figure S13The Distribution of Differentially Expressed Genes in Seed Coats of (A) Clark or (B) Harosoy Backgrounds at the 400\u2013500 mg Seed Weight Stage. The number of differentially expressed genes  was (A) 417 genes in Clark isolines and (B) 1068 genes in Harosoy isolines. In both backgrounds, the cell wall related genes occupied 5% of the chart area.(TIFF)Click here for additional data file.Figure S14The Expression Pattern of Differentially Expressed Transcription Factor Genes That Showed Higher Expression in the Seed Coat of Defective Isolines in Both Clark and Harosoy Background. Overexpressed in defective isolines. CS: Clark Standard, CD: Clark Defective, HS: Harosoy Standard, HD: Harosoy Defective.(TIF)Click here for additional data file.Figure S15The Expression Pattern of Differentially Expressed Transcription Factor Genes That Showed Higher Expression in the Seed Coat of Standard Isolines in Both Clark and Harosoy Background. Overexpressed in standard isolines. CS: Clark Standard, CD: Clark Defective, HS: Harosoy Standard, HD: Harosoy Defective.(TIF)Click here for additional data file.Figure S16The Distribution of Differentially Expressed Transcription Factor Genes into Different Classes in Clark at the 50\u2013100 mg Seed Weight Stage. The 59 differentially expressed transcription factor genes  were divided into 12 classes based on functional annotations.(TIFF)Click here for additional data file.Figure S17The Distribution of Differentially Expressed Transcription Factor Genes in (A) Clark or (B) Harosoy Backgrounds at the 100\u2013200 mg Seed Weight Stage. (A) The 16 differentially expressed transcription factor genes  were divided into 9 different classes (B) The 12 differentially expressed transcription factor genes  were divided into 10 different classes based on functional annotation.(TIFF)Click here for additional data file.Figure S18The Distribution of Differentially Expressed Transcription Factor Genes in Different Classes in (A) Clark and (B) Harosoy Backgrounds at the 400\u2013500 mg Seed Weight Stage. (A) The 43 differentially expressed transcription factor genes  were divided into 10 different classes (B) The 111 differentially expressed transcription factor genes  were divided into 15 different classes based on functional annotation.(TIFF)Click here for additional data file.Table S1The Total Number of Expressed Genes in Seed Coats of the Different Isolines. The total number of expressed genes at \u226510 RPKM or \u22651 RPKM in different backgrounds at different seed weight stages are presented in this table. CS: Clark standard, CD: Clark defective, HS: Harosoy Standard and HD: Harosoy defective.(DOCX)Click here for additional data file.Table S2Significantly Differentially Expressed Genes Found in the Seed Coats of Either Clark or Harosoy Backgrounds at the Indicated Stages of Seed Development.(XLSX)Click here for additional data file.Table S3The 364 Significantly Differentially Expressed Genes Found in Common in Both Clark and Harosoy Backgrounds as Defined in (XLSX)Click here for additional data file.Table S4The 109 Significantly Differentially Expressed Genes Common in Both Background But with Expression in Opposite Directions as Described in (XLSX)Click here for additional data file."}
+{"text": "Early diagnosis of macrophage activations syndrome (MAS) in systemic juvenile idiopathic arthritis (sjia) may be challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. However, the diagnostic value of the guidelines for hemophagocytic lymphohistiocytosis (HLH) or sjia-associated MAS has seldom been examined.To investigate the sensitivity and specificity of diagnostic guidelines for HLH and sjia-associated MAS in patients with sjia who developed MAS.The study sample included 362 children with sjia who had MAS (diagnosed and treated as such by the attending physician) and 2 control groups with potentially \"confusable\" conditions, including active sjia without MAS (n = 404) and a systemic febrile infection requiring hospitalization (n = 345). Diagnostic guidelines for HLH and sjia-associated MAS were applied to all MAS and control patients. Because no patient had NK-cell activity and soluble CD25 determination available and bone marrow aspirate was performed in only a few patients, these 3 criteria were excluded from HLH guidelines. HLH criteria were, therefore, met when at least 4 of the 5 remaining variables were present. Sjia-associated MAS criteria were met when at least 2 laboratory criteria or at least 1 laboratory criterion and 1 clinical criterion were present. Sensitivity and specificity of guidelines in discriminating patients with MAS from control patients were assessed.The table shows the comparison of sensitivity and specificity of diagnostic guidelines.The diagnostic guidelines for sjia-associated MAS revealed strong sensitivity and specificity, whereas HLH guidelines were highly specific, but lacked sensitivity. Sensitivity of HLH was mostly hampered by the excessive stringent threshold for cytopenia and hypofibrinogenemia, and the infrequent occurrence of splenomegaly in patients with MAS.None declared."}
+{"text": "Quantification of interstitial (diffuse) myocardial fibrosis by T1 mapping may prove useful in a range of conditions. Both native T1 maps and extracellular volume fraction (ECV) are being increasingly used clinically and have been shown to be sensitive to a wide range of conditions and associate with worse prognosis. However, quality control by T1 phantoms is essential  and thei2-agarose gel phantoms [NiClphantoms  were prephantoms . PhantomBoth high resolution and low resolution sequences had similar T1 means, standard deviation and coefficient of variation (CoV) for blood and myocardium native and post-gadolinium  may require further investigation.There was significant stability of the NiClNIHR Cardiovascular Biomedical Research Unit of Royal Brompton & Harefield NHS Foundation Trust and Imperial College London."}
+{"text": "To the Editor: Feline morbillivirus (FeMV) was first reported in Hong Kong and mainland China in 2012  of the L gene of the US strains (We generated amplicons from 10 (3%) of 327 samples; 3 samples were from cats with CKD and 7 from cats without CKD. Sequencing results confirmed that these 493 bp amplicons correspond to unique strains of FeMV . Approximately 15 months later, we obtained a follow-up urine sample from the still healthy cat, performed reverse transcription PCR (RT-PCR), and generated amplicons  by using RT-PCR and rapid amplification of cDNA ends. The major morbillivirus surface antigen is the HA glycoprotein, and we used pan-FeMV HA gene primer sets to detect additional viruses  , and antibodies to FeMVUS5 were detected in nonpermeabilized cells    Figure 2US1 is closely related to viruses from Asia, highlighting the global distribution of FeMV  clustered phylogenetically in a basal sister relationship with all other viruses from Asia and the United States (We used complete genome and H gene sequences in a comprehensive phylogenetic analysis. FeMV of FeMV , panel Ad States , panel BEcologic surveys continue to identify novel viruses that are homologous to known paramyxoviruses in many wildlife species, including bats and rodents (The detection of FeMV sequences in a clinically healthy animal after 15 months is a novel and surprising observation but is consistent with the known propensity for morbilliviruses to persist in vivo (Technical Appendix. Methods for the molecular and serologic detection of feline morbillivirus in clinical samples."}
+{"text": "Ribavirin (RBV) is a synthetic nucleoside analogue  used for the treatment of a number of viral diseases. RBV inhibits inosine 5\u2032-phosphate dehydrogenase (IMPDH), the enzyme required for synthesis of guanosine monophosphate (GMS) as well as DNA and RNA synthesis. Based on this mechanism of action, RBV is also used in the treatment of solid tumors, lymphoproliferative disease and some inflammatory diseases such as Crohn's disease. A number of nucleoside analogs including RBV diffuse across cell membranes through a membrane transporter protein called equilibrative nucleoside transporter-1 (ENT1). Our recent publication demonstrated that an autophagy response induced by hepatitis C virus (HCV) in a cell culture reduces RBV uptake and antiviral activity by diminishing the surface expression of ENT1 [Human ENTs are the nucleoside transporter proteins expressed on the cell membrane that occur as four isoforms ENT1-ENT4). These proteins play important roles in transporting nucleosides- and nucleotides-based small molecule drugs. The expression of ENT1 is critical for salvage of natural nucleotides and nucleosides for nucleic acid synthesis, neurotransmission, and regulation of cardiovascular activity . The exp. These pTaking into consideration the previously mentioned autophagy related mechanism that regulates the expression of ENT1, it is reasonable to speculate that cellular autophagy status could regulate the uptake and response to nucleoside based treatment of viral infection or cancer. RBV has been used for the treatment of a number of viral infections with modest antiviral activity. The decreased antiviral activity of RBV against virus disease could be related to the degree of cellular autophagy response and expression of ENT1. Based on our results, we propose that inhibiting cellular autophagy response should improve the RBV uptake and antiviral activity against other viruses. One report showed that RBV has a potent antitumor activity against metastatic breast cancer . The celThe responses to gemcitabine treatment of pancreatic cancer have been shown to be correlate with reduced expression of ENT1 transporter. Over expression of ENT1 enhances the gemcitabine response in human pancreatic cancer, tumor cells lacking ENT1 expression are highly resistant to gemcitabine . This is"}
+{"text": "There is an emerging evidence that critical illnes induces an alteration in the immune response of patients that makes them more susceptible to the development of nosocomial infections and influences its clinical response.The aim of this study is to characterize the immunocompetence status of critically ill patients undergoing mechanical ventilation and to determine impaired immune patterns associated with an increased risk of developing ventilator-associated pneumonia (VAP) and a poorer clinical evolution.All immunocompetent patients over 18 years old admitted to the Intensive Care Unit of the Hospital Universitario and Politecnico la Fe , undergoing mechanical ventilation for more than 48 hours were included. Patients with clinical suspicion of ventilator-associated respiratory infection were considered as cases and compared with a selection of controls matched by age, comorbidities, severity scales and days of mechanical ventilation. At the moment of intubation and each 72 hours until the moment of extubation, clinical surveillance was performed and respiratory samples  were taken to evaluate clinical and microbiological response. Samples of plasma and mini-BAL were also taken for immunoglobulins IgG1 - IgG4, IgM, IgA and IgE determination. Comparison of numerical and categorical variables was performed with the Mann-Whitney U test. Results were expressed as medians with interquartile (25% to 75%) ranges (IR) in brackets.16 cases and 14 controls were considered for analysis. Response to antibiotic treatment was evaluated in cases and patients were classified in responders (7 cases) and non-responders (8 cases). Initial empirical antibiotic treatment was more accurate in responders patients . At the moment of orotracheal intubation and beginning of mechanical ventilation, VAP patients showed lower serum IgA levels  (figure A), lower serum IgG1 and IgM and lower respiratory levels of IgG1, IgG2 and IgA, without statistical signification. At the moment of VAP diagnosis, responders patients showed higher levels of IgG2  (figure B), lower serum IgG1 and IgM  and higher levels of IgA  (figure C).Our findings show the protective role of IgA and IgG2 against the inflammatory aggression of mechanical ventilation and in the response against ventilator-associated pneumonia.This study was supported by the Spanish Society of Pneumology and Thoracic Surgery (SEPAR 129/2011)."}
+{"text": "The aim of the present study was to investigate the correlation between initialalveolar bone density of upper central incisors (ABD-UI) and external apical rootresorption (EARR) after 12 months of orthodontic movement in cases withoutextraction. 1) andafter 12 months of treatment (T2). ABD-UI and EARR were measured bymeans of densitometry.  A total of 47 orthodontic patients 11 years old or older were submitted toperiapical radiography of upper incisors prior to treatment .  No statistically significant correlation was found between initial ABD-UI andEARR at T Based on the present findings, alveolar density assessed through periapicalradiography is not predictive of root resorption after 12 months of orthodontictreatment in cases without extraction. Radiographs were taken using the RX Timex 70 C  and Pro 70-Intra  x-rayequipment operating with 70 kVp, 7 mA and a 0.25-second exposure time.oC). Intermediate washing was standardized at 30 seconds and fixing timewas standardized at 10 minutes.All procedures were approved by the State University of Maring\u00e1 Institutional ReviewBoard, Brazil (190 \u2044 2008). Each volunteer was submitted to periapical radiography ofthe upper incisor region either immediately prior to or immediately after bracketbonding , a trapezoidal region of interest was outlined in the alveolar boneprocess of the apical region of upper central incisors to estimate optical densityexpressed in grey level values ranging from 0 (black) to 255 (white).1 and TLT2; CLT1 andCLT2) were measured at a precision of 0.1 mm with the aid of CorelDRAWX4 software.,,,,,2 wascalculated using the following equation:,,Tooth length (TL) and crown length (CL) of upper incisors #11 and #21) at bothevaluation times  was also employed.Although no statistically significant differences were found between the first andsecond measures, the mean of each variable was used in the subsequent statisticaltests to minimize random error.2. Significance level was set at 5% (P< 0.05) for all statistical tests.Neither EARR nor ABD-UI had normal distribution (Lilliefors test). Thus,nonparametric Spearman correlation test was used to determine potential correlationsbetween initial ABD-UI and EARR at TNo significant differences were found between teeth #11 and #21 regarding EARR andABD-UI. After 12 months of treatment, mean EARR was 3.5%  . Three p,,,,Apical root resorption can occur in the early stages of orthodontic treatment,especially in upper incisors which generally undergo greater movement in comparison toother teeth.,Periapical radiography is the method of choice to assess apical root resorption stemmingfrom orthodontic treatment, mainly due to the cost-benefit ratio of this method.Periapical radiographs are known to have greater reliability in comparison to lateraland panoramic radiographs.,-In previous studies employing dual-energy x-ray absorptiometry (DXA), systemic BMD(lumbar spine and femur) was not correlated with maxillomandibular alveolar BMD.,,,A study investigating alveolar density of anterior and posterior regions of the maxillaand mandible found that only the densities of the anterior maxilla and posteriormandible were correlated.The dentoalveolar complex of each patient is unique in terms of size, orientation anddensity, and associations between EARR and alveolar density and morphology have not yetbeen established.,,,As cortical bone is denser than trabecular bone, a number of studies have investigatedassociations between bone density and root resorption in an indirect manner by analyzingthe proximity of roots and cortical bone during orthodontic movement.Kaley and PhilipsHoriuchi et al,,It makes sense to measure the total displacement of a tooth by the root apex which iswhere pathological resorption occurs.Based on the present findings, alveolar density in the apical region of upper incisorsassessed by means of periapical radiographs is not predictive of root resorption 12months after orthodontic treatment in cases without extraction."}
+{"text": "Hypertrophic cardiomyopathy is the most common monogenic disorder in cardiology. Despite important advances in understanding disease pathogenesis, it is not clear how flaws in individual sarcomere components are responsible for the observed phenotype. The aim of this article is to provide a brief interpretative analysis of some currently proposed pathophysiological mechanisms of hypertrophic cardiomyopathy, with a special emphasis on alterations in the cardiac mechanical properties. Hypertrophic cardiomyopathy (HCM) is a relatively rare inherited cardiovascular disease that affects approximately 1 in 500 young individuals and that accounts for 35% of sudden cardiac death cases in young athletes  and myosin binding protein C (MYBPC3) are the most commonly involved genes, followed by troponin I (TNNI3), troponin T (TNNT2), essential myosin light chain (MYL3), regulatory myosin light chain (MYL2), alpha tropomyosin (TPM1), and cardiac actin (ACTC)  . Myocardial deformation analysis in the form of magnetic resonance imaging (MRI) has revealed strain dissimilarities between the endocardial and epicardial layers of the left ventricle (LV) wall and among different LV segments  or slow (MYH7). There are certain developmental, environmental, epigenetic and hormonal factors  that regulate the expression of MYH6 and MYH7, which are encoded by a gene cluster on chromosome 14 Gupta, . MYH7 isSeveral studies have examined the mechanical properties of the epicardial and endocardial layers . In general terms, patients with unexplained syncope, documented ventricular tachycardia or aborted SCD, positive family history for SCD, maximal LV wall thickness >30 mm and abnormal drop in blood pressure during exercise, treated with an implantable defibrillator . The mechanisms analyzed in this paper shed some light on the relation of mutations to disease phenotype, although they may not necessarily apply to all patients. A better understanding of the pathophysiological mechanisms leading to hypertrophy will contribute to the further improvement of treatment and to risk stratification for sudden cardiac death.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "AbstractReduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies.Abbreviations: SGA = small for gestational age; IUGR = intrauterine growth restriction; FGR = fetal growth restriction; IUFD = intrauterine fetal demise; HIV = human immunodeficiency virus; PAPP-A = pregnancy associated plasmatic protein A; \u03b2-hCG = beta human chorionic gonadotropin; MoM = multiple of median; ADAM-12 = A-disintegrin and metalloprotease 12; PP-13 = placental protein 13; VEGF = vascular endothelial growth factor; PlGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1; UAD = uterine arteries Doppler ultrasound; RI = resistence index; PI = pulsatility index; VOCAL = Virtual Organ Computer\u2013Aided Analysis software; VI = vascularization index; FI = flow index; VFI = vascularization flow index; PQ = placental quotient Considered by the American College of Obstetricians and Gynecologists \u201cthe most common and complex problem in modern obstetrics\", fetal growth restriction still needs clear criteria because intrauterine fetal growth is not defined by clear parameters but mainly estimated on the basis of multiple factors. Research in this field is trying to find predictive parameters, with the goal of reaching an early diagnosis, which would lead to a better management of the condition [2]. Intrauterine growth restriction is defined as the pathologic inhibition of intrauterine fetal growth and the failure of the fetus to achieve its growth potential [3]. While the majority of such pregnancies will have a physiologically normal fetus that is simply small for gestational age (SGA), pathological fetal growth-restriction is a different category and the ability to differentiate such a condition from SGA is limited. A healthy fetus with estimated weight or birth weight below the 10th percentile according to population standards is commonly defined as SGA [5]. Pathological SGA is known as intrauterine growth restriction (IUGR) or fetal growth restriction (FGR). Fetal development is evaluated through comparison between estimated fetal weight or birth weight and references or standards for different gestational ages [6].Impaired fetal growth is seen in about 10% of pregnancies [ Why detecting intrauterine growth restriction?9]. IUGR is associated with increased fetal and neonatal mortality and morbidity, being linked to immediate perinatal adverse events  and also to adult pathologic conditions  [14]. Former studies showed that cerebral palsy was found to be 4-6 times more frequent in newborns below the 10th percentile compared to those between the 25th and the 75th percentile [15]. A strong association between FGR and stillbirth was also confirmed [16]. From the moment FGR was recognized as a cause of perinatal death, almost 50% of stillbirth were identified as FGR [17], resulting in a decrease of unexplained stillbirth from 67-70% to 15% [18]. Therefore, fetal growth impairment identification triggers a 4-time reduction in neonatal complications and death [14].  Fetal growth is known to be an important predictor of pregnancy outcome and reflects the interaction between physiological and pathological factors influencing the fetus [19]. In addition, the investigation of possible IUGR/FGR has the objective of an early detection and appropriate management that could lower the percentage of stillbirths and other perinatal complications, hoping that the identification of low risk fetuses would decrease the number of unnecessary surveillance [11].  In about 75% of the cases, IUGR remains unrecognized until birth and the diagnosis comes retrospectively, whereas in low-risk pregnancy the detection rate is about 15% [ IUGR: risk factors21]. The main factors assessed in clinical practice include: maternal factors , fetal factors , adnexal factors  [22]. The risk factors for IUGR comprise a wide range of conditions and their assessment should be seriously taken into account, as they are easy to perform and are routinely used during pregnancy [23]. Further diagnostic tests could have a better relevance in a selected high-risk population [24]. However, these clinical factors have shown a different impact for each individual case and their relevance, as effective screening tools have not been proved yet [25].  A positive history for risk factors of IUGR can raise the problem of an increased surveillance with the specific goal of an early detection of growth insufficiency [26]. For this purpose, biochemical serum markers, Doppler study of uterine arteries, placental volume and vascularization as well as first trimester growth pattern, were the object of study for IUGR/FGR assessment. As presented above, IUGR/FGR is linked to serious pregnancy complications and early assessment of the condition is a main topic of research today. Furthermore, preventive measures like administration of low dose aspirin showed efficacy in IUGR treatment if administered before the 16th week of gestation [ Serum markers linked to IUGR27]. The impaired spiral artery transformation is leading to weak development of the utero-placental circulation and is implied in the pathology of preeclampsia and IUGR [21]. The placentation process starts with the migration of trophoblastic cells that invade the walls of spiral arteries and transform them from small caliber high resistant vessels into wide caliber low resistant vessels that deliver blood at low pressure to the intervillous space. Then, the utero-placental circulation develops in two stages: the first stage (until the 10th week of gestation) consists in endovascular plugging of the spiral arteries by trophoblastic cells, subsequently followed by invasion and destruction of the intradecidual spiral arteries; the second stage (between 14-16 weeks of gestation) consists in the invasion of the inner miometrial part of the spiral arteries [21]. Several serum analytes have been studied in hope of finding a relevant marker linked to IUGR, but none of them proved to be sufficiently accurate to be used in routine clinical practice as single predictive marker. The combined approach using clinical data, serum markers, biophysical parameters  showed increased predictive relevance [28]. Maternal serum analytes were first studied with the aim of screening for aneuploidies during the first or second trimester of pregnancy and their use was then further extended in many studies to evaluate their utility as markers for impaired placentation. The trophoblastic invasion failure is thought to be responsible of the changes in the concentration of serum placental products [29]. Furthermore, in the group of 4390 women with singleton pregnancy evaluated by Spencer et al. in 2005 the maternal low levels of serum PAPP-A at 11-13 weeks of gestation resulted significantly associated to adverse pregnancy outcomes [30]. Low levels of PAPP-A were mentioned as predictors of IUGR also by Goetzinger et al. in 2009 and Poon et al. in 2009 . The sensitivity of detecting IUGR for a first trimester PAPP-A level below the 5th percentile ranges only between 8% and 33% and PAPP-A as single marker is an insufficient screening tool for IUGR [33].  Pregnancy associated plasma protein A (PAPP-A), an Insulin\u2013like Growth Factor Binding Protein Protease whose levels depend on placental volume and function, was assessed in several studies with congruent results. In 2000, Ong et al. evaluated 5584 singleton pregnancies at 10-14 weeks of gestation and measured maternal serum free beta human chorionic gonadotropin (\u03b2-hCG) and PAPP-A, concluding that low levels of maternal serum PAPP-A or \u03b2-hCG were associated with subsequent development of pregnancy complications [34]. Later, Gotzinger et al. showed that high levels of \u03b2-hCG were linked to SGA fetuses [31]. Overall, the predictivness of free \u03b2-hCG is unsatisfactory today [25]. Dugoff et al. evaluated 34271 pregnancies at 11-14 weeks of gestation and proved that maternal serum free \u03b2-hCG was mildly reduced in pregnancies that subsequently developed IUGR [36]. In 2008, in the name of the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada, Gagnon et al. reviewed the obstetrical outcomes associated with abnormal levels of single or multiple maternal serum markers used in the screening for aneuploidy. PAPP-A, alphafetoprotein, \u03b2-hCG, estriol, unconjugated estriol, inhibin-A were the analytes assessed and among the conclusions an unexplained low PAPP-A (< 0.4 MoM) and/or a low hCG (< 0.5 MoM) in first trimester were associated with an increased frequency of adverse obstetrical outcomes [37]. As in the first trimester biochemical screening starts as early as 8wa, the detection of a low level of hyperglycosylated human chorionic gonadotrophin correlated with a low PAPP-A and resulted a marker of impaired placentation, showing 90% specificity and 69% sensitivity when adjusted for mean arterial pressure and parity .41]. In 2007, Chaftez et al. showed that low levels of first trimester PP-13 were associated with preterm birth in women with IUGR [42]. In 2008, Spencer et al. found poor association between PP-13 and pregnancy outcome like IUGR [43]. In 2008, using the integrated assessment of PP-13, PAPP-A and uterine artery Doppler at 11-13 weeks of gestation, Poon et al. determined a 20% detection rate of FGR at a false positive rate of 5% [44]. Placental Protein 13 (PP-13) is a peptide involved in placental implantation and vascular invasion and remodeling [45]. Soluble fms\u2013like tyrosine kinase-1(sFlt-1) on the other hand, inhibits the effects of VEGF and PlGF by blocking their interaction with the specific receptors. The imbalance between the anti-angiogenic and angiogenic factors seems to be linked of preeclampsia and IUGR [45]. The recent meta-analysis performed by Conde-Agudela et al. in 2013 including 53 studies and 39974 women evaluated 37 new biomarkers among which: Angiogenesis-related biomarkers , Endothelial function/oxidative stress-related biomarkers ; Placental proteins/hormone-related biomarkers  and other markers like metabolomics and genetic biomarkers. Overall, none of the 37 novel biomarkers evaluated showed a significant accuracy for predicting IUGR [45]. Angiogenic factors implied in placentation like Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF) were also evaluated in many studies [ Ultrasound markers21]. The Doppler ultrasound sampling of uterine arteries (UAD) is a useful non-invasive method for the assessment of the interaction between fetal and maternal hemodynamic compartment. Starting from the early studies of Campbell et al. and Trudinger et al. in the 1980s, this procedure has been reported in numerous following surveys and showed to be a promising technique for the prediction of the IUGR risk [46-48]. In case of an incomplete trophoblastic invasion of the spiral arteries, the maternal compartment failsed to transform from a high resistance to a low resistance flow district and this impairment is associated with the development of preeclampsia and IUGR. In these cases, a Resistence Index (RI) or a Pulsatility Index (PI) above the 90th-95th percentile and/or the presence of unilateral or bilateral notching is associated with a value of the RI >0,58 or a value of the PI >1,45 [49]. Therefore, in 1994 North et al. and in 1998 Irion et al. stated that UAD was not a reliable screening test for nulliparous women [51]. Further studies performed in the 2000s have evaluated UAD between 10-14 weeks of gestation finding low positive predictive values for IUGR and a slightly better prediction value for preeclampsia with IUGR or IUGR alone with delivery in less than 32 weeks [55]. Most of the studies published to date, disregarding if performed during the first or second trimester, agree that UAD modifications are linked to IUGR but are not a reliable single predictive marker for defining a low risk category [56]. An interesting approach proposed by Gomez et al. in 2006 showed that the sequence of changes in the uterine flow between the first and second trimester correlates with subsequent appearance of IUGR and the highest risk is held by women with persistent low vascular indices [54].  The early studies that assessed UAD were performed during the second trimester of gestation, between weeks 18-23 [49-54]. Although an increased resistance in the uterine arteries is associated with poor obstetric outcome like preeclampsia, IUGR or prematurity, the positive predictive value was found to be only 15% for IUGR [57]. Hung et al. evaluated color and spectral Doppler of the spiral arteries between 13-19 weeks and 20-25 weeks concluding that spiral artery Doppler assessment was not a sensitive tool for detection of IUGR in a low risk population [58]. Furthermore, in studies comparing normal outcome pregnancies versus complicated pregnancies, spiral arteries sampling failed to show any statistically significant predictive value, making spiral arteries Doppler study an insufficient method for screening of IUGR [59].Spiral arteries have been subjected to assessment during the first trimester. M\u00e4kikallio et al. found that spiral arteries impedance decreased starting with the 5th week of gestation and uterine and arcuate artery lost their tonus starting with the 8th week .62]. In a region of interest, three indices are mostly calculated and used: Vascularization Index (VI): the ratio between color vessels and total vessels , representing the percentage of blood vessels in a region of interest; the Flow Index (FI): the sum of a color vessel\u2019s signal intensity divided by the number of color vessels, representing the amount of blood corpuscles in the vessels in a region of interest; the Vascularization Flow Index (VFI): the ratio between the sum of the color vessel\u2019s signal intensity and the total tissue vessels, representing the total number of blood corpuscles in the total tissue volume. In 2004, Merce et al. showed that the 3D-Power Doppler study of the placental vascularization in normal pregnancies is reproducible and seems to be a useful tool in performing \u201ca placental biopsy\" [63]. In 2008, Guiot et al. used this technique in the assessment of the 3rd trimester pregnancies complicated with IUGR and compared them to normal pregnancies, correlating VI, VFI and FI values to Umbilical Artery Doppler abnormalities (elevated Systolic/Diastolic ratios and absent End Diastolic Velocity), and the results showed that modifications in vascularization indices could be detected earlier than Umbilical Artery Doppler abnormalities [64]. In 2009, Noguchi et al. performed \u201cplacental vascular sonobiopsies\" starting with the second trimester, comparing normal and growth restricted pregnancies and proving the differences in vasculature [65]. Against these evidences, in vitro phantom studies performed by Raine-Fenning et al. and Schulten-Wijman et al. in 2008 questioned the technical and methodological aspects of this procedure, doubting the reproducibility\u00ac\u00ac\u00ac\u00ac [67]. On the other side, the sheep model study conducted by Olivier Morel et al. in 2010 demonstrated a good correlation between true uterine blood flow and flow parameters, as well as a good reproducibility of the technique [68]. The introduction of Virtual Organ Computer\u2013Aided Analysis software (VOCAL) proved useful in the quantification of blood vessel volume and of the flow in an acquired volume [69]. Another way of determining early fetal growth was proposed by Hafner et al. who compared Placental Quotient (PQ) [Placental Volume / Crown Rump Length] assessed during the first trimester with Uterine Artery Doppler at 22 weeks and concluded that PQ has low sensitivity in diagnosis of IUGR in low-risk population, comparable with that of Uterine Artery Doppler, but has the advantage of possible first trimester assessment [70]. In 2013, these authors refined their research showing that Placental Bed Vascularization Index assessed by 3D Power Doppler could be used for a quick and reliable first trimester assessment of severe pregnancy risks because it shows a 66,2% detection rate for severe pregnancy complications, higher than the 50% sensitivity of second trimester Uterine Artery Doppler [71].  In regard to placental volume assessment Rizzo et al. showed in 2009 that first trimester evaluation of placentas in a high risk group with low PAPP-A proved a good correlation between reduced placental volume and low fetus weight (<10th percentile) with Umbilical Artery Doppler modifications [ The multiparameter approach21]. The combined approach reflects various pathological pathways: Doppler ultrasound of the uterine arteries shows inadequate invasion of the spiral arteries and impaired secretory placental function is reflected by the disturbances of biomarker levels [72]. Preeclampsia is associated with IUGR and models of prediction by combining ultrasound assessment of uterine arteries, biochemical markers and maternal history were published concerning the assessment of both conditions, but the need for the development of a model for prediction of SGA without preeclampsia emerged [74]. With the purpose of identifying SGA fetuses not related to preeclampsia, Karagiannis et al. used a model of prediction containing Uterine Artery Doppler Pulsatility Index at 11-13 weeks of gestation, Mean Arterial Pressure, maternal serum PAPP-A, free \u03b2-hCG, Placental Growth Factor, PP-13, ADAM-12 and Fetal Nuchal Translucency. Although the study did not distinguish between the constitutional and pathological SGA, it raised the problem of increased surveillance for the whole population at risk for SGA, improving perinatal outcome by individualized management in late-second trimester and third trimester. The study also proved a good detection rate for SGA of 73% for those requiring delivery before 37 weeks and of 46% for those requiring delivery after 37 weeks [28]. Investigators tried to improve the prediction of IUGR by combining Doppler indices with biochemical and clinical parameters due to the insufficient predictive value of each marker alone [26]. A thorough history should be taken to all pregnant women at the first antenatal visit because risk factors determination results are easy and inexpensive. Different single approaches in the screening of this condition have been proposed but did not show sufficient sensitivity, therefore, combined models are proposed with the goal of a better predictive value. Large-scale prospective studies are required to prove the power of such integrated approaches in clinical practice.Although it is a public health problem with around 10% incidence in the pregnancy population, FGR is still a matter of debate starting from the definition, the multifactorial origin, the low levels of prediction, the questionable references like customized or uncustomized growth charts, and the methods of diagnosis and management. The main trajectory of research is towards the first trimester diagnosis, as the optimal interval in which a prophylactic treatment would influence placentation ends in the 16th week ["}
+{"text": "However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial  Amyotrophic lateral sclerosis (ALS) is a fatal paralyzing disease characterized by the selective degeneration of motor neurons in the spinal cord, brain stem and motor cortex. The majority (\u223c90%) of ALS cases are sporadic whereas some 10% of patients have dominantly inherited familial ALS (FALS). However, the forms share clinical features. The suggested causative factors for the motor neuron degeneration include oxidative stress, neuroimmune reactions, protein aggregation  are products of normal oxygen metabolism in cells  as superoxide and hydrogen peroxide  which is a highly reactive oxidant  mitochondria. Further in vivo studies revealed that mutSOD1 in spinal cords of G93A SOD1 rodents is destabilized and bound to the inner mitochondrial membrane  which oxidizes it to Ot Figure . Cells lA substantial proportion of SOD1 is found in the mitochondria  which all have a role in mitochondrial import and accumulation (Kawamata and Manfredi, A mitochondrial import mechanism for SOD1 independent of CCS has been described in yeast (Varabyova et al., For maturing into an active enzyme, SOD1 requires three post-translational modifications: the insertions of zinc and copper, intramolecular disulfide bond formation, and dimerization. Zinc is deposited close to the active site stabilizing the structure (Potter et al., Full activation of human SOD1 requires CCS (Wong et al., in vitro (Tiwari and Hayward, in vivo studies did not assess the localization of reduced mutSOD1, one could expect that it would be accessible to mitochondria where a part of that pool could be oxidized. In cell culture, oxidation of Cys111 residues led to accumulation of several SOD1 mutants in mitochondria (Ferri et al., In ALS, mutSOD1 is recruited to mitochondria especially in the spinal cord (Higgins et al., Furukawa and O\u2019Halloran  suggestein vitro (Rodriguez et al., Most forms of mutSOD1 show instability 2O2 (He et al., The IMS-located SOD1 has been suggested to be inactive in the intact mitochondria and activated through oxidative modification of its critical thiol groups by yet poorly known mechanisms (I\u00f1arrea et al., Insertion of copper is required for the activity of SOD1 and altered copper homeostasis is a common feature in mutSOD1 mice (Tokuda et al., in vivo, suggesting that formation of heterodimers may be physiologically relevant in FALS patients as well. It has been proposed that the heterodimers comprise a pool of more soluble and more toxic SOD1 whereas homodimers form less toxic aggregates (Weichert et al., 2O2 production is not known and warrants further elucidation. In the model proposed (Figure 2O2 leads to cytC catalyzed peroxidation and mitochondrial damage.In addition to proper folding and metal acquisition, dimerization is critical for dismutase activity. Mutant and wtSOD1 are able to form either homo- or heterodimers both in animal and cell culture models (Furukawa et al., Under physiological conditions SOD activity in IMS is suppressed by redox state control. However, upon mitochondrial stress SOD1 may undergo oxidative activation and compete with cytochrome C for superoxide released in the IMS, leading to increased ROS production. In ALS, mutSOD1 accumulates in IMS, thus contributing to the misregulation of dismutase activity. The presence of endogenous wt enzyme may provide dismutase activity to inactive mutant by heterodimerization. Here we propose that aberrant regulation of dismutase activity in IMS as a major mechanism for the toxicity should be further evaluated in future studies. Furthermore, the possible involvement of mitochondrial IMS dismutase activity misregulation in sporadic ALS warrants careful assessment.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Neisseria meningitidis serogroup X isolates from sub-Saharan Africa and Europe showed that serogroup X emergence in sub-Saharan Africa resulted from expansion of particular variants within clonal complex 181. Virulence of these isolates in experimental mouse models was high.The epidemiology of meningococcal disease varies by geography and time. Whole-genome sequencing of  Neisseria meningitidis, varies substantially by geography and time. The disease can occur as sporadic cases, outbreaks, and large epidemics. Most cases occur in what has been termed the \u201cmeningitis belt\u201d in sub-Saharan Africa, where the World Health Organization estimated that 12,464 suspected cases occurred during the 2013 meningitis season and that 1,131 were fatal  . Molecular typing of meningococci has used multilocus sequence typing (MLST) to determine CCs on the basis of the polymorphism of 7 housekeeping genes  , which runs on the Bacterial Isolate Genome Sequence Database (BIGSdb) platform  from culture grown overnight on gonococcal medium base agar plates with Kellogg supplements . Among genes involved in iron acquisition, the isolates from Africa, unlike those from France, lacked the carriage , panel BluxCDABE operon expressed by the PporB meningococcal promoter  but differed in LNP13407 (obtained in the 1990s), and we detected 23 genes for which alleles were identical in all isolates obtained since 2006 and in LNP13407 but differed in LNP14354 . fHbp (encodes factor H binding protein), lpt3 (encodes the phosphoethanolamine transferase), and lot3 . All serogroup X isolates obtained since the outbreak of 2006 (including those from the BIGSdb platform) harbored the lpt3 allele 45, which differs from allele 136 by the deletion of 2 codons (encoding Glu-211 and Ser-222 residues). These isolates do not react with the monoclonal antibody that recognizes immunotype L3,7,9 on the lipooligosaccharide (Most of these 41 genes encode hypothetical proteins; several encode proteins that are involved in meningococcal survival in the blood , panel CN. meningitidis serogroup X isolates in the meningitis belt of Africa supports the emergence of virulent serogroup X isolates and the belief that CC181 may be considered a hyperinvasive genetic lineage of meningococci. The occurrence of the periodic epidemic waves may be caused by the emergence and spread of successive new clones of meningococci with enhanced virulence and an ability to escape population immunity. Our data underline the need for whole-genome sequencing for reliable tracking of meningococcal isolates and emphasizes the need for an effective vaccine against serogroup X (The extensive characterization of"}
+{"text": "In There are errors in Notes: GDPpc: Gross Domestic Product per capita; QALYs: Quality Adjusted Life Years. Notes: These five countries were selected to reflect the range of results obtained in the incremental cost-effectiveness ratios (ICERs) in the 30 Latin American and Caribbean countries analysed . Each point represents 1 of the 1000 simulated ICERs in the probabilistic sensitivity analysis for each country. Probabilities of being Cost-Saving, or Cost-Effective at 1 and 3 GDPpc for all countries can be seen in"}
+{"text": "It is imperative for staff involved in clinical trials to receive appropriate education and training relating to their particular roles to be able to fulfil GCP requirements and ensure successful trial conduct . However, little is known about the ways training is being provided to trial staff.To investigate and summarize training methods currently used in RCTs of health-care interventions.A systematic review was undertaken to identify articles reporting methods and practices of staff training within RCTs. A set of codes was used for the systematic organisation of extracted data.7471 records were screened and 89 studies were identified; 78 (88%) focused on training in an individual RCT and 11 (12%) were network-based. Studies were mainly conducted in USA (55%) and internationally (27%). Most were multi-centre (94%) and funded by non-commercial funders (70%). Different combinations of live (face-to-face and remote) and recorded (text-based and multimedia) training methods were used. Training was mainly provided at a group-level (51%), by trainers from the research team (65%). Intervention delivery/fidelity (49%), protocol and trial-related procedures (39%), trial data (36%), patient recruitment (31%) and outcome assessment (18%) were the top five training objectives. Evaluation information was present in 88% of studies, however, a detailed evaluation was only given in 12% of them. Information on the cost of training was only reported in 4.5% of studies.There is substantial variability in the reported training process across RCTs of various intervention types, disease areas and sample sizes."}
+{"text": "There is an error in affiliation #3 for authors Xiaofan Guo and Hongning Zhou. Affiliation #3 should be: Yunnan Provincial Key Laboratory of Vector-borne Diseases Control and Research (in establishment) of Yunnan Institute of Parasitic Diseases."}
+{"text": "Pinus koraiensis mixed forest, the responses of composition and structure of Pinus koraiensis mixed forests to climatic changes are unknown and the key climatic factors controlling the composition and structure of Pinus koraiensis mixed forest are uncertain.Although some studies have indicated that climate changes can affect Pinus koraiensis mixed forests along a latitudinal gradient and an elevational gradient in Northeast China. In order to build the mathematical models for simulating the relationships of compositional and structural attributes of the Pinus koraiensis mixed forest with climatic and non-climatic factors, stepwise linear regression analyses were performed, incorporating 14 dependent variables and the linear and quadratic components of 9 factors. All the selected new models were computed under the +2\u00b0C and +10% precipitation and +4\u00b0C and +10% precipitation scenarios. The Max Temperature of Warmest Month, Mean Temperature of Warmest Quarter and Precipitation of Wettest Month were observed to be key climatic factors controlling the stand densities and total basal areas of Pinus koraiensis mixed forest. Increased summer temperatures and precipitations strongly enhanced the stand densities and total basal areas of broadleaf trees but had little effect on Pinus koraiensis under the +2\u00b0C and +10% precipitation scenario and +4\u00b0C and +10% precipitation scenario.Field survey was conducted in the natural Pinus koraiensis mixed forest. Although the Pinus koraiensis would persist, the current forests dominated by Pinus koraiensis in the region would all shift and become broadleaf-dominated forests due to the dramatic increase of broadleaf trees under the future global warming and increased precipitation.These results show that the Max Temperature of Warmest Month, Mean Temperature of Warmest Quarter and Precipitation of Wettest Month are key climatic factors which shape the composition and structure of  Pinus koraiensis is a pine species endemic to the region including East Russia, Korea, Japan and Northeast China Pinus koraiensis - broadleaf mixed forest is one of the major vegetation types and the typical conifer - broadleaf mixed forest and plays important role in carbon cycling in Northeast China Pinus koraiensis patches and the expansion of some broadleaf tree species from 1986 to 1994, and indicated that the reason for the shrinkage of Pinus koraiensis patches and the expansion of some broadleaf tree species might be the effects of climate change Pinus koraiensis or its mixed forest Pinus koraiensis would shift Northward under the HadCM2 climatic change scenario and under the average of another five climatic change scenarios  Pinus koraiensis to become broadleaf forests in Changbai Natural Reserve of Northeast China under the CGCM2 climate change scenario Pinus koraiensis mixed forest are uncertain.A field study of the North East China Transect (NECT) has observed the shrinkage of Pinus contorta and Pinus sylvestrisPinus koraiensis reflects the stand age of a Pinus koraiensis mixed forest, because the mean diameter of Pinus koraiensis in a stand naturally increases over time Linear or quadratic regression models can be built to simulate the relationships of compositional and structural attributes of plant communities with climatic and non-climatic factors, and such studies have been conducted in grasses, tropical trees, According to the recent CMIP5 (phase five of the Coupled Model Inter-comparison Project) climate change scenarios, the global temperature averaged in 2081\u20132100 is projected to likely exceed 2\u00b0C (RCP6.0 and RCP8.5 emission scenarios) above 1850\u20131900; although unlikely to exceed 4\u00b0C in all other RCP emission scenarios than RCP8.5 Pinus koraiensis mixed forests to spatial climatic changes, a field survey was conducted in the natural Pinus koraiensis mixed forests along a latitudinal gradient and an elevational gradient in Northeast China. The mathematical models were built for simulating the relationships of compositional and structural attributes of the Pinus koraiensis mixed forest with climatic and non-climatic factors, and two scenarios of the +2\u00b0C and +10% precipitation and +4\u00b0C and +10% precipitation were used to predict the possible changes of composition and structure in Pinus koraiensis mixed forests under the future global climatic change. The objectives of this study are to: (1) build mathematical models to quantify the responses of the composition and structure of Pinus koraiensis mixed forests to the climatic factors; (2) discover the key climatic factors which control the composition and structure of Pinus koraiensis mixed forest. Additionally, we hypothesized that the composition and structure of Pinus koraiensis mixed forests would significantly be affected and Pinus koraiensis mixed forests would be overtaken by broadleaf-dominated forests in the region under the future global warming and increased precipitation.To examine the responses of composition of and structure of All necessary permits were obtained for the described field studies. This study was approved by State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, the Chinese Academy of Sciences; Shengshan National Nature Reserve; Liangshui National Nature Reserve; Dongsheng Forestry Bureau; Changbai National Nature Reserve and Kuandian National Nature Reserve.Pinus koraiensis mixed forests without recent disturbance. All the broadleaved trees are deciduous and most of the conifers are evergreen (except for Larix) in the study region. From June to August is the warmest quarter (summer) and January is the coldest month of the year in the study region. Rainy season begins at May or June and ends at September, and the summer (from June to August) precipitation occupies 60% of annual precipitation This study was conducted in the Augusts of 2010 and 2012 in Northeast China, including ten sites: Kuandian, Dongsheng, Liangshui, Shengshan and Changbai from A to F . The forIn each plot, every living tree higher than 1.4 m was identified to species and then measured for its circumference with a tape measure at its breast height (1.3 m). The measured circumference of each tree was converted into its diameter at breast height (DBH) and calculated into its basal area using the circle formulas.Pinus koraiensis mixed forest were extracted from each plot. The fifteen attributes were: Mean DBH of Pinus koraiensis (MeanDBHPinus), Total Basal Area of Pinus koraiensis , Stand Density of Pinus koraiensis (StandDensityPinus), Total Basal Area of Acer and Fraxinus , Stand Density of Acer and Fraxinus (StandDensityAcer-Fraxinus), Total Basal Area of Quercus , Stand Density of Quercus (StandDensityQuercus), Total Basal Area of Abies and Picea , Stand Density of Abies and Picea (StandDensityAbies-Picea), Total Basal Area of Larix , Stand Density of Larix (StandDensityLarix), Total Basal Area of Ulmus , Stand Density of Ulmus (StandDensityUlmus), Total Basal Area of Betula  and Stand Density of Betula (StandDensityBetula) (Fifteen attributes of yBetula) .One-way ANOVA and correlation and regression analyses were performed using SPSS 13.0. Standard errors within sites were detected by one-way ANOVA with descriptive options. Significant differences (p<0.05) between sites were detected using One-way ANOVA with post-Duncan's test.Pinus koraiensis mixed forest. The independent factors used in the regressions were linear and quadratic components of Max Temperature of Warmest Month (TempWarmestMonth), Min Temperature of Coldest Month (TempColdestMonth), Mean Temperature of Warmest Quarter (TempWarmestQuarter), Mean Temperature of Coldest Quarter (TempColdestQuarter), Precipitation of Wettest Month (PrecipWettestMonth), Precipitation of Driest Month (PrecipDriestMonth), Precipitation of Wettest Quarter (PrecipWettestQuarter), Precipitation of Driest Quarter (PrecipDriestQuarter) and MeanDBHPinus. The 14 dependent variables were BasalAreaPinus, StandDensityPinus, BasalAreaAcer-Fraxinus, StandDensityAcer-Fraxinus, BasalAreaQuercus, StandDensityQuercus, BasalAreaAbies-Picea, StandDensityAbies-Picea, BasalAreaLarix, StandDensityLarix, BasalAreaUlmus, StandDensityUlmus, BasalAreaBetula and StandDensityBetula  included in its regression model.Pinus values under current climate, under the +2\u00b0C and +10% precipitation scenario and under the +4\u00b0C and +10% precipitation scenario. In order to examine the concordances between the simulated and observed values under current climate, scatter plots with simple error bars and regressions were generated using Sigmaplot 10.0. To represent the variations of stand densities and basal areas of Pinus koraiensis, other conifers and broadleaves under current climate under the +2\u00b0C and +10% precipitation scenario and under the +4\u00b0C and +10% precipitation scenario, vertical bar charts with error bars were generated using Sigmaplot 10.0.The selected models were computed using the currently observed MeanDBHPinus koraiensis mixed forest    were predicted to be zero  firstly increased and then decreased with increasing latitude, while the stand density of broadleaved trees decreased with increasing latitude and altitude , while Acer and Fraxinus and Pinus koraiensis serve as late successional species during the succession of Pinus koraiensis mixed forest Pinus (which represents the stand age of a Pinus koraiensis forest) Pinus and BasalAreaAcer-Fraxinus, suggesting that Pinus koraiensis and Acer and Fraxinus are late successional species and naturally increase in their total basal areas over time. However, negative relationship existed between MeanDBHPinus and StandDensityPinus when MeanDBHPinus was below 47.6 cm  Pinus koraiensis but the negative effects of summer temperatures on other conifers (Abies and/or Picea and Larix) and the positive effects of summer temperatures on some broadleaved trees (Acer and/or Fraxinus and Quercus) were observed (Pinus koraiensis trees compared with other conifer trees (Abies and/or Picea and Larix); (2) increased summer (growing-season) temperatures may enhance the growths of many broadleaved trees (Acer and/or Fraxinus and Quercus).Climate warming has positive and negative effects on plants. Prolonged growing seasons and increased growing-season temperatures have been found to enhance the growth of some plants, especially the growth of many deciduous broadleaved trees observed . Our resPinus koraiensis were observed (Pinus koraiensis populations. We suggest that the Pinus koraiensis in the region may not necessarily maintain itself under the +2\u00b0C and +10% precipitation and +4\u00b0C and +10% precipitation scenarios if proper migrations of local populations do not occur in time.A wide-ranged pine species is usually composed of many genetically-different local populations. Each local population has evolved to adapt to its local climate, and has its unique response curve to climate change observed , and thePinus koraiensis within 150 years in current Pinus koraiensis mixed forest under climate warming scenarios Pinus koraiensis could persist for at least 300 years under the warming climate Pinus koraiensis would persist, while the broadleaf trees would overtake Pinus koraiensis to become dominant species under either of the two warming scenarios (Studies using a forest gap model alone usually predicted the extinction of cenarios .Pinus koraiensis mixed forests to the climatic factors. TempWarmestMonth, TempWarmestQuarter and PrecipWettestMonth strongly affected the stand densities and total basal areas in Pinus koraiensis mixed forest and therefore they are suggested to be key climatic factors which shape the composition and structure of Pinus koraiensis mixed forest. The composition and structure of Pinus koraiensis mixed forests were significantly affected, and although Pinus koraiensis would persist, the current forests dominated by Pinus koraiensis in the region would all shift and become broadleaf-dominated forests due to the dramatic increase of broadleaf trees under the future global warming and increased precipitations.These results show that some mathematical models were successfully built to quantify the responses of the composition and structure of"}
+{"text": "Magnetic Resonance Imaging of the Small Bowel  is becoming increasingly popular as the first imaging modality for the diagnosis and follow-up of small bowel diseases. The aim of this work was to evaluate the role of recent MRI sequences and techniques in evaluation of small bowel disease.The study population included 24 patients who were referred to multiple radiology centers by gastroenterologist for magnetic resonance enterography (MRE) for evaluation. The examination was done on 1.5 Tesla superconducting magnet MRI.All studied patients had small bowel lesions. 15 patients were neoplastic (64%) and 9 patients were inflammatory (36%). Among 15 cases of small-bowel neoplasm; 12 were malignant; and 3 were benign. The malignant cases were classified as follows; lymphoma (6 patients); adenocarcinoma (4 patients); GIST (1 patients) and carcinoid tumour(1 patient). Nine patients out of 24 had inflammatory bowel diseases. Eight cases out of 9 proved to be specific inflammatory disease and 1 chronic non specific ileocolitis. Seven cases out of 8 proved to be Crohn\u2019s disease and 1 proved pathologically to be TB of small bowel. The final diagnosis was confirmed by surgical or endoscopic data and follow up.MRE is accurate non-invasive modalities in assessing the intra-luminal, parietal and extra-luminal small bowel tumour without the need for ionizing radiation. MR signal appearances of the lesions, combined with the contrast enhancement behavior and the characteristic of the stenosis, can help in differentiating neoplastic from other non-neoplastic diseases of small bowel."}
+{"text": "The presence of joint inflammation in juvenile idiopathic arthritis (JIA) patients can be made by physical examination and confirmed by imaging. The discrepancy between physical examination and MRI for evaluation of synovitis in a target joint is possibly explained by the fact that clinical measures mostly reflect overall disease activity instead of measures specific for the joint imaged by MRI.To compare clinical disease activity of the major target joint upon physical examination with a validated MRI score for the knee in JIA.MRI datasets and corresponding clinical parameters of disease activity of the knee were analyzed in 167 JIA patients . Local physical examination of the knee included absence or presence of swelling, warmth, pain or limitation-of-motion (LOM) as assessed by experienced pediatric rheumatologists. A blinded radiologist (6 years of experience in MRI in JIA) analyzed synovial hypertrophy (SH) on a scale from 0-12 on all MRI datasets following the validated Juvenile Arthritis MRI Scoring system (JAMRIS). SH was \u2018present\u2019 when the total JAMRIS score was >2. Diagnostic accuracy of the local physical examination parameters for detection of arthritis was determined with MRI as reference standard.Sensitivity and specificity of the parameters scored by local physical examination compared with MRI varied from 39-71%. The overall positive predictive value for synovitis was very low (21-28%), while the negative predictive value was relatively good (71-74%). Median time between the clinical assessment and the MRI was 38 days (IQR 28-53 days). Subgroup analysis on 51 patients with <31 days (median 25 days) between clinical assessment and MRI did not improve the diagnostic accuracy.The presence of swelling, warmth, pain or LOM on physical examination did not predict the presence of synovitis upon MRI. The time between clinical assessment and MRI appeared to have no influence on the diagnostic accuracy of the physical examination inflammation parameters. While the discrepancy between physical examination and MRI persists, follow-up studies are warranted to unravel the difficulties in assessment of disease activity.None declared."}
+{"text": "For multimodal pain therapy (MPT), a bio-psycho-social therapy approach for patients suffering from chronic pain, a core outcome set (COS) is currently lacking. Following the recommendations from initiatives such as Outcome Measures in Rheumatology (OMERACT) and Harmonizing Outcome Measures for Eczema (HOME), the study \u201cValidation and Application of a patient relevant core set of outcome domains to assess multimodal PAIN therapy\u201d (VAPAIN) aims to develop an accepted and valid COS for MPT.An online survey consisting of two rounds was conducted using the mOMEnt software provided by the COMET initiative. 25 stakeholders in MPT  were nominated by their associations and asked to participate. During both rounds, participants were asked to rate the importance of proposed domains regarding a) effectiveness trials (ES) and b) daily record keeping (DRK). Domains to be rated were identified through a systematic review of reported outcomes in MPT studies. During round 1, survey participants were allowed to name additionally relevant outcomes and were asked to name the number of minimal/maximal number of outcome domains to be included in the COS. During round 2 participants received feedback regarding their own previous ratings and also regarding ratings from other participants had to name which outcomes should be included in the COS.All participants completed round 1, but only 22 round 2 (88% response rate). The maximal and minimal number of outcome domains to be included in the COS ES was 9 and 4, and for the COS DRK 6 and 3. Pain intensity/severity (18/22), health-related quality of life (17/22), and pain-related disability (11/22) was named most frequently by the survey participants as being part of the COS for ES. Pain intensity (15/22), psychological distress (9/22) and both analgesic medication intake and pain-related disability (7/22) were named for the COS DRK.The results of this online survey regarding outcomes in studies evaluating MPT are mostly in line with the results from the preceding systematic review on outcome domains. Furthermore, the domains for the COS for effectiveness trials and daily record keeping were not fundamentally different. The identified preliminary outcome domains will be consented during a face-to-face meeting (consensus conference) in a moderated group discussion to determine a COS for MPT."}
+{"text": "Rationale. Visual impairment is one of the most common clinical manifestations of multiple sclerosis (MS). Some multiple sclerosis patients complain of poor vision although the Snellen visual acuity is 20/20. This study reveals that sensitive measurements like visual evoked potential (VEP) and optical coherence tomography (OCT) can evidence subclinical disturbances of visual pathway. These methods examine the relation between the visual function (VEP) and retinal nerve fiber layer (RNFL) thickness, as a structural biomarker for axonal loss in patients with multiple sclerosis (MS). The findings in this study indicate the utility of combining structural and functional testing in clinical research on patients with MS.Purpose. To detect visual impairment in a population of visually asymptomatic patients affected by clinically definite multiple sclerosis (MS) and to compare the utility of optical coherence tomography (OCT) versus visual evoked potentials (VEP).Material and methods. Fourteen patients (28 eyes) affected by clinically definite MS, without a history of optic neuritis and asymptomatic for visual disturbances, were initially fully examined  from an ophthalmic point of view and then measured by OCT (RNFL thickness) and VEP.Patients with a history of glaucoma or other retinal or optic nerve disease were excluded.Results. Of fourteen patients (28 eyes), VEP was abnormal in 11 cases  and OCT (RNFL thickness) was abnormal in 5 cases , while 3 patients had no abnormalities on neither tests.Conclusions. Optical coherence tomography (OCT) is less sensitive than visual evoked potentials (VEPs) in detecting visual subclinical impairment in patients with multiple sclerosis (MS). VEP remains the preferred test for the detection of clinical and subclinical optic neuritis. OCT may provide complementary information to VEP in cases with clinical definite MS and represent a valuable research instrument for the study of optic nerve disease in populations. The findings in this study reveal the utility of combining structural and functional testing in clinical research on patients with MS.Abbreviations: multiple sclerosis = MS, optical coherence tomography = OCT, visual evoked potential = VEP, retinal nerve fiber layer = RNFL, best corrected visual acuity = BCVA. Just over a decade ago, MS clinical trials did not include visual outcomes, but experts recognized the need for more sensitive measures of visual function . Optical coherence tomography is used to monitor retinal ganglion cell axon loss in glaucoma, diabetic retinopathy, traumatic optic neuropathy, chiasmal lesions and optic neuritis [4-8]. Recently, OCT has been studied in patients with multiple sclerosis (MS). Two studies showed that the eyes without a history of optic neuritis among MS patients have decreased RNFL thickness compared with the eyes of control subjects, suggesting that retinal ganglion cell axonal loss occurs separately from acute optic neuritis in MS patients .Optical coherence tomography (OCT) is a noninvasive high-resolution technique that uses near-infrared light to generate cross-sectional tomographic images of tissues, including the retinal nerve fiber layer (RNFL) .This suggests that OCT can be used to monitor axonal injury and visual dysfunction in MS and may be an useful outcome measure in clinical trials [15]. In this study, we compared OCT versus VEP in the detection of visual dysfunctions in a population of visually asymptomatic patients with clinically definite MS.The alteration in visual evoked potential (VEP) latencies by using pattern stimuli is considered one of the most characteristic electrophysiological signs observed in patients with MS .The retinal nerve fiber layer (RNFL) measurements were obtained after 3 consecutive scans centered on the optic nerve head. OCT software Cirrus, Carl Zeiss Meditec generated a mean RNFL thickness measurement for 360 degrees around the optic disc, four retinal quadrants and 12 clock for our segment (30 degrees for each hour position). All scans were performed without pupil dilatation [VEPs were elicited by checkerboards reversing at 2 Hz  on a television monitor located 1 m from the patient.15].VEP measurements were obtained with the patient wearing a visual aid, if needed and the fellow eye was occluded. A fixation spot was used on the center of the screen during stimulation. The latency of the first major positive peak in the VEP (P100 wave) was measured. Most investigators currently interpreted pattern reversal VEP based almost entirely on the latency of P100. A P100 latency >115ms was considered abnormal .Multiple sclerosis is a progressive disease in which subclinical RNFL thinning may occur, even in patients who have not been clinically diagnosed with optic neuritis [20]. Visual evoked potentials (VEP) remain the preferred test for the detection of clinical and subclinical optic neuritis [1].The alteration of the visual evoked potential (VEP) latencies during pattern stimulation is considered one of the most characteristic electrophysiological signs in patients with MS, visually affected or unaffected [20].The study showed that in patients affected by MS with no history of optic neuritis and no visual symptoms, there is a large prevalence of visual pathway involvement [2]. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye [1].Clinically, it will be helpful to establish the baseline RNFL thickness and functional measurements in all MS patients at the time of the MS diagnosis. Change in RNFL thickness and/or visual function over time is likely the best approach in monitoring the disease progression [3].Based on OCT studies in MS, RNFL thickness is reduced significantly among patients (92 \u00b5m) versus controls (105 \u00b5m) and is particularly reduced in MS eyes with a history of optic neuritis (85 \u00b5m) [3].Combining information from structural and functional tests and following individuals longitudinally is probably the best strategy for assessing and monitoring the optic nerve involvement in patients with MS [4]. Imaging the RNFL allows a direct measurement of the unmyelinated axons of the central nervous system. The capacity to image central nervous system axons quickly and noninvasively, to minimize expense, and to correlate structural abnormalities with visual dysfunction add to the appeal of OCT as an imaging biomarker and outcome measure in clinical trials .The validation of OCT as an imaging biomarker in MS is important because several aspects of the information it generates are unique [The important correlation between the functional and anatomic aspect confirms the value of VEP and OCT to appreciate the subclinical involvement of the optic nerve."}
+{"text": "The management of Adhesive Capsulitis(AC) is controversal. Both capsular distension after intraarticular injection and mobilization therapy are known as highly effective treatment of painful and limited shoulder joint. The aim of this study was to determine the synergistic effect of intensive mobilization technique combined with capsular distension for patients with adhesive capsulitis in improving shoulder ROM, pain and function.A total of 28 subjects suffering from AC were randomized into two groups. Group A received fluoroscopically guided capsular distension with steroid injection followed by intensive mobilization technique twice per week for 4 weeks and group B only received capsular distension with steroid injection.Patients were assessed using the Shoulder Pain and Disability Index (SPADI), Constant-Murley Shoulder Function Assessment Score (CS), Active Range of Motion(AROM) and Verbal Numeric Score(VNS). All measurements were obtained before injection and mobilization and 4 weeks after the procedures in order to compare with effects of the treatments.All measured value was significantly difference in group A and B(P<.05). Only external rotation ROM was not significantly difference in group B. The statistical differences were observed between group A and B in SPADI, CS, AROM and VNS (P<.01).Treatment using steroid injection with distension followed by intensive mobilization technique is recommended rather than injection treatment alone for the treatment of AC. In order to maximize the effectiveness of the two treatments further studies for optimal mobilization techniques will be needed."}
+{"text": "Therefore, the current study demonstrated importance of mechanical factor in stem cell differentiation and showed promising protection of brain from HI injury using ELCs treatment.Neonatal hypoxic-ischemic (HI) brain injuries disrupt the integrity of neurovascular structure and lead to lifelong neurological deficit. The devastating damage can be ameliorated by preserving the endothelial network, but the source for therapeutic cells is limited. We aim to evaluate the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from adipose-derived stem cells (ASCs) and the possible intracellular signals to protect HI injury using cell-based therapy in the neonatal rats. The ASCs expressed early endothelial markers after biochemical stimulation of endothelial growth medium. The ELCs with full endothelial characteristics were accomplished after a subsequential shear stress application for 24 hours. When comparing the therapeutic potential of ASCs and ELCs, the ELCs treatment significantly reduced the infarction area and preserved neurovascular architecture in HI injured brain. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) was important for ELC migration and following  Hypoxic and ischemic (HI) brain injuries which result from lacking of oxygen or blood supply lead to permanent neuron damage and neurological deficit. During birth, HI insults in developing brain, such as asphyxia and ischemic stroke, are the leading cause of neonatal mortality and lifelong functional loss among newborns . The und ex vivo expanded EPCs or ECs showed therapeutic effect in several disease models, including neonatal HI brain injury, stroke, myocardial infarction, and vascular injury after angioplasty [Endothelial progenitor cells (EPCs) in circulation system are positively correlated with the outcome of hypoxic brain injury, and the more EPCs in circulation showed better recovery . The defioplasty \u201317. The ioplasty .Although the usage of EPCs is promising in brain therapy, the shortage of autologous EPCs limits its clinical application. We previously demonstrate the induction of endothelial differentiation by synergistic biochemical and biomechanical stimulations in human placenta-derived multipotential cells (PDMCs) . The appHuman liposuction aspirates were obtained from healthy donors with informed consent to protect the information and rights of patients as approved in accordance with procedures of the institutional review board of the National Cheng Kung University Hospital (NCKUH). The human ASCs were isolated following the protocol described previously . Briefly2) for 24 hours immediately after the EGM induction. The LSS was created by a flow chamber which allowed medium to flow through the cell-seeding glass slide and applied LSS to cells [The combined chemical and mechanical stimulation was used to induce the ELCs as previously established induction protocols . For theto cells . The endto cells . The lev5 cells) were trypsinized and resuspended with 1\u2009mL complete medium and added onto the polymerized Matrigel (BD Biosciences). After incubation in 5% CO2 incubator for 5 hours, the formation of tube-like structure was observed and quantified in the tube length using phase contrast microscope.Forming tube-like structure which is an important indicator of endothelial function was measured in ASCs, early EPCs, and ELCs as previously described . In brie5\u2009cells/100\u2009\u03bcL each time. The pups returned to dam for recovery for one week before the brain samples were harvested.The Sprague-Dawley (SD) rats were provided by the animal center in NCKU with the approval of the experiment procedure by the Institutional Animal Care and Use Committee at NCKU. Neonatal HI brain injury is created according to previous study . Concise\u03bcm-thick slice for the following staining. The corresponding plates 15, 18, 27, 31, and 39 in rat brain according to the rat brain atlas were stained with 0.1% cresyl violet solution for 1 hour to reveal neurons [Damage severity of brain was determined by the volume of ischemic region on outer surface and Nissl staining at P14. The rat brains were perfused with normal saline and 4% paraformaldehyde. Upon isolation, each brain was given a score based on the lesion size of outer surface of brain. The size of the lesion was divided into 3 grades, score one (lesion size less than 1/3 hemisphere), score two (the lesion size greater than 1/3 but lesser than 1/2), and score three (the lesion size greater than 1/2 hemisphere) . After d neurons .The integrity of neurovascular structure was assessed by immunofluorescence staining. The brain slices were incubated with the primary antibodies against neuronal nuclear antigen  for identifying neuron and against rat endothelial cell antigen-1  for identifying vessels. To further verify the mechanism of the protection effect of different treatment, the marker of angiogenesis, isolectin IB4 antibody , was used to visualize new forming vessels. The antihuman nuclei antibody  was utilized to recognize transplanted human cells in rat brain. The primary antibodies were labeled by fluorescent-labeled secondary antibodies , and the signals were observed at excitation-emission wavelengths of nm 470 to 505\u2009nm and 596 to 615 with a tissue scanning fluorescent microscope  using a 20x objective lens.4 per well) are loaded into the upper compartment of Boyden chamber; the migration ability of the cells through 8\u2009\u03bcm-pore membranes (Neuro Probe) to the lower compartment which filled with medium with or without hypoxia mimetic reagent desferrioxamine  will be measured. The cells are cultured in Boyden chamber for 6 hours, and then the cells on the lower surface of membrane will be fixed by 4% paraformaldehyde (Sigma) and stained with Giemsa to quantify the transmigrated cell numbers. To further clarify the mechanism of boosting migration ability of ELCs under hypoxic condition, the ELCs were pretreated with neuropilin-1 (NRP1) blocking peptide  or inhibitor of VEGFR  1 hour before being loaded into the chamber. The migrating cell area was quantified by ImageJ software.The ability of stem cells to migrate into lesion site is important for tissue protection and regeneration. The injured brain area will release environmental cue to trigger the migration of the stem cells. We use Boyden chamber assay to compare the chemotaxis and transmigration ability of different cells. Shortly, different cells (2 \u00d7 10 in vitro hypoxic condition was achieved by treating the ASCs or ELCs with 50\u2009mM DFO. The cells were cultured in hypoxic condition for 6 hours with or without the pretreatment of DG2 (20\u2009\u03bcM) for 1 hour, followed by the collection of cell lysates. The gene expression level of VEGFR1, VEGFR2, CD31, vWF, angiopoietin 1 (ANG1), and neuropilin 1 (NRP1) was measured using RT-PCR with the primer sequence listed in previous study [\u03b2-actin  [To further illustrate the underlying signaling under hypoxic condition, theus study . The act, Sigma) . The p-Ap < 0.05.For all experiments at least 3 independent groups were performed to demonstrate the consistency outcome. All data were expressed as the mean \u00b1 standard SEM. Statistical analysis was performed using the one-way analysis of variance (ANOVA) with Fisher's test of the Origin statistic software . The statistical significance was defined as The endothelial differentiation for early EPCs and ELCs was induced from human ASCs using biochemical and biomechanical stimulations. After EGM induction, the early EPCs did not show obvious change in morphology and remained spindle shaped which was similar to undifferentiated ASCs . InsteadThe therapeutic effect of ASCs and ELCs was tested using neonatal HI brain injury model in rats. The severity of brain injury was compared among the rat pups receiving different treatments, including PBS, ASCs, and ELCs. The brain score determined based on infarction size on the outer surface of brain showed sever damage after HI insult in PBS group . TransplWe further investigated the integrity of neurovascular structure by immunofluorescence staining of specific antibodies against neuron (NeuN)  and vess in vivo local hypoxic environment that may have different responses in ASCs and ELCs. We further used in vitro Boyden chamber assay to investigate themigration ability of various cells under normal and hypoxic conditions. The transmigrated cells were labeled in dark blue color after migrating from the loaded upper compartment of chamber to the lower compartment with or without adding DFO for studying the cell mobility in normoxia (vehicle) and hypoxia (DFO) (The HI injured brain created ania (DFO) . The ELCia (DFO) . To illuia (DFO) . The chaia (DFO) . The levia (DFO) . The resTo confirm the role of NRP1 and VEGFR2 in promoting ELCs migration and remaining of endothelial differentiation under hypoxic condition, blockage of NRP1 or VEGFR signals in ELCs was tested by using specific NRP1 blocking peptides (DG2) or a small molecular targeting tyrosine kinase receptor (BIBF1120), respectively. Under regular condition (normoxia), the transmigration ability of ELCs was slightly decreased with the inhibition of NRP1 (DG2) or VEGFR (BIBF1120) signaling . The enhTo further confirm the signaling in brain tissue after receiving different therapeutic cells, the p-VEGFR2 and p-Akt were coimmunofluorescent staining with the angiogenesis marker IB4 . The appIn this study, we demonstrated the ASCs can be differentiated into endothelial lineage by synergistic stimulation of growth factor and shear stress. The therapeutic effects of both ASCs and ELCs were tested in HI injured brain. Main finding of present study supported that transplantation of ELCs showed better capacity than ASCs in preserving neurovascular structure after HI brain injury in rats. The ELCs were able to migrate and incorporate into the vascular structure in brain tissue. In addition, the ELCs can promote the angiogenesis in the impaired area as compared to ASCs. The involvement NRP1 and VEGFR2 is important for ELCs to facilitate the migration ability under hypoxic condition through Akt pathway.The angiogenic potential in early EPCs and late EPCs is comparable; there is divergence in their functions . Early EThe cell-based therapy using EPCs shows protective effect on restoring blood flow and preventing tissue damage. Upon transplantation, the EPCs home the ischemic site and incorporate into the damaged vessel structure. Studies address the fact that there are two main mechanisms for the therapeutic effect of EPCs therapy. First, the EPCs have potential to differentiate into mature ECs . After aThe crosstalk between ECs and neuron are prominent for the normal structure and function of nervous system. The ECs in central nerve system are highly specialized which connect tightly with each other and form blood barrier . The bloSeveral chemoattractants will be secreted in the injured tissue after HI insult to recruit circulating cells into the damaged area. VEGF is an important chemotactic factor for EPCs to participate in cell mobilization . VEGF acThe current study demonstrates the importance of chemical and mechanical factors in inducing the differentiation of ELCs from ASCs and the potential of using ELCs in protecting rat neonatal HI brain injury. Both ASCs and ELCs therapies can prevent the brain from HI insult by decreasing the infarction volume. Yet, ELCs showed a promising outcome in protecting the architecture and integrity of neurovascular unit. The transplantation of ELCs preserved not only the networks of vascular structure, but also the number of neurons. The mechanism for protective effect in ELCs may act through the increase of migration capacity and neovascularization after HI injury. The increase of NRP1 and VEGFR2 was identified with phosphorylation of Akt signaling in ELCs under hypoxic condition. Inhibition of NRP1 signal diminished the promotion of ELCs transmigration and Akt phosphorylation under hypoxia. Inhibition of VEGFR2 totally abolished the cell migration and endothelial differentiation in ELCs. Taken together, these results indicate that shear stress induced ELCs can be a promising cell resource for autologous cell therapy in HI brain injury."}
+{"text": "To The Editor: Woodrats (Neotoma spp.) are natural hosts of Whitewater Arroyo virus (WWAV) and other Tacaribe serocomplex viruses (family Arenaviridae) in the western United States and northern Mexico . Virtually all serum samples were acute-phase specimens, and a specific diagnosis was achieved for only 55 (31.8%) of the 173 study participants.Serum samples were tested for IgG against WWAV, Amapar\u00ed virus (AMAV), an arenavirus that is antigenically closely related to the Tacaribe serocomplex viruses known to cause hemorrhagic fever  of the 173 study participants. None of the 173 study participants were positive for IgG against AMAV or LCMV. The IgG titers against WWAV in the positive samples were 320 (n = 1), 1,280 (n = 3), and \u22655,120 (n = 4). WWAV was the apparent homologous virus in the 7 persons with antibody titers \u22651,280. The apparent homologous virus in the person with the titer of 320 could not be determined from ELISA data. The presence of IgG against WWAV in acute-phase serum samples  implied past infection with WWAV or an arenavirus antigenically closely related to WWAV.The state of residence , sex ratio , and mean age  of antibody-positive persons reflected the characteristics of the entire study population. The clinical features in each of the antibody-positive persons included fever, headache, myalgia, and thrombocytopenia. The diagnoses given for these persons were acute parvovirus infection (n = 1) by IgM assay, adult respiratory distress syndrome (n = 1) by clinical progression, and not determined (n = 6).The results of this study indicate that a small fraction of the adult population in the southwestern United States has been infected with North American Tacaribe serocomplex virus(es). We note that the dominant epitopes in ELISA for IgG against arenaviruses are associated with the viral nucleocapsid (N) protein, and that amino acid sequence of the N protein of WWAV and amino acid sequences of N proteins of other Tacaribe arenaviruses from Arizona or New Mexico showed differences as high as 15.1% in a previous study (,It might be the case that human IgG against some Tacaribe serocomplex viruses in the southwestern United States does not react strongly against WWAV in ELISA. If so, the true prevalence of antibody against North American Tacaribe serocomplex viruses in this study might be >4.6%. Accordingly, future work should include development of broadly reactive assays for detection of human IgM and human IgG against North American Tacaribe serocomplex viruses, including those associated with wild rodents in Mexico ("}
+{"text": "Non-alcoholic fatty liver disease (NAFLD) affects almost one third of adults in European countries. A well-known factor of influence is overnutrition and insulin resistance . In conRecently, Marta Benet and colleagues from Barcelona and Valenica in Spain have published a transcriptomic signature to identify compounds with an increased risk of inducing steatosis . ). in vitIn this context the identification of the steatogenic FOXA1/HEX/SREBP1C signature by Benet and colleagues (2014["}
+{"text": "Brown adipose tissue (BAT) has long been known to dissipate energy as heat and contribute to energy expenditure, but its presence and physiological role in adult human physiology has been questioned for years. Recent demonstrations of metabolically active brown fat depots in adult humans have revolutionized current therapeutic approaches for obesity-related diseases. The balance between white adipose tissue (WAT) and BAT affects the systemic energy balance and is widely believed to be the key determinant in the development of obesity and related metabolic diseases. Members of the transforming growth factor-beta (TGF-\u03b2) superfamily play an important role in regulating overall energy homeostasis by modulation of brown adipocyte characteristics. Inactivation of TGF-\u03b2/Smad3/myostatin (Mst) signaling promotes browning of white adipocytes, increases mitochondrial biogenesis and protects mice from diet-induced obesity, suggesting the need for development of a novel class of TGF-\u03b2/Mst antagonists for the treatment of obesity and related metabolic diseases. We recently described an important role of follistatin (Fst), a soluble glycoprotein that is known to bind and antagonize Mst actions, during brown fat differentiation and the regulation of cellular metabolism. Here we highlight various investigations performed using different  Obesity is a major health problem spreading at an epidemic pace throughout the world without any sign of abatement. According to the World Health Organization report, more than 1 billion adults (~ 15% of world population) are overweight [body mass index (BMI) > 25]  lineage and are called beige cells or brite (brown-in-white) cells  have recently been identified in adult humans  superfamily is comprised of over 30 members that include several structurally dimeric cytokines such as TGF-\u03b2, activins, and bone morphogenic proteins (BMPs)/growth and differentiation factors (GDFs) which are evolutionarily highly conserved , also termed as growth/differentiation factor-8 (GDF-8) is a member of the TGF-\u03b2 superfamily that regulates skeletal muscle mass  is a secreted glycoprotein that has been recognized for many years as a high affinity binding and neutralizing protein for several members of the TGF-\u03b2 superfamily including activins and Mst  entitled \u201cComposition and methods for treating or preventing metabolic syndrome disorders\u201d is in process. Authors declare no other potential conflict of interest."}
+{"text": "OnabotulinumtoxinA (OnabotA) was approved for treatment of chronic migraine (CM) following the PREEMPT trials, 2, and Written informed consent to publication was obtained from the patient(s)."}
+{"text": "Mycobacterium tuberculosis, innovations in TB drug discovery and evolving strategies to bring new agents with best performance is an essential investigation. Taking this into account, there is a pressing need to develop new and more effective anti tubercular agents. The coordination of metal with organic drugs is a promising strategy that has been successful in many cases with different pharmacological activities. The emergence of new cases and the adverse effects of first and second-line antituberculosis drugs have led to renewed research interest in metal drug complexes in the hope of discovering new antituberculosis drugs. The aim of the present study is to assess the antituberculosis activity of Ni (II) and Cu (II) complexes of polymer ligand poly (3-nitrobenzylidene-1-naphthylamine-co-methacrylic acid).Tuberculosis (TB) is a disease that produces several million deaths annually. With the appearance of multi drug resistant microbial strains of M. tuberculosis H37 Rv strain by microplate alamar blue assay (MABA) method using pyrazinamide as standard.Antituberculosis activities of the ligand and its complexes were assessed against The minimum inhibitory concentration values of the ligand and its complexes on comparison with standard  indicate that the complexes exhibit promising antituberculosis activity. Cu (II) complex shows more activity (10 \u00b5g/ mL) followed by Ni (II) complex (20\u00b5g/ mL) and ligand (35 \u00b5g/ mL).Among the synthesized compounds, the Cu (II) complex may be used as therapeutic substitute in the treatment of tuberculosis by replacing the routine drugs."}
+{"text": "Unequal distribution of dermal collagen and elastic fibers in different orientations is reported to be one of the multi focal causes of scar related complications.To study the correlation pattern between the variables of dermal collagen in horizontal (CH) and in vertical (CV) directions as well as that of dermal elastic fibers in horizontal (EH) and vertical (EV) directions.Current research comprised of histo-morphometrical study of 120 skin samples collected in horizontal and vertical orientations from anterior chest area and lateral chest areas of formalin embalmed human cadavers (n = 30). The quantitative fraction of dermal collagen and elastic fiber content was obtained by tissue-quant image analysis. Spearman correlation coefficient (r) was computed to determine the linear association between the variables (CH/CV/EH/EV). The results were interpreted according to the degree of association after taking into consideration the significant correlation (p < 0.01 or p < 0.05) with respect to coefficient (r) values.Significant positive correlation between CH and CV and between EH and EV were observed in both anterior  and lateral chest areas . However, the negative correlations were observed between CH and EH for anterior chest area (r = -.55) and between CV and EV at lateral chest area (r = -.43).Positive correlation among dermal collagen and elastic fibers between horizontal and vertical directions, and their negative correlation within same direction could be one of the factors for the speckled behavior of scar related complications in the chest area."}
+{"text": "Provisional evidence-based classification criteria for Familial Mediterranean Fever (FMF), Cryopyrin Associated Periodic Syndrome (CAPS), Tumor Necrosis factor Receptor Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency (MKD) have been recently developed based on data coming from the Eurofever registry. However, no consensus on how to combine clinical criteria with results of molecular analysis has been reached so far.To understand how physicians involved in the clinical care of patients with Autoinflammatory diseases (AIDs) classify patients with inherited periodic fever in daily practice.By using the Delphi and Nominal Group Technique, we started a process made of three consecutive e-mail surveys. In the first survey, clinicians/biologists and other health professionals working in the field of autoinflammation were asked to identify the variables that they consider as important, in their clinical practice, for the diagnosis of patients with inherited periodic fever. This survey was open not to influence the experts.We sent the first survey to 124 experts. The overall rate of response was 107 (86%): 101 experts responded to be interested in the survey and 88 completed and confirmed it for at least one disease; 6 experts responded not to be interested. No clinical variable was chosen by all the experts for any disease the five most cited clinical variables for FMF were recurrent fever (80% of experts), abdominal pain (67%), arthritis (53%), thoracic pain (47%) and arthralgia (36%). The five most cited clinical variables for CAPS were fever (75%), urticarial rash (71%), hearing loss (49%), ocular involvement (40%) and arthralgia (35%). The five most cited clinical variables for TRAPS were long lasting fever (92%), rash (84%), periorbital edema (59%), myalgia/myositis (57%), and abdominal pain (55%) while the five most cited clinical variables for MKD were abdominal pain (61%), fever (59%), skin rash (41%), diarrhea (43%) and arthralgia (39%). A confirmatory genetic test resulted a relevant element for the diagnosis of FMF, TRAPS, CAPS and MKD while the response to treatment for FMF and CAPS.The preliminary results of the first Eurofever Delphi Survey show a high rate of response by Expert, underlying the interest of the scientific community in this topic. A wide heterogeneity in their response was observed. At the end of the Delphi process, we will obtain different set of clinical criteria whose performance will be tested in comparison to already existing criteria in a cohort of patients affected by AIDs. The final step will be a Consensus among experts (geneticists and clinicians) in order to define the best combination of clinical and genetic data for the definitive classification of patients with inherited periodic fevers."}
+{"text": "Medical errors are particularly frequent in Neonatal Intensive Care Units (NICUs) , increasWe carried out our study from 2011 and 2012 in Department of Medical and Surgical Neonatology of Bambino Ges\u00f9 Children\u2019s Hospital. We recorded throughout retrospective methods nursing reports to detect an error or incidents. We used voluntary reporting, non punitive, of medical errors by health care providers.From 2011 and 2012 we detected 29 adverse events in Neonatal Department; 15 (58%)of whom were therapeutic errors concerning of drug process: 2 (13%) order, 1 (7%) preparation, 7 (46%) prescription, 5 (33%) administration (Figure The voluntary reporting system represents the best option to detect the human errors. In our experienced the introduction of shared protocols, of the nurse staff training, and the following of the JCHAO directives have been achieved to identify all procedures performed for patient care. To reduce the ADRs the Paediatric Investigation Plans should be required by the Paediatric Committed to guarantee safer and tolerated drugs, especially for newborns."}
+{"text": "Contemporary inhabitants of the Balkan Peninsula belong to several ethnic groups of diverse cultural background. In this study, three ethnic groups from Bosnia and Herzegovina - Bosniacs, Bosnian Croats and Bosnian Serbs - as well as the populations of Serbians, Croatians, Macedonians from the former Yugoslav Republic of Macedonia, Montenegrins and Kosovars have been characterized for the genetic variation of 660 000 genome-wide autosomal single nucleotide polymorphisms and for haploid markers. New autosomal data of the 70 individuals together with previously published data of 20 individuals from the populations of the Western Balkan region in a context of 695 samples of global range have been analysed. Comparison of the variation data of autosomal and haploid lineages of the studied Western Balkan populations reveals a concordance of the data in both sets and the genetic uniformity of the studied populations, especially of Western South-Slavic speakers. The genetic variation of Western Balkan populations reveals the continuity between the Middle East and Europe via the Balkan region and supports the scenario that one of the major routes of ancient gene flows and admixture went through the Balkan Peninsula. It is believed that part of the Illyrians was assimilated and the other part was forced to move south - into the territory of present-day Albania th until 19th century the Peninsula was under the Ottoman control The Balkan Peninsula has been continuously settled by anatomically modern humans (AMH) since the Upper Paleolithic era Today, the Western Balkan territory  is inhabDuring the last two decades the variation of uniparentally inherited markers such as mitochondrial DNA (mtDNA) and the non-recombining part of Y chromosome (NRY) have been exploited in population genetic studies in order to disentangle the problems of the diversity and dispersal of humans both in global and local contexts The study of the variation of mtDNA in the population of Bosnia and Herzegovina has shown - like in case of the variation of NRY - that the majority of detected mtDNA hgs among Bosnians belong to the common West Eurasian gene pool The aim of this study was to characterize, in a larger geographical context, the autosomal gene pool of eight Western Balkan populations from six countries - Bosnia and Herzegovina, Croatia, Serbia, former Yugoslav Republic of Macedonia, Montenegro and Kosovo. All studied samples were characterized also for mtDNA and NRY diversity. One of the main questions we address here is whether the whole genome approach with the accent on the variation of autosomal SNPs is in concordance with the information about genetic affinities of the populations of Western Balkan region, revealed by the studies of uniparental markers.Genome-wide autosomal markers of 70 Western Balkan individuals from Bosnia and Herzegovina, Serbia, Montenegro, Kosovo and former Yugoslav Republic of Macedonia . The genome-wide SNP data generated for this study can be accessed through the data repository of the National Center for Biotechnology Information \u2013 Gene Expression Omnibus (NCBI-GEO): dataset nr. GSE59032, 2>0.4) were excluded from the analysis in the window of 200 SNPs (sliding the window by 25 SNPs at a time). The final dataset consisted of 220 727 SNPs and 785 individuals from African, Middle Eastern, Caucasus, European, Central, South and East Asian populations  was reduced with the exclusion of East and South Asians and Africans, in order to increase the resolution level of the populations from the region of interest  for the same dataset used for PCA were estimated between populations, and regional groups for all autosomal SNPs, using the approach of Weir and Cockerham ST values for the populations specified in Pairwise genetic differentiation indices  between different ethno religious groups of Western Balkan region with Middle Eastern populations. The Ottoman rule over the Balkans during 15\u201319 cc AD led inter alia to the conversion of the local people to Islam, the largest number of whose assumed descendants live in contemporary Bosnia and Kosovo ibd sharing for each of these populations and Middle Eastern populations . The details of the dataset has been characterized in The analysis was designed to compare patterns of shared tracts that are identical by descent (http://faculty.washington.edu/browning/beagle/beagle.html) ibd between pairs of individuals. The fIBD algorithm was applied to the 22 autosomes in 10 iterations and the IBD threshold was set to 1e\u201310. Since the power of the fIBD algorithm to detect segments shorter than 1 centiMorgan (cM) is low, we considered only ibd segments longer than 1cM. We summarized ibd sharing for six classes of ibd segments . We estimated an average number of ibd segments per pair of individuals for Muslim and non-Muslim populations of Western Balkan vs Middle Eastern populations  algorithm implemented in BEAGLE software package  and non-Muslim  of the Western Balkan populations share around 1.5 ibd segments per pair with the population from the Middle East  patterns of ibd sharing with Middle Eastern populations for shorter classes of ibd segments . This is slightly higher with Turks, and lower with Saudis, Syrians, Iranians and Palestinians  and only Bosniacs have higher ibd sharing with Turks (p\u200a=\u200a0.0097 for 5\u20136 cM ibd segments)  we first analyzed the number of dle East . This isulations . Next, wstinians . For lonegments) . Howeveribd segments reveals similar patterns of ibd sharing for Muslim and non-Muslim Western Balkan populations with populations of Middle East, providing thereby little support to a gene flow scenario during the conversion to Islam (15\u201319 cc AD) in the Balkans. Our analysis of ibd sharing agrees with other analyses  of the Western Balkan populations, the influence of the clan structure to the present genetic variation should be seen the most in the Y chromosomal gene pool of the studied populations \u2013 this, however, is not the case. To conclude: the linguistic or religious differences seem to have had no impact on the present variation of uniparentally inherited or autosomal markers in a region.Compared to the rest of the Western Balkan populations, the Kosovars have a somewhat different cultural and demographic background. All studied Western Balkan populations, except Kosovars, belong to the South Slavic branch of the Indo-European (IE) language family n Balkan . Howevern Balkan , suggestn Balkan , Text S1We have analyzed and present here the new data of genome-wide autosomal diversity of five Western Balkan populations. The variation analysis of 660K autosomal SNPs of 70 individuals from Western Balkan populations revealed that the genetic uniformity that has been shown by studies of uniparentally inherited markers of these populations can be seen also at the whole-genome level. Thus, culturally diverse Western Balkan populations are genetically very similar to each other. These results, together with the high-resolution analysis of the variation of mtDNA and NRY, let us to affirm that the genetic profiles of Western Balkan populations resemble that of their closest geographical neighbors, and in the global context are in concordance with the geographical distribution of the studied population.The major variants of the gene pool of present-day Western Balkan populations have developed from a common source without being influenced by major population-specific bottlenecks. In a more general perspective, our results reflect clear genetic continuity between the Middle Eastern and European populations. It has been suggested recently that the Neolithic migrants from Anatolia took mainly the maritime coastal route and island hopping to reach Europe The autosomal analysis as well as mtDNA and NRY data presented in this study contribute to an existing database and for understanding the origins of the peopling of this part of Europe.Figure S1ADMIXTURE plots of autosomal SNPs of Western Balkan region in a global context on the resolution level of 3 to 15 assumed ancestral populations (K). A. Box and whiskers plot of the cross validation (CV) indexes of all 15\u00d7100 runs of ADMIXTURE; B. Log-likelihood (LL) scores of all 15\u00d7100 runs of ADMIXTURE. Inset shows the variation in the fractions  of runs that reached the highest LL values; C. Bar plot displaying individual ancestry estimates for studied populations.(TIF)Click here for additional data file.Figure S2Principal component (PC) analysis (PC1 versus PC2) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S3Principal component (PC) analysis (PC1 versus PC3) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S4Principal component (PC) analysis (PC1 versus PC4) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIFF)Click here for additional data file.Figure S5Principal component (PC) analysis (PC1 versus PC5) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S6Principal component (PC) analysis (PC2 versus PC3) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S7Principal component (PC) analysis (PC2 versus PC4) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S8Principal component (PC) analysis (PC2 versus PC5) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S9Principal component (PC) analysis (PC3 versus PC4) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S10Principal component (PC) analysis (PC3 versus PC5) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S11Principal component (PC) analysis (PC4 versus PC5) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S12Principal component (PC) analysis based on the frequencies of mtDNA (panels A and C) and NRY haplogroups (panels B and D) of Western Balkan (WB) populations in a context of selected Central and South Europeans and Iranians from the Middle East Click here for additional data file.Figure S13Average total length of genome shared identical by descent between Bosniacs, Kosovars and Near Eastern populations. Panels A-E indicate five length classes of ibd segments: 1\u20132, 2\u20133, 3\u20134, 4\u20135, 5\u20136 cM, respectively. Bosniacs and Kosovars are tested Muslim populations from Western Balkans; Macedonians, Montenegrins, Bosnian Croats and Serbs, Croatians, Serbians are non-Muslim populations from Western Balkans, used as a background. Red color of the Western Balkan population name and red circle around the symbol of Middle Eastern population indicates significantly higher ibd sharing between these populations as compared to non-Muslim background.(TIF)Click here for additional data file.Figure S14Median-joining network of mtDNA hg H lineages of Western Balkan populations: A: subhg H1 and its sub-branches; B: other subhgs of hg H. A total number of 19 H1 and 49 other H haplotypes are reported. Numbers on links indicate the mutations: blue color indicates HVS1 and HVS2 mutations, black color coding region mutations. Polymorphic nucleotide sites are numbered according to Reconstructed Sapiens Reference Sequence. Node size is proportional to absolute haplotype frequency, as it is reported in figure legend.(TIFF)Click here for additional data file.Figure S15Median joining network of mtDNA hg U lineages. A total number of 34 U haplotypes are presented. A diagnostic mutation A1811G has been added into the network, but not genotyped in the sample. For further details, see the legend of (TIF)Click here for additional data file.Figure S16Median joining network of mtDNA lineages for hgs J and T in the Western Balkan region. A total number of 24 J and 10 T haplotypes are presented. For further details, see the legend of (TIF)Click here for additional data file.Figure S17Median joining network of mtDNA lineages of hgs HV, V and R0a. A total number of 11 V, 8 HV and 2 R0a haplotypes are reported.For further details, see the legend of (TIF)Click here for additional data file.Figure S18Median joining network of mtDNA lineages from hgs W, I and N1b. A total number of 6 W, 1 I and 3 N1b of haplotypes are reported. For further details, see the legend of (TIF)Click here for additional data file.Figure S19Phylogenetic tree of mtDNA K1a13a complete sequences. Two samples of Bosnian Croats (BHCB15 and BHCHZ20), and two from Croatia [Croatia.m.(S)199 and Croatia.m.(S)34] are sequenced in this study, the others are from Phylotree mtDNA Build 15. The mutations are given relative to the Reconstructed Sapiens Reference Sequence.(TIF)Click here for additional data file.Figure S20Phylogenetic tree of mtDNA N1a complete sequences. One sequence of Croatian from Croatia is sequenced in this study, the others are from Phylotree mtDNA Build 15. The mutations are given relative to the Reconstructed Sapiens Reference Sequence.(TIF)Click here for additional data file.Figure S21Phylogenetic tree of mtDNA R0a2 complete sequences. Macedonian (MAC16) and Croat from Bosnia and Herzegovina (BHCCB19) are sequenced in this study, the others are from Phylotree mtDNA Build 15. The mutations are given relative to the Reconstructed Sapiens Reference Sequence.(TIF)Click here for additional data file.Table S1Sample of populations used for autosomal analyses.(XLS)Click here for additional data file.Table S2The ethnolinguistic characteristics of studied Western Balkan populations.(XLS)Click here for additional data file.Table S3F3-statistic calculated for all possible triplets of f3 of TreeMix dataset.(XLSX)Click here for additional data file.Table S4Average number of IBD segment per pair of individuals.(XLSX)Click here for additional data file.Table S5MtDNA HVS-1 and HVS-2 haplotypes of analyzed Western Balkan populations relative to Reconstructed Sapiens Reference Sequence.(XLSX)Click here for additional data file.Table S6Y chromosome variation in Western Balkan populations.(XLSX)Click here for additional data file.Table S7MtDNA gene and nucleotide diversity of analyzed Western Balkan populations.(XLSX)Click here for additional data file.Table S8st-distances of mtDNA HVS1 variation between Western Balkan populations.F(XLSX)Click here for additional data file.Table S9Results of AMOVA and Mantel test based on mtDNA HVS-1 haplotype or haplogroup frequencies.(XLSX)Click here for additional data file.Table S10Estimated coalescense time for the most frequent mtDNA haplogroups in studied Western Balkan populations.(XLSX)Click here for additional data file.Text S1Description of the sample and methods of the analyses of mtDNA and NRY.(DOCX)Click here for additional data file.Text S2Results of the analyses of mtDNA and NRY variation.(DOC)Click here for additional data file."}
+{"text": "In recent years, emerging evidence has shown the potential risks of arterial hyperoxia, but observational studies failed to indisputably demonstrate its impact on clinical outcome of critically ill patients. Importantly, the lack of a clinical definition of hyperoxia and methodological limitations hamper the interpretation and clinical relevance of these studies.We aimed to systematically evaluate previously used metrics for defining hyperoxia and associations with outcome of intensive care unit (ICU) admission.2). Worst PaO2 was defined as the PaO2 associated with the lowest PaO2/FiO2 ratio. In logistic regression models, we analysed the associations between hospital mortality and severe hyperoxia (PaO2> 200 mmHg) defined by either identified metric, calculated over the total ICU admission.Arterial blood gas (ABG) analyses between July 2011 and July 2014 were extracted from the patient data management system (PDMS) database of three large tertiary care ICUs in the Netherlands. Data from all admissions where more than one ABG was available were supplemented with anonymous demographic and admission and discharge data from the Dutch National Intensive Care Evaluation (NICE) registry. Identified oxygen metrics from a systematic review of the literature included the first, highest, worst, and mean arterial oxygen tension  died before hospital discharge. All identified metrics showed statistically significant associations between severe hyperoxia and hospital mortality. The risk estimates differed substantially between the metrics used for defining hyperoxia (P < 0.001). The strongest effects were found for the mean and the highest PaOIn this multicenter cohort study, severe arterial hyperoxia was associated with hospital mortality and this association was independent of the used metric for hyperoxia. However, the metric choice greatly influences the effect size for hospital outcome.This work was financially supported by an unrestricted grant issued by the Netherlands Organization for Health Research and Development (ZonMw).ADDIN EN.REFLIST"}
+{"text": "Patent foramen ovale (PFO) occurs in a quarter of the population but half of those with cryptogenic stroke (CS). Difficulty in identifying the pathogenic PFO versus the innocent bystander has contributed to controversy surrounding outcomes following PFO closure. We aimed to investigate whether right atrial flow patterns could help define the mechanism for CS in the setting of PFO.3, temporal resolution:50-55ms, 20 phases, SENSE, factor 2) was used. Analysis was performed with GTflow v2.0 (Gyrotools). Contours were placed manually in the superior vena cava (SVC) and inferior vena cava (IVC) in the axial plane at the junction with the right atrium. Net flow was assessed at these points. The relative position of the SVC and IVC at these points was measured. A pathline analysis of atrial flow was performed .4D flow cardiac magnetic resonance (CMR) was performed in 10 subjects  with proven PFO and CS and in 10 controls  with normal trans-thoracic echocardiograms. CMR was performed at 3T  with a 6-channel cardiac array. A retrospectively ECG-gated and respiratory-gated TFE sequence x240mm(FH)x142mm(LR), spatial resolution:3mmBody mass index (BMI) and heart rate (HR) were comparable but blood pressure was higher in the PFO/CS group with three patients taking anti-hypertensives (Table). Four variations of right atrial flow were observed Figure :a) vortical b) helico-vortical c) helical [SVC and IVC flow twist together in a helix]d) multiple vortices [arising variably from SVC and IVC flow]Vortical flow was most prevalent in the control group whilst the PFO/CS subjects were more likely to show one of the other flow patterns (Graph). Peak systolic and diastolic flow in both SVC and IVC were comparable between groups. However, peak diastolic flow in the IVC occurred earlier in the cardiac cycle when corrected for heart rate in the PFO/CS group than controls . The antero-posterior distance between the SVC and IVC was comparable between groups. The right-left distance between the SVC and IVC was greater in the PFO/CS group than the controls A spectrum of right atrial flow patterns can be seen in the normal heart. The relative position of the SVC and IVC may influence the generation of these. Our findings suggest that variant flow patterns in the right atrium may contribute to the pathogenesis of CS in the presence of PFO, we hypothesise, by promoting a passage for paradoxical embolism. Further work is needed to better define the subsets of CS patients in whom the PFO should be regarded as pathological.Academy of Medical Sciences and Newcastle Hospital Charities."}
+{"text": "The frequency of contact allergens is often regionally different and hence it regional identification is important for the prevention of allergic contact dermatitis (ACD).Aim of this study was evaluation of the frequency of particular positive results of patch test (APT).A total number of 127 patients from Outpatient Allergic Clinic MED-ALL Medical Centre (age 2-76 years old) with suspected ACD were examined using the most common allergens from the patch tests from the European Standard Series including nickel, pallatium, chrome, cobalt, fragrance-mix I and II, balsam of Peru, formaldehyde and propolis and one extra allergen -- house dust mite (HDM). The data obtained were subjected to statistical analysis.The highest positivity of APT was seen against HDM (67%), then nickel (51%), chrome (40%), cobalt (39%), pallatium (16%), propolis (16%), fragrance-mix I , balsam of Peru , fragrance-mix II  formaldehyde . In the group of patients with positive results with HDM higher percentage is in younger group<18 years old (70%) with almost 68% of cases with strong positive results (++ or +++).HDM allergens play an important role in determining the clinical severity of allergic dermatitis and should be included in basic patch test series."}
+{"text": "At present there are two methods to determine the chromosome health of unborn fetus in pregnant women. One is through maternal serum screening that is considered as simple but less sensitive method and the second options involves invasive methods like amniocentesis or chorionic villus sampling (CVS) for women who are found to be positive in maternal serum screening. Recent studies have demonstrated that non-invasive prenatal testing (NIPT) using cell-free fetal DNA (cfDNA) present in circulating maternal blood is considered as one the most effective method of screening for trisomy 21.The single nucleotide polymorphism (SNP) based Non-invasive Pre-natal test, being offered by Quest Diagnostics in technical collaboration with Natera Inc to determine chromosomal copy number by looking for specific patterns of (SNPs). This second generation technology analyzes cfDNA in a single reaction targeting 19,500 single nucleotide polymorphisms which are the most informative portions of an individual\u2019s DNA selected across all the analyzed chromosomes.et al., 2013 paper on total of 242 cases that include thirty two cases aneuploidy included trisomy 21 (n=25) which were correctly identified with 100% sensitivity and 100% specificity with no false positive and false negative. Another study by Zimmerman et al., 2012 study on 166 samples from pregnant women, including 11 trisomy 21, three trisomy 18, two trisomy 13, two 45, X, and two 47,XXY samples including 146 low risk pregnancies. The study also correctly reported the chromosome copy number of all five chromosomes in 145 samples that passed a DNA quality test.Two published study demonstrated in the women undergone both invasive chorionic villus samplings followed by karyotyping in conjunction with non-invasive prenatal testing the efficacy of test. Data from Nicolaides The studies had demonstrated that SNP based NIPT is considered as an effective method of screening for common chromosomal abnormalities with detection rate of more than 99% and false positive rate of less than 0.1%. The initial finding shows NIPT approach has potential to avoid invasive procedure and can be provided an option to high risk pregnancies i.e. those with advanced maternal age, screens positive for biochemical screening and history of pregnancies with previous aneuploidies."}
+{"text": "Addiction is associated with medical consequences, due to direct drug effects, poor adherence to health-care recommendations, and poor quality of care. But little is known about how the spectrum of illicit drug use in primary care patients affects quality of medical care measures for chronic conditions. The objectives of this study were to determine the association between drug use  and quality measures indicating failure to meet criteria for good blood pressure (BP) and blood glucose (BG) control among primary care patients identified by screening as using illicit drugs who also have hypertension and/or diabetes.The study population was adult patients presenting for primary care visits in an urban, safety-net hospital with recent illicit drug use or prescription drug misuse identified by screening and either hypertension or diabetes mellitus. The outcomes were failure to control: a blood pressure (primary), defined as systolic BP of 140 or higher or diastolic BP of 90 or higher, and b) blood glucose (secondary), defined as hemoglobin A1c of 8 percent or higher  and Healthcare Effectiveness Data and Information Set [HEDIS] measures). Main independent variables were: days of drug use in the past month; drug type ; and severity of use . We fit separate longitudinal logistic regression models for each measure of drug use and each outcome.Overall, 40 percent (66/164) of the sample with hypertension failed to meet criteria for BP control and 42 percent (26/62) of those with diabetes failed to meet criteria for BG control. No significant associations were detected for any measure of drug use and BP or BG control, except those reporting cocaine use had higher odds of failing to meet criteria for BG control compared to those reporting marijuna use (adjusted odds ratio (AOR) 8.8, 95% CI: 1.9, 41.9). Higher severity of drug use was associated with higher odds of failing to meet criteria for BG control in an unadjusted model ; however, this association was not significant after controlling for age, gender, and race/ethnicity.In this cohort of primary care patients with drug use, type of drug but not frequency of use or severity was significantly associated with failure to meet quality measure criteria for control of hypertension and diabetes.Trial registrationidentifying number NCT00876941"}
+{"text": "In nerve transfer, we transfer a physiologically active nerve to a distal, more important but irreparably paralyzed nerve. This surgical procedure is best done early within 6 months of the injury. Nerve transfer can be broadly classified into four categories: (1) Extraplexal; (2) Intraplexal and (3) Targeted nerve transfer.Prime extraplexal donors are the spinal accessory, phrenic and intercostal nerves. There are many combination of nerve transfer, depending upon the loss of action and available motors.For shoulder abduction: 1) Spinal accessory to supra-scapular: this transfer can be done from a dorsal approach; 2) Triceps branch of radial nerve to axillary from an anterior approachFor elbow flexion: 1) Spinal accessory to biceps and brachialis split sural nerve transfer: this extraplexal transfer involves using a reversed sural nerve graft and the two ends are used for the biceps and brachialis separately; 2) Ulnar to brachialis and median to bicepsFor Elbow extension: 1) Ulnar nerve to triceps; 2)Intercostal to TricepsFor wrist extension: Median nerve to ECRB branch of Radial nerveFor Finger extension: Transferring the FDS branch of median to posterior interosseous nerveFor distal Ulnar nerve neurotisation to prevent Claw deformity and sensation:Pronator quadratus branch of median to deep motor branch of Ulnar nerve"}
+{"text": "We found that non-functional alleles of white, unable to produce a coding transcript, could reactivate in trans the expression of a wild type copy of the same gene silenced by heterochromatin. This new epigenetic phenomenon of transcriptional trans-reactivation is heritable, relies on the presence of homologous RNA\u2019s and is affected by mutations in genes involved in post-transcriptional gene silencing. Our data suggest a general new unexpected level of gene expression control mediated by homologous RNA molecules in the context of heterochromatic genes.In order to study the role played by cellular RNA pools produced by homologous genomic loci in defining the transcriptional state of a silenced gene, we tested the effect of non-functional alleles of the  trans-reactivation. We found that genes, unable to produce a functional coding transcript, but with the potential of transcribing other RNA\u2019s within their gene body, strongly reactivate the transcription of a wildtype copy of the same gene silenced by heterochomatin. This new epigenetic phenomenon is heritable, relies on the presence of diffusible RNAs able to carry and transfer epigenetic information and is affected by mutations in genes involved in Post-Transcriptional Gene Silencing. Our data strongly suggest that homologous non-coding RNA can reactivate the expression of genes silenced by heterochromatin, thus defining a new unpredicted level of gene expression control in the context of heterochromatic genes.We discovered a new epigenetic phenomenon we called  In recent years it has become increasingly evident that the expression of eukaryotic genomes is far more complex than it had been previously explored. An emerging body of evidence, coming from next generation sequencing approaches, is showing that the genomes of all studied eukaryotes are almost entirely transcribed, generating an enormous number of non-coding RNAs (ncRNAs) . The ENCparamutation v) (C). All autosomal lines tested carried an X chromosome with a w1118 allele. In order to clean the lines from the w1118 allele, we back crossed the original lines with deletions of the w gene (Df(1)w), before testing them for their interaction with the w* suppressing alleles. To help follow the transmission of individual chromosomes, female chromosomes are represented in pink while male chromosomes are shown in blue.Detailed description of cross schemes and fly genotypes tested as experimental and control classes to measure (JPG)Click here for additional data file.S5 Fig(A) Loss of function mutations in smaug (smg1) and pumilio (pum13), two RNA binding protein involved in mRNA destabilization in flies, are embryonic lethal. Thus, the ability of smg1 and pum13 loss of function alleles to modify the levels of eye pigmentation (trans-reactivation) we scored in wm4h/w* females (+) was tested in heterozygosis (pum and smg). Polytene chromosome FISH using genomic probes covering the entire w gene (with the exception of the first intron) and coding sequences for the hsp70 gene (mapping chromosome 3R) on homozygous wwt/wwt(B), and transheterozygous wm4h/\u0394w(C) combinations. FISH signals for white (red) and hsp70 (green) genomic sequences are indicated by arrowheads. The asterisk indicate the region of pericentric heterochromatin. The X indicates the chromosome where the w gene maps.(JPG)Click here for additional data file.S6 Figtrans-generational inheritance of wm4htrans-reactivation from (F1) trans-heterozygous wm4h/w* females when crossed with parental w*/Y (A) or \u0394w /Y (B) males. To help follow the transmission of individual chromosomes, female chromosomes are represented in pink while male chromosomes are shown in blue. (C) Trans-generational inability of a wild type w+ allele (coming from an OreR stock) to trans-reactivate in F2 the wm4h locus. Eye pigment quantification and representative eye pictures of the parental (P), F1 and F2 progenies for each genotype tested are shown.Detailed description of cross schemes and fly genotypes tested as experimental and control classes to measure (JPG)Click here for additional data file.S7 Fig(A) and control (B) classes to measure trans-reactivation of wm4h during the process of gynogenesis. (C) Cross scheme used to test in heterozygosis the ability of loss of function alleles (Mut) to modify trans-reactivation. (D) Eye pigment quantification was conducted on adult flies of the indicated genotype and the Log2 ratio of wm4h/w* trans-reactivation in the mutant background over the normal levels of wm4h/w* trans-reactivation  was used as a measure of the influence of the mutation tested in the onset of trans-reactivation. To help follow the transmission of individual chromosomes, female chromosomes are represented in pink while male chromosomes are shown in blue.Detailed description of cross schemes and fly genotypes tested as experimental (JPG)Click here for additional data file.S1 Tablew* alleles tested for their ability to modify in trans-heterozygosity the wm4h eye color variegation. Stocks that increased eye color variegation are highlighted in orange (Suppressors), the ones that did not have any effect are highlighted in light red (-). Tested white genomic deletions are highlighted in light grey. Finally, the mutation class, the mutagen employed and the Nature of the lesion, for each w* allele tested is reported when known.Genotypes of stocks carrying the (DOCX)Click here for additional data file."}
+{"text": "The prevention and treatment of caries and non-carious lesions by means of remineralization has been studied for many decades. The theoretical basis for remineralization as a means of caries prevention and treatment is based on the retention of protein matrix in dental enamel at early stage of caries (white spot) and on the possibility of its remineralization.The detection of new structural formations and emerging information about morph-chemical properties of human and animal enamel have facilitated identification of a new approach not only to for caries prevention but also the creation of new, more effective formulations for oral health hygiene as well as, structural and metabolic reparation of tooth enamel.For ultrastructure and morph-chemical tooth enamel reconstruction, we applied dentifrice gel ROCS Medical Minerals which contains calcium glycerophosphate, magnesium chloride and xylitol. Participants were 10\u201330 years old, without any significant medical conditions. Each patient received 15 applications of the gel. Total of 57 subjects were divided to 4 groups depending on the diagnosis. All the subjects had indications for remineralizing therapy.st group consisted of 15 patients with early stage of caries (white spot).\u2022 The 1nd group was made up of 19 patients with systemic hypoplasia (spotted form).\u2022 The 2rd group consisted of 10 young subjects with significant hypersensitivity without any visible lesions .\u2022 The 3th group consisted of 13 subjects with hypersensitivity due to wedge-shaped lesions, abrasion or enamel erosion.\u2022 The 4The application of gel containing the new mineral complex of magnesium and calcium resulted in a positive remineralizing effect which was obtained in patients with early stages of caries as well as those with non-caries lesions. Further, white spots (early stage of caries) completely disappeared in 80% cases after 15 applications of the dentifrice. Thus, it appears that 15 procedures of remineralizing therapy with ROCS Medical Minerals are enough for mineralizing of white hypoplastic spots. Most patients with hypersensitivity (82% and 93% in two groups) noticed significant reduction of painful reactions after two 15-minutes applications. Finally, all subjects noticed a significant improvement of teeth appearance .In conclusion, the results suggest high efficacy of the mineral magnesium-calcium remineralizing complex in patients with early stages of caries as well as those with non-carious lesions."}
+{"text": "Recent studies in the United Kingdom ,2] have have2] hWe surveyed Scottish intensive care trainees to ascertain whether such deficits are widespread and persistent.Trainees were invited to complete a web-based questionnaire on three occasions in June 2014. Responses in the form of ticked boxes or free text were collated and analysed for trends.Ninety-nine trainees replied, of whom 96 were based in anaesthesia, one in emergency medicine and two in allied medical specialties. Alarmingly, 70 respondents (71%) had been involved in managing an airway emergency in a patient with a tracheostomy or laryngectomy, 63 (90%) on a critical care unit and 40 (57%) on a general ward. Deficits in staff training and equipment were identified as contributory by 28 (40%) and 10 (14%) respondents, respectively. Most trainees (68%) felt quite confident in caring for neck breathers, with confidence increasing as training progressed. However, the majority of trainees accrued such confidence through exposure to these patients on theatre lists (80%). Only a minority had participated in simulated emergencies (33%) or a formal training course (14%). Almost half (49%) rated their training as deficient or absent and the vast majority (96%) felt there was a place for more formal tuition in caring for patients with a tracheostomy or laryngectomy.Our findings suggest that we are failing to prepare trainees for the challenges of managing airway emergencies in neck breathers. Divergence of anaesthesia and intensive care training in the UK may further compound this problem by reducing exposure to controlled subglottic airway management in theatre. The Scottish Intensive Care Society Trainee Committee has sought to address these deficits in training and reduce the burden of avoidable harm by incorporating sessions on tracheostomy management into its educational programme."}
+{"text": "High numbers of tumour infiltrating lymphocytes has been associated with a significantly improved prognosis. Some of the key cell types involved are Cork Cancer Research Centre (CCRC) has long utilised an ablative cancer treatment that involves delivering a pulse of electrical energy (electroporation) directly to the tumour. This treatment results in the formation of reversible pores in the cell membrane, allowing up to a 1000 fold increase in chemotherapy drug absorption (Electrochemotherapy). A significant benefit of this non thermal ablation is the release of tumour associated antigens into the microenvironment, leading to activation of APCs and subsequent cross presentation of the antigens to circulating T and B cells. While ECT facilitates the priming of a favourable immune response, the combination of iCOS antibody, capable of stimulating T cell proliferation, causes a very robust mediated regression of treated tumours. In addition, ICOS is involved in humoral immune responses  and increases the production of IL-4.+ and CD8+ T cells, CD45R+ B cells and CD11c+ DCs, post treatment.Preclinical work in aggressive murine models has yielded very encouraging results. The combinational therapy has achieved cures in both colorectal (CT26) and metastatic lung (LLC) cancer cell lines. Follow up immunohistochemical staining confirmed the presence of tumour infiltrating CD3"}
+{"text": "Sedation management during weaning from mechanical ventilation is an important task for ICU nurses. Nurse-led sedation protocols have a favorable impact on weaning outcome , 2.To identify sedation practices among ICU nurses and to determine barriers towards use of sedation protocols.A cross-sectional, self-administrated survey was developed. Consensus on content validity was achieved through a Delphi procedure among experts. The survey was distributed and collected during the annual congress of the Flemish Society of Critical Care Nurses (Dec. 2014).423 attendants completed the survey (response rate: 66%) of which 342 ICU nurses were included for further analysis. These are employed in general (73%) or university hospitals (27%) and are working in mixed (66%), surgical (18%) or medical (13%) ICUs.Short working agents are most frequently chosen for analgo-sedation. A majority of respondents administer sedatives in continuous infusion with bolus doses (81%). Less than half of nurses have a sedation protocol (44%) but only minority consistently uses it (8%). Nurses in university hospitals reported higher availability of sedation protocols compared to general hospitals . Patient-targeted protocols are most available (53%). They are mostly developed particularly by MDs (79%) and nurses (52%). Level of sedation is generally evaluated per 2 hrs (56%) and with use of a RASS scale (59%). Daily interruption of sedation (DIS) is applied variably  and usually to evaluate the neurological status (86%) and to shorten the duration of ventilation (44%). 78% of nurses report not to apply DIS at night. Patients' discomfort is the most important barrier to execute DIS (49%). Nearly half of respondents pointed out respiratory deterioration is the greatest concern during DIS (47%). For 40% of nurses it is risk of self-extubation and removal of the catheters. Agitation/confusion (66%) and lack of comfort and pain (46%) are the most frequently reported problems associated with sedation reduction.There appears to be a considerable discrepancy between recommendations and sedation practice. This data demonstrate room for quality improvement initiatives."}
+{"text": "Few studies have investigated the use of viscoelastic devices for monitoring of treatment with LMWHs and to our knowledge there are no studies comparing different LMWHs or different visocoelastic methods.Enoxaparin (Klexane) and tinzaparin (Innohep) were added to 2 ml citrated blood from 10 intensive care patients to obtain plasma concentrations of 0, 0.5, 1.0 and 1.5 IU/ml enoxaparin and tinzaparin, respectively. The study was approved by the local ethics committee and with written consent (relatives). Clot formation and clot retraction was studied using ROTEM and ReoRox.ROTEM analysis showed prolonged clot formation (CT) with increasing concentrations of enoxaparin and tinzaparin (more so). ReoRox analysis showed that the initiation of clot formation COT1) increased with increasing doses of enoxaparin and tinzaparin (more so), as did the progression of clot formation (COT2 - COT1), thus resulting in a prolongation until complete clot formation (COT2). See Table  increaseClot initiation was prolonged with both drugs and detected by both ROTEM and ReoRox. Clot formation was more decreased with tinzaparin than enozaparin and only detected by ReoRox."}
+{"text": "Impaired right ventricle (RV) function is associated with worse outcome in ARDS. Pulmonary artery pressure waveform analysis provides information about phenomena that affect RV performance. In particular, pulmonary vascular wave reflection (WR) is directly related with RV stress. We hypothesised that open lung ventilation (OLV), compared with conventional ARDS-net ventilation (CV), would improve conditions for RV performance in an ARDS model. This hypothesis was tested by measuring pulmonary vascular wave reflection (WR).To evaluate the effect of two mechanical ventilation (MV) strategies on WR in an experimental model of ARDS.8 anesthetized and muscle relaxed pigs were submitted to a two-hit lung injury model combining repeated lung lavages with injurious MV. After lung injury was induced, animals were randomized (4 pigs in each group) to one of two strategies of MV: OLV, PEEP 2cmH2O above the PEEP corresponding with the maximal dynamic compliance in a decreasing PEEP trial after a recruitment manoeuvre; or CV, PEEP adjusted according to the ARDSnetwork table. In both groups tidal volume was 6ml/kg, respiratory rate to maintain PaCO2 between 55-65 mmHg and FIO2 to maintain PaO2 55-80 mmHg.1 and quantify WR. The following indexes of WR were calculated: Backward wave amplitude (APbw); Reflection index (RI) which is the ratio between the backward wave amplitude and the sum of backward and forward wave amplitude. Evaluation was done before (BL) and after lung injury (ARDS) and after 4 hours of management in the respective MV strategy.Pulmonary artery (PA) flow and pressure waveforms (1000Hz sampling rate) were acquired by a high-fidelity microtip manometer and an instantaneous transonic pulmonary flow probe placed in the main PA by a small lateral thoracotomy. These signals were used to separate the forward and backward components of the pressure waveformWe did not find any significant changes by induction of ARDS but both APbw  and RI  were lower in OLV comparing with CV.In this experimental ARDS-model OLV decreased WR in the pulmonary vascular system comparing with CV, indicated that OLV could reduce the stress on the RV and improve conditions for RV performance."}
+{"text": "Traumatic injury of the central nervous system (CNS) has severe impact on the patients\u2019 quality of life and initiates many molecular and cellular changes at the site of insult. Traumatic CNS injury results in direct damage of the axons of CNS neurons, loss of myelin sheaths, destruction of the surrounding vascular architecture and initiation of an immune response. Class III semaphorins (SEMA3s) are present in the neural scar and influence a wide range of molecules and cell types in and surrounding the injured tissue. SEMA3s and their receptors, neuropilins (NRPs) and plexins (PLXNs) were initially studied because of their involvement in repulsive axon guidance. To date, SEMA3 signaling is recognized to be of crucial importance for re-vascularization, the immune response and remyelination. The purpose of this review is to summarize and discuss how SEMA3s modulate these processes that are all crucial components of the tissue response to injury. Most of the functions for SEMA3s are achieved through their binding partners NRPs, which are also co-receptors for a variety of other molecules implicated in the above processes. The most notable ligands are members of the vascular endothelial growth factor (VEGF) family and the transforming growth factor family. Therefore, a second aim is to highlight the overlapping or competing signaling pathways that are mediated through NRPs in the same processes. In conclusion, we show that the role of SEMA3s goes beyond inhibiting axonal regeneration, since they are also critical modulators of re-vascularization, the immune response and re-myelination. Class III semaphorins (SEMA3s), apart from their classical axon repulsive properties, exert regulatory functions in a variety of non-neuronal cells associated with CNS trauma.Neuropilins (NRPs) are pleiotropic receptors involved in multiple signaling pathways controlling tissue remodeling following CNS trauma.Semaphorin signaling is regulated at several levels, including receptor complex formation, proteolytic cleavage and interaction with extracellular matrix molecules.Interfering with class III semaphorin signaling might be beneficial for axonal re-growth, re-vascularization, re-myelination and manipulation of the immune response following CNS trauma.The semaphorin family consists of secreted and transmembrane glycoproteins that are involved in many cellular functions. Semaphorins (SEMAs) are subdivided into eight classes based on amino acid sequence similarities and structural features. The first two classes of SEMAs are found in invertebrates, class III till VII belong to vertebrates, while class VIII semaphorins are only expressed by viruses  injuries due to their presence in neural scar tissue. The expression of SEMA3s following CNS trauma is suggested to be important in both the acute and sub-acute/chronic phases of scar formation. To date there is data showing Sema3A mRNA up-regulation as early as 1 day after CNS penetrating lesions  and a small CSPG called Decorin. ChABC digests the chondroitin sulphate (CS)\u2014 glycosaminoglycan (GAG) chains of CSPGs, while decorin suppresses multiple repulsive proteoglycans in the extracellular matrix. Among the repulsive molecules that could be affected from treatment with the above approaches is SEMA3A which in earlier in vitro, but was unable to enhance axonal regeneration and functional recovery after SCI in vivo  from Sema3A-induced apoptosis after optic nerve axotomy  enhances axonal regeneration in an in vitro model of cerebral ischemia. VEGF rescued cultured CNS neurons from hypoxia and glucose deprivation induced apoptosis  and receptor complexes consisting of NRPs and VEGFRs , there is degeneration of the vascular architecture and the hypoxic regions display dysregulated hyper revascularization. Interestingly, the newly formed blood vessels are not capable to reach the neural retina. The inflammatory and ischemic stress induced expression of Sema3A by RGCs prevented revascularization of the eye since RGC-derived Sema3A repelled blood vessels and inhibited EC growth , which in turn, inactivates integrin receptors. Secondly, Sema3E induces the activation of ADP-ribosylation factor 6 (Arf6) positive vesicles that promote internalization of integrin receptors. In contrast to these functions of SEMA3s as inhibitors of angiogenesis and integrin functions, Sema3C promotes angiogenesis in vitro by activation of integrins  and their receptors are key modulators of the immune response  secrete cytokines that can be toxic for CNS neurons, while the non-classical anti-inflammatory type 2 macrophages (M2) can promote neuroregeneration across neuronal repulsive substrates  signaling, which is NRP1-independent, exerting anti-proliferative and immunosuppressive effects that induce fibrosis and non-canonical signaling pathway which is NRP1-dependent and can antagonize canonical signaling  As mentioned earlier in this review blockage of SEMA3s signaling might favor revascularization and thus the innate ability of the organism for effective clearance and recycling of the excessive inflammatory cells through the circulatory pathway; and (2) NRP1 receptors of inflammatory cells may become available for TGF-\u03b2 signaling, which suppress the immune response perhaps more sufficiently than SEMA3s. Therefore, the role of SEMA3s in modulating the immune response after traumatic CNS injury needs to be investigated in more detail.Trauma of the CNS induces mechanical forces that cause loss of OLs and demyelination of axons at and surrounding the injury site. The loss of myelin sheaths decreases the conduction velocity of action potentials and could result in axonal degeneration. The reestablishment of myelin sheets around demyelinated axons and around newly sparsely formed regenerating axons, a process called remyelination, is therefore important to regain neuronal function after brain and spinal cord injuries  axonal regeneration; (2) re-vascularization; (3) immune response; and (4) re-myelination (Figure  axonal rIn the sub-chronic and chronic phase of CNS injury SEMA3s may inhibit axonal regeneration by inducing apoptosis of neurons and by preventing axons to penetrate scar tissue. They may also restrict re-vascularization by SEMA3B inhibition of the recruitment of pericytes that normally stabilize new blood vessels and by SEMA3A mediated elevation of the vascular permeability of blood vessels even when the expression of VEGFA declines. This increased vascular permeability may have a direct impact on the chronic immune response where SEMA3s are shown to inhibit the proliferation of recruited T-lymphocytes and antagonize the synthesis of cytokines such as IL-2, IL-4, IL-10 and IFN\u03b3. Furthermore SEMA3A induces apoptosis of microglia that express NRP1 and thereby influence the survival and axonal regeneration capacity of injured CNS neurons. Additionally SEMA3A induces cell death of M2 macrophages and could thereby induce a \u201cpro-inflammatory\u201d M1 macrophage environment in the scar. An intriguing but yet not fully established hypothesis is that SEMA3s might modulate TGF-\u03b2 non-canonical signaling via NRPs at inflammatory cells near the scar tissue. Finally, re-myelination is also affected by SEMA3s at the chronic stages of injury. In particular SEMA3A inhibits the recruitment and differentiation of OPCs and inhibits the mobility of migrating Schwann cells. In contrast, SEMA3F promotes OPC migration and remyelination. Lastly, SEMA3A signaling via NRP1 might antagonize furin-processed SEMA3F, EGF and PDGF signaling pathways that all posses the ability to stimulate remyelination.Since the discovery of Sema3A in 1993, SEMA3s signaling and their receptors were increasingly recognized to be involved in key processes influencing axonal outgrowth and guidance. However, substantial evidence indicates that SEMA3s also participate in cell-to-cell communication systems that underlie angiogenesis, inflammation and re-myelination. It will be necessary to combine the knowledge obtained from the research fields of vascular biology, cancer biology, immunology and glial biology in order to better understand the role of SEMA3s signaling in CNS trauma. A combinatorial approach involving these fields of research may be necessary in order to move closer towards a therapy for traumatic CNS injury. SEMA3s are an important target in strategies that aim to repair traumatic spinal cord and brain injuries, however the sometimes overlooked pleiotropic nature of their NRP receptors needs to be addressed/understood in a more thorough fashion in future studies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Growing demand of resources increases pressure on ecosystem services (ES) and biodiversity. Monetary valuation of ES is frequently seen as a decision-support tool by providing explicit values for unconsidered, non-market goods and services. Here we present global value transfer functions by using a meta-analytic framework for the synthesis of 194 case studies capturing 839 monetary values of ES. For 12 ES the variance of monetary values could be explained with a subset of 93 study- and site-specific variables by utilizing boosted regression trees. This provides the first global quantification of uncertainties and transferability of monetary valuations. Models explain from 18% (water provision) to 44% (food provision) of variance and provide statistically reliable extrapolations for 70% (water provision) to 91% (food provision) of the terrestrial earth surface. Although the application of different valuation methods is a source of uncertainty, we found evidence that assuming homogeneity of ecosystems is a major error in value transfer function models. Food provision is positively correlated with better life domains and variables indicating positive conditions for human well-being. Water provision and recreation service show that weak ownerships affect valuation of other common goods negatively (e.g. non-privately owned forests). Furthermore, we found support for the shifting baseline hypothesis in valuing climate regulation. Ecological conditions and societal vulnerability determine valuation of extreme event prevention. Valuation of habitat services is negatively correlated with indicators characterizing less favorable areas. Our analysis represents a stepping stone to establish a standardized integration of and reporting on uncertainties for reliable and valid benefit transfer as an important component for decision support. Goods and services obtained from nature\u2013ecosystem services (ES)\u2013are essential for human well-being , 2. ManyDespite this critique ES are valued in prominent assessments of natural capital , 18, 19,A first major critique refers to benefit transfer in its basic form. Benefit transfer averages monetary values (point estimates) from study sites and transfer them to a similar unsampled area by accounting for land use/land cover types only , 28, 29.A second critique originates from the complexity and heterogeneity of human-environmental systems. Due to the variation in site characteristics, e.g. socio-economic or biophysical feature , 31, andWith this publication we i) provide a conceptual base supporting the establishment of a standardized integration and reporting on uncertainties of benefit transfer. Building on this we ii) assess the transferability of monetary values of ES and identify major sources of uncertainty by using meta-analytical value transfer functions.We generated a spatially explicit database of 194 globally distributed cases studies covering 839 monetary values of ES from peer reviewed data collections , 36. We We combined two, peer reviewed databases with monetary valued ES , 36, seer >0.75 or r< -0.75) and Spearman\u2019s rho (\u03c1>0.75 or \u03c1< -0.75), for two categorical covariates chi-square test and for testing categorical and continuous one-way ANOVA. From 291 covariates 93 remaining were combined with the maps of standardized monetary values by overlay operation in ArcGIS. Combined maps were used as input for the value transfer functions . A BRT computes the relative influences (importance) of covariates for a BRT model, i.e. they identify major determinants of the variance in monetary values of ES. BRT also provide elasticity curves  that account for non-constant marginal value changes over distinct socio-ecological conditions and thus quantify the change of monetary values in response to an alteration in one covariate (i.e. ceteris paribus) ; see S2 We tested different parameter of the BRT algorithm such as learning rate, tree complexity, minimal number of observations in terminal nodes and number of trees see , and choStatistical significant value transfer functions could be computed for 12 ES types based on 839 monetary values . Most important covariates were quantified and monetary values in unsampled areas extrapolated . If therIn an additional step confidence intervals were estimated to examine generalization failure of value transfer functions from training data . We reruFor the discussion of the results we conceptualized three major sources of uncertainty of value transfer functions: (i) Sample error, such as measurement error in input studies for value transfer functions or publication selection bias; (ii) errors originating from statistical estimation of BRT models (model performance and suitability of chosen approach for benefit transfer); and (iii) transfer error from generalization that encompasses distortions due to value transfer without fully accounting for site and study characteristics. Only covariates with >1%  were analyzed for the six groups of covariates. Additionally, in a fourth point we provide information of the spatial application of the value transfer functions.All studies considered in the synthesized database  come froThe final 12 cross-validated value transfer functions explain from 18% (water provision) to 44% (food provision) of the variance of monetary values . FurtherResults from the quantification of the importance of covariates for the value transfer functions indicate which site and study characteristics need to be considered in order to minimize transfer error from generalization. In The application of the value transfer function for spatial extrapolation of values in unsampled areas results in a map shown in In the following section we discussed the results in detail for 6 out of 12 ES. Food and water provision, climate and extreme events regulation as well as recreation and habitat service were selected, because they represent the highest variance of monetary values from each ES group , see Available input data: With 158 monetary values the largest data set is available for food provision. The majority of case studies examine fish provision (51%) in lower latitudes (93%) and in coastal ecosystems or inland wetlands (69%). Lower latitudes  are most likely food-insecure regions with a high vulnerability to climate change . CoastalModel uncertainty: The value transfer function shows the lowest uncertainty and explains 44% of the variance in the data. Estimations of the confidence intervals show that for 91% of the terrestrial earth surface monetary values can be computed with low and medium uncertainty (1 to 80 Int.-$-2007 per ha), due to a high number of data points .Importance of covariates: Most important covariates are climate indicators (22%), followed by geographic and nature endowment (15%) and valuation methods (15%). Further influential are social covariates such as better life domains of human well-being (12%) and religion (3%) as well as the economic covariate agricultural subsidies (3%).2 per grid cell). Variance explained by distance to sea (9%) is a logical consequence from the distribution of studies and the focus on fish as food resource. In more landlocked areas the importance of fish in the food supply reduces and so does the monetary valuation of fish. Moreover, the type of biome explains 6% of the variance, but does only partly coincide with the land use classification used on the case studies itself. These show that coastal wetlands, coastal systems and cultivated areas (aquaculture) are most valued, and confirm previous findings from [Ecology: Covariates indicating climate and those on geographic and nature endowment show low values in areas with prevailing unfavourable growing conditions  and low human-induced alteration of ecosystems  <11%) or high amounts of alternative food products , followed by benefit transfer (17%) and group valuation (5%). With group valuation significant lower values are derived. Most studies (75%) based on group valuation were conducted for fish in India, a country where fish consumption represents only 2% of protein intake , which mSociety: The valuation of food increases with a lower unemployment rates (<10% of labour force) and a high number of people in working age (15\u201359 years), good education system  as well as with improving sustainable well-being measured by years of life satisfaction achieved per unit of resource used (Happy Planet Index). These covariates directly relate to the better life domains of the Organisation for Economic Co-operation and Development (OECD), which are essential metrics for human well-being . This shEconomy: With increasing subsidies in agricultural sector the value for food provision decreases. Subsidies distort markets by promoting the production of agricultural commodities beyond market demand, thus, they encourage farmers and fishermen to rely on them instead of consumer wants .Application of value transfer function: Spatial extrapolation of values shows for food the highest uncertainties and lowest values are in India and parts of Africa . On contAvailable input data: For water provision one of the smallest datasets was available (26 case studies). Most of the case studies were conducted in climate sensitive lower latitudes (63%). Climate change is affecting the hydrologic cycle and directly impacts the water resource base, usage, and management, in particular in lower latitudes .Model uncertainty: The value transfer function for water provision shows the highest uncertainties and explains 18% of the variance . ConfideImportance of covariates: Most influential are ecosystem-based covariates that indicate biodiversity and water availability (67%), followed by type of biome (3%). Further important are covariates of social and economic indicators (22%).2 per grid cell), in particular, agricultural frontier areas of cropland foster high values for water provisioning . Third, deforestation explains 3% of the variance and is positively correlated with water values. Water availability, moreover, depends on the spatial (3%) and temporal allocation of water resources (2%). The more unequal rivers and lakes are distributed in an area the higher is the value for water provision. Seasonal variability or long-term climatic changes cause extended periods of droughts or water abundance. The type of biome explains 3% of the variance. However, the applied land use classification system differs from the actual biome type of the case studies. Taking case study based classification into account coastal wetlands and freshwater (rivers/lakes) show highest values, confirming [Ecology and society: Areas of high biodiversity threat and conservation value are positively correlated with monetary values and explain 21% of the variance. Biodiversity and water supply are strongly interrelated , 53. Drinfirming , 28, 29.Economy: The portion of privately owned forests is positively correlated with water provision value (5%). This confirms that weak ownerships might affect valuation of other common goods negatively . SimilarApplication of value transfer function: Spatial extrapolation of values shows the most certain and highest values in areas of high population growth and increasing pressures on water security, for instance in China, India, Java, eastern USA, south Mexico and Western Central America, south coast of Western Africa, and Mediterranean Europe . TransfeAvailable input data: From a total of 36 case studies , carbon sequestration was most frequently examined (68%), followed by other greenhouse gases (<2%) or remain unspecified (24%). The majority of studies were carried out in tropical and temperate forests (25%) as well as inland and coastal wetlands (45%). These biomes are seen as regions highly suitable for carbon sequestration , 59. MorModel uncertainty: With 38% of variance explained in monetary values the transfer model for climate regulation represents the third best prediction performance . For mosImportance of covariates: The most important covariates are ecosystem-based variables of nature threats (49%). Also relevant but explaining less of the variance are covariates indicating input measures of climate sensitive economic sectors (20%) and other economic variables (6%), followed by scale (7%), methods (6%) and social variables (4%),3) exist. Furthermore, the economic covariate inequality of income (6%) shows that the more unequal income is distributed the higher the value for climate regulation.Ecology and economy: Covariates of nature threats show that high values are associated with areas of high risk that unique biodiversity will soon be lost (30%) and high risk of erosion (19%). Covariates indicating input measures of climate sensitive economic sectors (e.g. energy production and water business) are positively correlated with monetary values for climate regulation. Most important covariates are: proportion of electricity production from hydroelectric sources (12%), annual mean of solar radiation (6%) and the water storage capacity of dams per country (2%). Values are high, for instance, in areas of lower latitudes where up to 99% of electricity is produced by hydroelectric power plants and where big artificial constructed water reservoirs , followed by direct market prices (16%) and avoided costs (11%). For direct market prices the highest values and for benefit transfer and replacement costs the lowest ones can be observed.Society: Social covariates of relevance are population density per country (2%) or the age of population (2%). Population density is negative correlated with monetary values. Surprisingly, case studies in countries with on average older population report higher values of climate regulation. One might hypothesize older people may have made in their lifetime perceiving changes in climatic conditions and associated consequences, thus, valuing climate regulation service higher than younger persons. This might be an indication for the \u201cshifting-baseline\u201d hypothesis, i.e. shifts of the reference points of human perception for estimating changes .Application of value transfer function: Applying the value transfer function shows that the most certain and highest values are computed for areas under threat of habitat alteration due to climate change or other land degradation processes. Examples are areas like the Sahel Zone, tropical islands and mountains, Mediterranean ecosystems, Eastern USA and parts of Europe . On contAvailable input data: The majority of case studies (82%) were conducted in areas of high vulnerability to extreme events and sites which are increasingly exposed to extreme events due to climate change \u201363. In 4Model uncertainty: The value transfer function for prevention of extreme events represents medium prediction performance and explains 21% of the variance in monetary values . TransfeImportance of covariates: The impact of extreme events depends on both ecological conditions and societal vulnerability. We found that with 64% the highest explanatory power is represented by covariates showing the inherent conditions of ecosystems, followed by socio-economic characteristics (33%) and covariates dealing with the spatial and temporal scale (3%).Anthropogenic pressure on the ecosystem: Extreme event prevention is valued high in areas with advanced anthropogenic alteration of ecosystems characterized by highly changed biomass (HANPP 13%), high agricultural induced soil erosion rates (10%), degraded freshwater resources and riverine biodiversity (10%), dense infrastructure (5% market access), dense settlements with major markets (4% Anthromes) and high population density (3%). Hence, the risk awareness to weather extremes and natural hazards increases with number of people potentially effected and higher level of land-use and degradation. The more risk aware a society is, the more weight it places on strategies that preserve or build ecosystem resilience, and the higher the value it would allocate to ecosystem configurations that are more robust . This isSpecies richness and unemployment: We also found that areas with high species richness (4%) and high level of conservation priority (3%) show high valuation for extreme event prevention. These areas are characterized by high population, the highest population growth rates globally , 56 and Application of the benefit transfer function: Using the value transfer model for spatial estimations of extreme event prevention show that the most certain and highest valuations are situated in densely populated areas with advanced anthropogenic altered environments . The larAvailable input data: The database for the ES recreation services captures with 96 the most case studies. The majority of studies were conducted in major non-religious and Christian sites (73%) as well as lower latitudes (77%). Studies in developing countries  < 4024 US-$) are underrepresented (26%). Subcategories of recreation services investigated are tourism (41%), hunting (<1%), ecotourism (<1%) and unspecific recreation (47%).Model uncertainty: The value transfer function for recreation services is with 33% variance explained the fourth most certain model . ConfideImportance of covariates: With 32% ecosystem-based covariates are the most influential group. In comparison with other value transfer functions, however, this is the lowest value . Further2 and a soil moisture index of 1 to 1.6. This corresponds to areas in the (sub-) tropics, see Ecology: More homogeneous environments receive lower values for recreation. The value transfer function shows that areas are low valued with intensive agricultural use (6%), a high number of people living on degraded land (2%) and low number of terrestrial protection areas (4%) and biodiversity (2%) as well as low ethnic diversity (1%). Surprisingly there is a negative effect of marine protection areas (4%) and length of coastlines (1%). This is due to the low number of case studies carried out in coastal areas (17%) and marine protection areas (16%). Furthermore, covariates on land use/land cover types explain 9% of the variance and show that wetlands and freshwater areas (river/lakes) are highest valued. The most important climatic covariates are solar radiation (3%) and soil moisture (2%). The latter one is strongly correlated with precipitation. Highest monetary values are shown for areas with 100 to 190 W/mEconomy and society: Economic covariates show that recreation is highly valued in wealthy countries. These countries are characterized by high market access (3%), low GDP growth (3%), low consumer prices (2%), positive trade balance and a high level of export to import ratio (3%). In wealthy countries the access to a greater share of ES and substitutes is provided, thus, the basis for recreation given. However, in areas with a high unemployment rate (6%) recreation values are high, too. We hypothesize these are sites where tourism is already established and an important economic factor. With increasing portion of privately owned forests the value for recreation is higher (1%). This shows that with the granting of property rights the valuation of common goods might be positively affected  and emphApplication of value transfer function: Applying the value transfer function shows that the most certain and highest values are in the USA, most of the Mediterranean area, Caribbean islands, and Colombia . These aAvailable input data: The database for habitat service contains one of the smallest numbers of case studies .Importance of covariates: The group of ecosystem-based covariates contributes with 90% to the value transfer function . These aEcology and society: Habitat services are valued less in marginal areas, i.e. harsh growing conditions due to low soil quality (24%), arid climate zones with high drought potential (16%) and high UV exposure (26%). Marginal areas are mostly sparsely populated (1%) and characterized by low market access (3%). Also those areas are the home of poor people , 73 withApplication of value transfer functions: Spatial extrapolation shows the most certain values in low valued marginal areas like the highlands and drylands of Asia and sub-Saharan Africa, transition zones of the grassland to deserts of Australia as well as southern Latin Americas Andes Mountains, and the highlands and drylands of North America .Although \u201cmoney\u201d is seen as a well-known and easily understandable indicator, monetary valuation of ES is ambiguous and shows only a fraction of the multiple characteristics that give utility to the beneficiary . ApplyinThe data availability and the quality of input studies determine the sampling error. We only included valuation studies that were reviewed by experts as a minimal assurance of study quality. Although the peer review approach is often criticized it is also appreciated as an efficient method that increased the scientific progress over the past decades . The majAnother concern with respect to the input data refers to the aggregation of the monetary values. In order to create a comparable data base for spatially explicit value transfer modelling, monetary values need to be disentangled. Only values measured under marginal changes in the socio-ecological system were considered . We utilUtilizing BRT for spatially explicit, meta-analytic value transfer functions have inherent causes of error, too. Although this method is acclaimed to be one of the most sophisticated approaches for benefit transfer , 82 the The spatial application of the value transfer functions in unsampled areas generates transfer errors from generalization, which are determined by uniformity, spatial extent and resolution  as well as temporal aspects , 83. We Regionalization error encompasses extrapolation errors due to generalization from a local case study to a wider region . All valThe major achievement of this study is, first, to clearly distinguish between major sources of uncertainties and to quantify patterns in the influence of different study- and site-characteristics that affect value transfer functions and predicted ES values. Second, the study identifies regions for which sufficient knowledge on our natural capital is available, i.e. a statistically defensible benefit transfer model can be applied in combination with uncertainty values. Third, we provide global maps of the \u201cwhite spots\u201d on our knowledge on accounting natural capital and ES. This provides guidance for future analysis and concerted action on the assessment of natural capital and ES within the work program of IPBES  and the The integration of the presented value transfer functions in a fully automated spatial benefit transfer tool, such as the Ecosystem Valuation Toolkit , would bS1 FigThis map is the completion of the (TIF)Click here for additional data file.S2 FigTreemaps A) to L) represent models with covariates greater than 1%, their relative influence (or importance) and response. Rectangle groups delimited by bold black lines and numbered from 1 to 7 reflect groups of covariates mentioned in the main article (1) scale, 2) economy, 3) policy, 4) society, 5) ecology, 6) valuation methods, 7) rest <1%). The sizes of rectangles show the relative influence of covariates on a BRT model, in percentage. Rectangle colours illustrate the strength of relationship between monetary values and covariates. Greenish colours symbolize positive correlation and reddish negative, expressed in International-$-2007 per hectare. Multiple colours can occur for nonlinear effects of variables. Bluish colours represent categorical variables and show the maximum range between the levels.(TIF)Click here for additional data file.S3 FigThe graphs show the model performance for twelve parameter configurations. In the table below these configurations are specified. In addition to learning rate (lr), number of trees (nt) and minimal number of observations in the terminal nodes (mintn), there is also the selected model visualized. The selected model represents the final BRT model used for value transfer. It reduces the deviance of residuals in the model (squared error loss) the most and thus explains the variance of monetary values best.(TIF)Click here for additional data file.S1 TableThe table gives an overview of the case study references that were included for the boosted regression trees.(PDF)Click here for additional data file.S2 TableThe table shows sources of covariates either from valuation databases , 36 or f(PDF)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file."}
+{"text": "Parkinson Disease (PD) is a neurodegenerative disease for which no cure is available yet. It is the second largest neurological disease affecting an estimated 571 per 100,000 people in Europe with rising prevalence due to the aging population  sensory cues from the music as well as from the dance partner  reported no adverse events during dance classes  reported one single fall with no injury , ParkinsonFonds (20094), and EU (ERC-291339). EV received research-funding from ZonMw (630000012), Parkinson Vereniging (2013R16), ParkinsonFonds (20094), and the Hersenstichting (F2013141).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ablation of adult neurogenesis in mice has revealed that young adult-born granule cells (abGCs) are required for some of the behavioral responses to antidepressants (ADs), yet the mechanism by which abGCs contribute to AD action remains unknown. During their maturation process, these immature neurons exhibit unique properties that could underlie their ability to influence behavioral output. In particular, abGCs in the DG exhibit a period of heightened plasticity 4\u20136 weeks after birth that is mediated by GluN2B-expressing NMDA receptors. The functional contribution of this critical window to AD responsiveness is unclear. Here, we determined the behavioral and neurogenic responses to the AD fluoxetine (FLX) in mice lacking GluN2B-containing NMDA receptors in abGCs. We found that these mice exhibited an attenuated response to FLX in a neurogenesis-dependent behavioral assay of FLX action, while neurogenesis-independent behaviors were unaffected by GluN2B deletion. In addition, deletion of GluN2B attenuated FLX-induced increases in dendritic complexity of abGCs suggesting that the blunted behavioral efficacy of FLX may be caused by impaired differentiation of young abGCs. Adult hippocampal neurogenesis is a process that results in the generation of new neurons in the dentate gyrus (DG) throughout life Gross, . After tDuring the maturation process, abGCs exhibit distinct properties that could underlie their ability to influence behavioral output  of Grin2b. In the presence of Cre, exon 9 gets excised. Western blotting performed using an antibody that targets the C-terminal domain downstream of exon 9 has shown decreased GluN2B expression following Cre recombination, demonstrating that excision of exon 9 results in the complete absence of GluN2B, not merely a truncated protein product  was injected  once per day for 2 days just prior to the start of AD treatment. For dendritic morphology analysis, AD treatment began ~5 weeks after TMX administration and BrdU  was injected 4 times over 8 h the day before AD treatment began. For all mice, FLX (18 mg/kg/day in water) or vehicle  was delivered by oral gavage and in the drinking water (160 mg/mL) at a schedule of 5 consecutive days gavage followed by 2 consecutive days of water, then repeated for the duration of treatment.All behavioral experiments were conducted in male mice 18\u201324 weeks of age.In the novelty suppressed feeding (NSF) test, chronic AD treatment decreases latency to feed in the center of a novel arena after overnight food deprivation  is a behavioral despair test during which the mobility of mice suspended by their tail is measured. A depressed-like state is characterized by greater immobility while ADs are able to decrease immobility  consisting of both open and closed arms and were given 5 min to explore. The test was video recorded and activity was measured using TopScan software. Their preference for open (anxiogenic) or enclosed (anxiolytic) spaces was used to assess anxiety Hogg, .http://fiji.sc/Fiji) where dendritic length was measured using the freehand trace tool and Sholl analysis was conducted using the Sholl analysis plug-in with parameters previously described , brains postfixed, cryoprotected, and sections (35 \u03bcm) of the entire DG were labeled for BrdU, glial fibrillary acidic protein (GFAP), neuronal nuclei (NeuN), doublecortin (DCX), Ki-67, or green fluorescent protein (GFP) , as previously described , while an encoding region immediately preceding the first transmembrane domain of GluN2B is flanked by loxP sites . TMX injection in adult mice leads to deletion of GluN2B and expression of YFP in neural precursor cells (NPCs) and their subsequent progeny  or in an assay of anxiety that was insensitive to FLX in this strain of mice (EPM). While some studies in rodents do find that chronic AD treatment results in an anxiolytic phenotype in the EPM -dependent mechanism. Chronic SSRIs have been shown to increase BDNF in the DG . RH is supported by the National Institute of Mental Health (R37 MH068542 [MERIT]), the National Institute on Aging (R01 AG043688), the National Institute of Neurological Disorders and Stroke (R01NS081203), NYSTEM (C029157), and the Hope for Depression Research Foundation (RGA 11-024). MK was supported by a NIH grant (K01MH099371), a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation, and NYSTEM (C029157).RH receives compensation as a consultant for Roche and Lundbeck. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Mortality of ICU patients is a global parameter reported as an end-point in numerous studies. However, causes and characteristics of patients' death are studied only in particular pathologies such as sepsis, cardiac arrest or ARDS , 2)..2]).The aim of our study was to analyse causes and circumstances of death in a general ICU population.We performed a prospective observational study. Every ICU included all death occurring during a month randomised in the year of the study. Demographic data were collected as well as circumstances of death (organ failure and organ support at this time). An organ failure was defined by a SOFA sub-score \u2265 3. Population of the study was dichotomised in expected death  and unexpected death . Data are expressed as median and IQR. Comparisons were made by a Mann-Whitney or chi-squared tests as appropriate. A p value < 0.05 was considered as statistically significant.Ninety-six ICUs included 698 dead patients during the study time. Main characteristics of the population and their comparison between expected (n=473) and unexpected deaths (n=225) are reported in the table.At the time of death, 586 (84%) patients presented at least one organ failure: cardiovascular (58%), respiratory (31%), renal (33%), neurologic (30%), liver (8%) and coagulation (8%). At the same time, an organ support was used in 440 (63%) patients: catecholamines (63%), mechanical ventilation (85%), renal replacement therapy (28%) and liver dialysis (1%). Comparison of these parameters between groups is reported in the figure.Patients who died in ICU presented, most of the time, at least one organ failure. Expected death patients exhibited more neurologic and respiratory failures whereas cardiovascular failure was more prominent in unexpected death. In the latter group of patients, the proportion of organ support was higher corresponding to a greater intensity of care."}
+{"text": "The PI3K-AKT pathway has been shown to complement activation of the MAPK pathway in melanocyte transformation in preclinical models. We have utilized clinical specimens and cell lines to examine the regulation, functional role, and clinical significance of the PI3K-AKT pathway in melanoma.All analyses of clinical specimens were performed under protocols approved by the MD Anderson Institutional Review Board. Identities of cell lines were confirmed by STR-fingerprinting, and cell lines were genotyped by sequenom analysis for hotspot mutations. Reverse phase protein array (RPPA) analysis was performed by the MD Anderson RPPA Core Facility.Proteomic analysis of frozen melanoma clinical specimens and cell lines demonstrated that phosphorylation (activation) of AKT (P-AKT) correlated inversely with PTEN protein expression. Confirmatory analysis of PTEN expression by an immunohistochemical (IHC) assay on archival tumor samples identified a linear correlation between PTEN measurement by IHC and RPPA. Significantly increased expression of P-AKT was observed in melanomas with complete loss of PTEN protein expression compared to tumors with any other pattern of PTEN expression. Integrated analysis of BRAF/NRAS mutation status, PTEN expression, and clinical outcomes was performed using lymphadenectomy specimens from patients who underwent surgery for stage IIIB/C melanoma. Complete loss of PTEN expression correlated with shorter overall survival and time to brain metastasis on univariate and multivariate analyses. Testing of human melanoma cell lines demonstrated that cells with baseline or compensatory activation of the PI3K-AKT pathway were generally resistant to apoptosis induction following BRAF or MEK inhibition. Extended molecular profiling found that a subset of melanoma cell lines with de novo and acquired resistance to MEK inhibitors are characterized by increased expression of PGC1alpha and a metabolic phenotype of high oxidative phosphorylation (OxPhos). The resistant high OxPhos cell lines all demonstrated synergistic growth inhibition and apoptosis induction with combined targeting of MEK and mTORC1/2. mTORC1/2 inhibition decreased PGC1alpha expression in vitro and in vivo, and caused cytosolic localization of MITF. Treatment with a MEK inhibitor and an mTORC1/2 inhibitor demonstrated marked synergy in a BRAF-mutant, MEK inhibitor resistant human melanoma cell line in vivo.Activation of the PI3K-AKT pathway correlates with clinical outcomes and resistance to MAPK pathway inhibitors in melanoma. These findings support the rationale to determine the clinical benefit of inhibiting the PI3K-AKT pathway in this disease."}
+{"text": "We hypothesize that changes of shape of arterial blood pressure (ABP) high-frequency waveform signal can be reflective of body's response to stress, in particular to hemorrhage.To apply Machine Learning (ML) and sequential pattern extraction to ABP waveforms to reliably detect slow bleeding.62 healthy pigs are anesthetized, intubated, ventilated, and instrumented prior to and during a controlled bleeding at a rate of 20 ml/min. ABP is recorded at a 250 Hz rate. To estimate the likelihood of bleeding, our algorithm:(1) Extracts 10 s disjoint intervals of ABP waveform and standardizes the time series to zero mean and unit standard deviation;(2) Discretizes the standardized data into a sequence of symbols each reflective of a particular value of the standardized ABP;(3) Identifies which sequential patterns of symbols are present in the current interval data from among patterns previously extracted from training data using SPADE algorithm ;(4) Feed the identified sequential patterns into previously trained ML classifier (Random Forest) to predict current bleeding status of the subject. The procedure is empirically evaluated using leave-one-pig-out crossvalidation.Figure In addition, our method enables easy interpretation of learned patterns. An example in Figure ML and sequential pattern extraction enables effective monitoring of ABP waveforms for indications of hemorrhage. The presented approach can be used to enhance current practice of hemodynamic monitoring while helping clinicians interpret patterns of patients' physiological response to stress.Work partially supported by NSF (award 1320347) and by NIH (grant NR013912)."}
+{"text": "Magnetic resonance (MR) conditional pacemakers are increasingly implanted into patients who may need cardiovascular MR (CMR) subsequent to device implantation. While the safety profile appears good, limited data exists regarding the indication and outcome of these examinations for clinical management.CMR and pacing data from consecutive patients with MR conditional pacemakers performed at our centre was retrospectively reviewed. Images were acquired at 1.5T (Siemens Magnetom Avanto). The indication for CMR and any resulting change in management was recorded. The quality of CMR was rated by an observer blinded to clinical details and data on pacemaker and lead parameters collected pre- and post- CMR.45 CMR scans on 42 patients performed between 2011 and 2014 were assessed. All scans were completed successfully with no significant change in lead thresholds or pacing parameters. Steady state free precession (SSFP)cines were non-diagnostic in 6/45 (13%) scans, but diagnostic in all patients when using gradient echo sequences (GRE). Late gadolinium enhancement imaging was performed in 39 patients and appeared less susceptible to artefact than cine images.The CMR data resulted in a new diagnosis in 19 (42%) of examinations, clinical management was changed in a further 14 (31%).CMR in patients with MR conditional pacemakers provided diagnostic or management-changing information in the majority (73%) of our cohort. The use of gradient echo cine sequences, which are less susceptible to metal artefacts, can reduce rates of non-diagnostic imaging.The study was funded by the NIHR Cardiovascular BRU. CER is supported by the British Heart Foundation."}
+{"text": "To compare the effectiveness of constraint induced movement therapy versus motor relearning programme to improve motor function of hemiplegic upper extremity after stroke.A sample of 42 patients was recruited from the Physiotherapy Department of IPM&R and Neurology OPD of Civil Hospital Karachi through non probability purposive sampling technique. Twenty one patients were placed to each experimental and control groups. Experimental group was treated with Constraint Induced Movement Therapy (CIMT) and control group was treated with motor relearning programme (MRP) for three consecutive weeks. Pre and post treatment measurements were determined by upper arm section of Motor Assessment Scale (MAS) and Self Care item of Functional Independence Measure (FIM) Scale.Intra group analysis showed statistically significant results  in all items of MAS in both groups. However, advanced hand activities item of MAS in MRP group showed insignificant result . Self-care items of FIM Scale also showed significant result  in both groups except dressing upper body item  in CIMT group and grooming and dressing upper body items  in MRP group showed insignificant p-values.CIMT group showed more significant improvement in motor function and self-care performance of hemiplegic upper extremity as compared to MRP group in patients with sub-acute stroke assessed by the MAS and FIM scales. Thus CIMT is proved to be more statistically significant and clinically effective intervention in comparison to motor relearning programme among the patients aged between 35-60 years. Further studies are needed to evaluate CIMT effects in acute and chronic post stroke population. Stroke is the third leading cause of death and the most common cause of disability in the developed and developing countries. In Pakistan it is the leading cause of mortality and morbidity after cancer and ischemic heart disease.3Rehabilitation of upper extremity is a challenge, various therapeutic strategies like neurodevelopmental technique (NDT), splinting, biofeedback and electrical stimulation are designed, however the best method to improve upper limb function is still not clear.9This study is a randomized controlled trial carried out to evaluate the effectiveness of CIMT over motor relearning programme. Constraint induced movement therapy (CIMT) is proved to be effective in western countriesIn this randomized controlled trail 42 males and females stroke patients having first attack of stroke and hemiplegic upper extremity had functional level of \u2265 20 degrees of wrist extension and \u226510 degrees of extension of all digits were included. Subjects were between 35-60 years of age and diagnosed with ischemic or hemorrhagic strokes confirmed by CT/MRI scan. Patients were excluded if they had cognitive deficit, recurrent or cerebellar strokes, severe aphasia, balance and equilibrium problems, severe shoulder pain affecting therapy or other neurological deficits.The research was started after approval from institutional review board (IRB) of Dow University of Health Sciences (DUHS). Sample was recruited from Physiotherapy department of Institute of Physical Medicine & Rehabilitation (IPM&R) and Neurology OPD of Civil Hospital Karachi through non-probability purposive sampling technique. Informed consent was taken from the patients. Then patients were randomly allocated to CIMT group and MRP group by using computer-generated random numbers kept in sealed envelopes. Each group had 21 patients. After baseline assessment, patients in CIMT group were asked to perform tasks only with the hemiplegic upper extremity with the unaffected hand restraint in a mitt. The patients in MRP group were asked to perform tasks with both affected and unaffected upper extremities. Tasks were attempted in different positions like supine lying, sitting and standing.th visit. All the exercises were demonstrated to the patients by the therapist and were performed under the supervision of the therapist. Details of exercises are given in Both interventions consisted of 6 sessions per week, two hours duration of each session, for three consecutive weeks. Pre and post treatment evaluation of motor function of hemiplegic upper extremity was determined by using upper arm section of Motor Assessment Scale. Upper limb section of MAS includes, Upper arm function item, hand movements item and advanced hand activities item. An activity of daily livings (ADLs) was measured by using self care item of Functional Independence Measure Scale (FIM) which includes 5 items  for quantitative data. A Non parametric Wilcoxon Signed Ranks test was conducted to find the significance of interventions used within the groups . To test the significance of changes in scores on each of the outcome measures  between the groups , a Non parametric Mann Whitney test was used both at the baseline and at the end of 3A sample of 42 patients participated in the study and no patient dropped out. There were total 28 male participants (66.67%) and 14 (33.33%) female participants in both groups, the distribution of males and females in each groups was almost equal. The mean age of the participants was 49.67 years (SD = 7.01) in CIMT group and 49.47 years (SD = 8.19) in MRP group. Total patients who suffered from ischemic stroke were 32 (76.2%) and number of patients having hemorrhagic stroke were 10 (23.8%) respectively. At the end of third week, mean scores significantly increased in all items of both outcome measures (MAS and FIM) in both CIMT and MRP groups. However, mean value in CIMT group was greater than in MRP group, showing better improvement in CIMT group  & III. Ird week. Post treatment P-value showed statistically significant results  in all items of MAS and FIM Scale accept dressing upper body item.For inter-group analysis a non parametric Mann Whitney test was used at baseline and at the end of 3This study showed the effectiveness of constraint induced movement therapy (CIMT) over motor relearning programme (MRP) to improve motor function of hemiplegic upper extremity in sub-acute stroke patients. The affected patients in the present study were between two weeks to three months post stroke. CIMT initiated within 2 weeks of stroke onset is more effective in upper extremity rehabilitation.12This study results are in agreement with Myint et al. (2008)9In the present study an alteration was made from the original protocolCIMT is considered to attain its beneficial effects by 2 associated but independent mechanisms: overcoming learned nonuse and use-dependent neural plasticity.18The second mechanism by which CIMT has been established to give good functional results is use-dependent neural plasticity.20CIMT group showed more significant improvement in motor function and self-care performance of hemiplegic upper extremity as compared to MRP group in patients with sub-acute stroke assessed by the MAS and FIM scales. Thus CIMT is proved to be more statistically significant and clinically effective intervention in comparison to motor relearning programme among the patients aged between 35-60 years. Further studies are needed to evaluate CIMT effects in acute and chronic post stroke population."}
+{"text": "Maturity Onset Diabetes of the Young 3 (MODY3) is the most common monogenic form of diabetes, characterized by early age of onset (before the age of 25), autosomal dominant transmission and severe defect in insulin secretion ,2. MODY bmf gene expression knockout on beta cell mass and islet organisation in a transgenic mouse model of MODY3.To study the role of Bmf (Bcl-2 modifying factor) in the pathogenesis of MODY3, immunohistochemical staining of male and female pancreatic islets for insulin- and glucagon-positive expression utilising confocal microscopy followed by Image J analysis were used to investigate the effect of Bmf gene expression knockout was observed to significantly increase beta cell mass in DN-HNF1a-expressing transgenic male pancreas (p=0.04) but had no observable effect on transgenic female pancreas. Surprisingly, islet disorganisation was seen in both male and female transgenic mice and was not rescued by bmf knockout.Data generated from this study indicate a possible role for Bmf in beta cell mass reduction and thereby the pathogenesis of MODY3 but demonstrates no effect on islet organisation. These data can be built upon by further research to examine in greater detail how Bmf contributes to the characteristic loss of beta cell mass in MODY3 and in mediating DNHNF1a-induced apoptosis."}
+{"text": "We assessed and compared abiotic preferences of aquatic macroinvertebrates in three river basins located in Ecuador, Ethiopia and Vietnam. Upon using logistic regression models we analyzed the relationship between the probability of occurrence of five macroinvertebrate families, ranging from pollution tolerant to pollution sensitive,  and physical-chemical water quality conditions. Within the investigated physical-chemical ranges, nine out of twenty-five interaction effects were significant. Our analyses suggested river basin dependent associations between the macroinvertebrate families and the corresponding physical-chemical conditions. It was found that pollution tolerant families showed no clear abiotic preference and occurred at most sampling locations, i.e. Chironomidae were present in 91%, 84% and 93% of the samples taken in Ecuador, Ethiopia and Vietnam. Pollution sensitive families were strongly associated with dissolved oxygen and stream velocity, e.g. Leptophlebiidae were only present in 48%, 2% and 18% of the samples in Ecuador, Ethiopia and Vietnam. Despite some limitations in the study design, we concluded that associations between macroinvertebrates and abiotic conditions can be river basin-specific and hence are not automatically transferable across river basins in the tropics. Benthic macroinvertebrates have often been used for water quality monitoring and assessment Most macroinvertebrate-based water quality assessment methods have been developed in temperate climate regions where relationships between environmental variables and the occurrence of macroinvertebrate taxa are well documented. Due to the infancy of the macroinvertebrate-based monitoring and assessment in the tropics The aim of this study was to assess if abiotic preferences of aquatic macroinvertebrates differed between three river basins in the tropics. We investigated associations between physical-chemical variables and macroinvertebrate occurrences in one Ecuadorian, one Ethiopian and one Vietnamese river basin. Five representative macroinvertebrate taxa, ranging from pollution tolerant to pollution sensitive were selected and their preferences towards environmental conditions were compared using regression-based ecological models.\u22121), dissolved oxygen concentration (mg.L\u22121), pH (-), stream velocity (m.s\u22121) and water temperature (\u00b0C) (Samples were taken in the Chaguana river basin (Ecuador), Gilgel Gibe river basin (Ethiopia) and Cau river basin (Vietnam) \u2013S3. In eure (\u00b0C) .Benthic macroinvertebrates were sampled, identified and quantified according to the method described in Gabriels et al. Boxplots were used for data exploration. The first series of boxplots visualized the seasonality of the physical-chemical variables per river basin. The second series of boxplots summarized for each macroinvertebrate family and per physical-chemical variable and river basin the conditions under which the taxon was present and absent. Boxplots were constructed with the R software The univariate associations between explanatory variables were assessed with pairwise Spearman's rank correlations, which is often used in ecology due to its nonparametric nature The occurrence of five macroinvertebrate families was related to the physical-chemical water quality conditions using a regression-based model and these relationships were compared between three river basins situated in the tropics. Logistic regression models (LRMs) were used to infer relationships between occurrences of five aquatic macroinvertebrate families and environmental data. LRMs have been frequently used to model the presence or absence of a species in relation to environmental variables A hierarchical backward elimination model selection method was carried out to build the LRM. The starting model included five physical-chemical variables , season and river basin (represented as country). In addition to the main effects, two-way interactions between the physical-chemical variables and the river basin as well as between season and river basin were included  and S2. Residual plots and the extended Hosmer-Lemeshow test for LRMs based on GEE The outcome of the LRM per family was visualized as the estimated probability that the family was present as a function of a physical-chemical variable. The explanatory variables different from the one on the x-axis, were set to their river basin specific medians and the season to \u201cdry\u201d. The river basin-specific observed range of the corresponding physical-chemical variable were plotted as horizontal boxplots below the response curves and were subdivided between presence and absence points. The gray-colored ends of the response curves indicate extrapolation outside the observed range of the corresponding physical-chemical variable.For the data exploration, the effects of season and river basin on the continuous physical-chemical variables were assessed using a linear regression model fitted with GEE for accounting for the clustered sampling scheme. Only few p-values were reported in the main text to prevent information overload, all p-values were summarized in The observed range of physical-chemical water quality conditions was not always equal between river basins. Seasonal effects were observed for all physical-chemical variables and the seasonal effect of conductivity and stream velocity was similar for the three river basins \u2013S8. DissThe prevalence values, known as the relative frequencies of occurrence of taxa , i.e. the effect of water temperature on the occurrence differed between river basins . AlthougThe effect of water temperature on the probability of occurrence of Baetidae differed between river basins p<0.01; . Indeed,Associations between the DO concentration, pH, stream velocity and water temperature relative to the probability of occurrence of Hydroptilidae were similar across river basins . Only thThe associations between water temperature (p<0.01), stream velocity (p\u200a=\u200a0.02) and DO concentration (p\u200a=\u200a0.02) and the probability of occurrence of Libellulidae differed between river basins . WhereasAssociations between stream velocity  and S54,\u22121 for optimal health For pollution tolerant macroinvertebrate families (e.g. Chironomidae (TS2)) only few significant associations between physical-chemical conditions and the occurrence of the families were found  suggestiHabitat suitability of macro-invertebrates probably depends on more factors than those included in our statistical analysis. For instance, additional to the variables that were included in our analysis, Al-Shami et al. Seasonal changes of environmental variables were taken into account The outcome of the LRM per family was visualized as the estimated probability that the family was present as a function of a physical-chemical variable e.g. \u20135. WithiThe fact that river basin dependent associations were found is not surprising. For instance, Bonada et al. Since the range of the observed physical-chemical conditions were not always equal between river basins, in some cases extrapolations outside the observed range were shown . For insNo relation was found between the occurrence of Leptophlebiidae and stream velocity in the Ethiopian and the Vietnamese river basin. However, according to the data Leptophlebiidae occurred in both river basins in upstream sampling sites with a moderate to high stream velocity. The reason for the non-significant relation is the prevalence of the present-points. In the Vietnamese and Ethiopian river basin, Leptophlebiidae were only present in 18% and 2% of the samples, respectively. Consequently, the occurrence of Leptophlebiidae seems statistically not associated with stream velocity. Therefore, due to unbalanced dataset prevalence it is possible that not all models obtained represent true ecological relations Presence and absence data are commonly used in macroinvertebrate research e.g.,  as they As an alternative to the conventional taxonomic division of the benthic invertebrates one can use functional traits to categorize macroinvertebrate assemblages e.g., . Such a Overall, LRMs based on GEE are a flexible way to model the probability of occurrence of macroinvertebrates as a function of environmental variables. We revealed similar as well as dissimilar abiotic preferences of macroinvertebrates between the three river basins, but these estimated probabilities are restricted to the observed range of the predictor within each river basin. In conclusion we found that associations between macroinvertebrates and abiotic conditions can be river basin-specific.Figure S1Sampling sites in the Chaguana river basin in Ecuador.(DOCX)Click here for additional data file.Figure S2Sampling sites in the Gilgel Gibe river basin in Ethiopia.(DOCX)Click here for additional data file.Figure S3Sampling sites in the Cau river basin in Vietnam.(DOCX)Click here for additional data file.Figure S4Boxplots showing the seasonality (dry (blue) and wet (red) season) of the stream velocity.(DOCX)Click here for additional data file.Figure S5Boxplots showing the seasonality (dry (blue) and wet (red) season) of the water temperature.(DOCX)Click here for additional data file.Figure S6Boxplots showing the seasonality (dry (blue) and wet (red) season) of the conductivity.(DOCX)Click here for additional data file.Figure S7Boxplots showing the seasonality (dry (blue) and wet (red) season) of the pH.(DOCX)Click here for additional data file.Figure S8Boxplots showing the seasonality (dry (blue) and wet (red) season) of the dissolved oxygen.(DOCX)Click here for additional data file.Figure S9Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S10Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S11Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S12Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S13Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S14Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S15Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S16Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S17Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S18Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S19Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis).(DOCX)Click here for additional data file.Figure S20Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S21Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S22Bottom: Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis).(DOCX)Click here for additional data file.Figure S23Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S24Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S25Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S26Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S27Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S28Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S29Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S30Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S31Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis).(DOCX)Click here for additional data file.Figure S32Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S33Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S34The probability of Chironomidae being present in relation to the stream velocity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S35The probability of Chironomidae being present in relation to the water temperature measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S36The probability of Chironomidae being present in relation to the conductivity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S37The probability of Chironomidae being present in relation to the pH measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S38The probability of Chironomidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S39The probability of Baetidae being present in relation to stream velocity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S40The probability of Baetidae being present in relation to water temperature measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S41The probability of Baetidae being present in relation to conductivity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S42The probability of Baetidae being present in relation to pH measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S43The probability of Baetidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S44The probability of Hydroptilidae being present in relation to stream velocity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S45The probability of Chironomidae being present in relation to the Hydroptilidae measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S46The probability of Hydroptilidae being present in relation to the conductivity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S47The probability of Hydroptilidae being present in relation to pH measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S48The probability of Hydroptilidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S49The probability of Libellulidae being present in relation to stream velocity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S50The probability of Libellulidae being present in relation to the water temperature measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S51The probability of Libellulidae being present in relation to the conductivity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S52The probability of Libellulidae being present in relation to pH measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S53The probability of Libellulidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S54The probability of Leptophlebiidae being present in relation to stream velocity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S55The probability of Leptophlebiidae being present in relation to the water temperature measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S56The probability of Leptophlebiidae being present in relation to the conductivity measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S57The probability of Leptophlebiidae being present in relation to pH measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S58The probability of Leptophlebiidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia  and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Table S1Seasonal differences per physical-chemical variable and per country. A p-value less than 0.05 demonstrates a significant difference between seasons for the mean physical-chemical variable that is considered for a specific country. Significant relations are indicated in bold.(DOCX)Click here for additional data file.Table S2Country-wise differences per physical-chemical variable and per season. A p-value less than 0.05 demonstrates a significant difference between countries for the mean physical-chemical variable that is considered for a specific season. Significant relations are indicated in bold.(DOCX)Click here for additional data file."}
+{"text": "Diabetic polyneuropathy (DPN) has an insidious and non-homogeneous installation making it difficult to determine its onset. Therapeutic and preventive actions should target patients depending on their DPN severity status. Methods for supporting the decision making process of classifying patients can improve early health actions.Analyze the use of 2 artificial intelligence methods for classifying the DPN severity degree: (a) fuzzy modeling and (b) multiple correspondence analysis (MCA) and Kohonen map.Retrospective analysis of 195 patients. The fuzzy model determined a DPN degree score (0-10) by the combination of fuzzy sets derived from clinical variables , using if-then rules to combine the inputs with the output sets (Mamdani process), with membership functions determined by a team of 4 DPN specialists. The MCA method grouped 16 DPN-related categorical variables  into micro and macro-classes (groups) after the algorithm learned the grouping pattern of the variables in the patients' cohort. A Kohonen map was used to better represent the clusters of variables that could identify different DPN severities.Loss of tactile and vibration perceptions were decisive for classification of DPN severity using the fuzzy system, and its sensitivity and specificity in discriminating patients with and without DPN was very high (ROC=0.985). The MCA and Kohonen map identified 4 macro-classes of variables: (1) DPN absence, (2 and 3) intermediate status , and (4) severe .The fuzzy model contributes to the early detection of DPN using typical clinical variables, and although this method strongly relies on the specialist subjectivity, it is very reliable. Software for classifying DPN severity using this Fuzzy model is available and can be easily implemented in any clinical setting as a decision support system. The MCA"}
+{"text": "The still unclear mechanisms causing ventilator-induced diaphragm dysfunction (VIDD) are considered intrinsic to the diaphragm muscle fibers. VIDD delays and complicates weaning from mechanical ventilation (MV) and accordingly contributes to prolonged ICU stay by 50%, with older patients being more affected than the young. The main aim of this study was to measure the effects of aging and 5 days of MV on rat diaphragm muscle fiber structure and function. We also aimed to investigate the biological age of the old rats to obtain data useful to design future experimental studies focusing on the effects of age in an ICU setting.We used a unique ICU rat model, which allows us to maintain the vital parameters stable under deep sedation and MV for long durations . Diaphragm fiber cross-sectional area (CSA) and force-generating capacity (specific force = absolute force / CSA) were measured in young (6 months) and old (28 to 32 months) F344/ BN hybrid rats in response to 5 days of deep sedation and volume-controlled MV. To investigate the biological age of the old rats, we performed a second set of experiments, comparing muscle fiber CSA and specific force in fast and slow-twitch distal hind limb muscles in three different age groups: young adults (6 months), middle aged (18 months) and old rats (28 months).P < 0.001) of the diaphragm fibers in response to 5 days of MV in both young and old animals. Maximum force decreased 39.8 to 45.2% (P < 0.001) in both young and old animals compared with controls, resulting in a dramatic loss of specific force. This increase in CSA and the concomitant decrease in specific force observed in both young and old diaphragm fibers are compatible with an ineffective compensatory hypertrophy in response to the MV. The comparison of the limb muscles fibers from young, middle aged and old animals confirmed the 28 to 32 month rats to be senescent from a skeletal muscle point of view.This study demonstrated an unexpected increase in CSA (These results demonstrate intrinsic changes in diaphragm muscle fibers of significant importance for the prolonged and complicated weaning from MV. Moreover, the increased number of frail diaphragm muscle fibers observed after MV in old age, both controls and mechanically ventilated, offers a further age-related possible mechanism which may be of significant clinical importance. These results also provided useful information to design future experimental studies focused on the effect of age in an ICU setting, pharmacological intervention strategies as well as mechanisms underlying rat strain differences."}
+{"text": "The objectives of the study were (1) to explore the pattern of public spending on road safety programmes corresponding to 5-E strategy , and (2) to investigate road safety policy directions.The government budget documents from 5 ministries including Ministry of Transport, Education, Interior, Public Health and Royal Thai Police were reviewed. Two researchers identified budget used in road safety projects with 5-E strategies independently; the kappa analysis was used to test inter-rater reliability. Information from Thai Health Promotion Foundation and Road Safety Fund was also gathered using a developed excel-based template. Semi-structured interviews were conducted among road safety experts. Some mathematical and statistical analyses were applied to evaluate the efficiency of road safety policy.Thailand devoted around 18 billion Baht each year to prevent road traffic accidents. The majority of public budget was allocated to engineering strategies (50%), followed by enforcement (23%), emergency medical services (12%), evaluation (8%) and education (7%). The road safety experts, however, suggested that the strategies of education, enforcement and particularly evaluation are Thailand\u2018s key success factors. Thus, an area-based road safety information system should be developed. Data Envelopment Analysis suggested an inefficiency of law-enforcement system in Thailand by comparison with other countries worldwide.Despite insufficient data and evidence to clarify the outcomes of road safety policy and programmes, it is possible to conclude that (1) there is an underinvestment in road safety in Thailand and (2) the government allocates budget inappropriately. This study suggests allocating more public spending on road safety management data systems that empower local service providers to access and analyse current accident information. Investing in strategies of education and enforcement effectively influencing road user behaviour would be the right way to achieve the ultimate goal."}
+{"text": "Even with the availability of new and more effective diagnostic procedures over the past decades, autopsy remains one of the most reliable methods to validate clinical diagnoses. The aim of this review was to determine whether autopsy plays a role in extending knowledge about the cause of death in patients with cirrhosis who died in the ICU.We conducted a retrospective review of medical records and postmortem findings in critically ill patients with cirrhosis who were admitted to a major university teaching medical ICU (MICU) between August 2007 and August 2013. Agreement between diagnoses before death and postmortem findings were compared using the Goldman system [n = 19, 45%).Of 641 patients admitted with diagnosis of cirrhosis, 86 (13%) died in the MICU. Forty-five (52%) patients underwent an autopsy. Forty-two autopsy reports were available for review, three histologic and microbiological reports were missing. Major missed diagnoses  were present in seven patients (17%), four in class I (10%) and three in class II (7%) (Table Despite declining rates worldwide, autopsy remains an important tool for quality and safety assurance. In this retrospective study, autopsy showed that knowledge of the correct premortem diagnosis would have altered therapy in 10% of critically ill cirrhotic patients."}
+{"text": "There is an error in the first sentence of the Introduction. The correct sentence is: Behavioral studies indicate involvement of the prefrontal cortex and medial temporal lobe (MTL) during memory tasks that require short-term (200ms- 30s) information retention [1\u20134]. The publisher apologizes for this error."}
+{"text": "There are errors in Equation (3). In the description of Equation (3), the equilibrium frequencies PIX are incorrectly defined in terms of pi, where in fact they should be defined in terms of phi. Please see the corrected description of Equation (3) here."}
+{"text": "The differential diagnosis of hypertrophic phenotype remains challenging in clinical practice, in particular between hypertrophy cardiomyopathy (HCM) and increased left ventricular wall thickness (LVWT) due to systemic hypertension. Diffuse myocardial fibrosis is the characteristic feature in HCM, whereas hypertensive response is underpinned by addition of myofibrils in otherwise normal myocardial tissue. Late gadolinium enhancement (LGE) imaging provided important new way of differentiation between these two entities by separating those cases with evidence of regional fibrosis. Whereas approximately 60% of patients with HCM reveal visually discernable LGE, T1 mapping is highly discriminative, irrespective of the presence of LGE.Sixty patients with diagnosis of unequivocally hypertrophic cardiomyopathy and fifty patients with hypertensive cardiomyopathy underwent routine cardiac MRI protocol including assessment of function and scar (3-Tesla). T1 values were measured conservatively within septal myocardium in midventricular short-axis slice prior to administration of 0.2 mmol/kg of gadobutrol.HCM group showed higher LV mass and maximum LVWT than the hypertensive group . There was LGE in 20% of hypertensive  and in 84% of hypertrophic cardiomyopathy  (p < 0.001). Patients with HCM showed significantly higher T1 values compared to hypertensive patients . Native T1 values were concordant to LVWT and LV mass . T1native held superior diagnostic accuracy compared to conventional functional parameters and the presence of LGE to discriminate between hypertrophic or hypertensive cardiomyopathy  comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital National Health Service Foundation Trust. Dr. Rocio Hinojar was supported by the Fundacion Alfonso Martin Escudero."}
+{"text": "Hyperfibrinolysis (HF) is a major issue of trauma-induced coagulopathy but has also been described in many other medical or surgical settings such as cardiopulmonary surgery, gastro-intestinal bleeding, liver transplantation and post-partum hemorrhage.The aim of this study was to describe the HF in a cohort of patients experiencing severe bleeding from trauma and non-trauma source and to highlight the differences between both groups.\u00ae) between 2010 and 2014 were included. Demographic and clinical parameters, standard laboratory and ROTEM\u00ae results were collected. HF diagnosis was established when the 60 minute clot lysis index (CLI60) was below 85% of the maximum clot firmness. HF was classified as fulminant HF (immediate breakdown of the clot within 30 minutes), intermediate HF (breakdown of the clot between 30 and 60 minutes) and late HF (complete clot lysis after more than 60 minutes). Data are expressed as n (%) and median [interquartile range].We conducted an observational, retrospective study in two academic trauma centers from a French university institution. All patients diagnosed with HF on rotational thromboelastometry (ROTEMSixty-four patients were included (39 trauma and 25 non trauma). Overall mortality was 64% . Median ISS for trauma patients was 49 . Patients severity assessed with SAPS II was not different between groups  whereas 28 day survival was greater in non-trauma patients  (Figure  to 73 vsFulminant HF is more frequent in trauma patients and is associated with an increased mortality. The decreasing incidence of HF observed during the study period might be due to the systematic prehospital administration of tranexamic acid in trauma patients since 2011 in our city area."}
+{"text": "Virus replication efficiency is influenced by two conflicting factors, kinetics of the cellular interferon (IFN) response and induction of an antiviral state versus speed of virus replication and virus-induced inhibition of the IFN response. Disablement of a virus's capacity to circumvent the IFN response enables both basic research and various practical applications. However, such IFN-sensitive viruses can be difficult to grow to high-titer in cells that produce and respond to IFN. The current default option for growing IFN-sensitive viruses is restricted to a limited selection of cell-lines (e.g. Vero cells) that have lost their ability to produce IFN. This study demonstrates that supplementing tissue-culture medium with an IFN inhibitor provides a simple, effective and flexible approach to increase the growth of IFN-sensitive viruses in a cell-line of choice. We report that IFN inhibitors targeting components of the IFN response  significantly increased virus replication. More specifically, the JAK1/2 inhibitor Ruxolitinib enhances the growth of viruses that are sensitive to IFN due to (i) loss of function of the viral IFN antagonist (due to mutation or species-specific constraints) or (ii) mutations/host cell constraints that slow virus spread such that it can be controlled by the IFN response. This was demonstrated for a variety of viruses, including, viruses with disabled IFN antagonists that represent live-attenuated vaccine candidates , Influenza Virus), traditionally attenuated vaccine strains  and a slow-growing wild-type virus (RSV). In conclusion, supplementing tissue culture-medium with an IFN inhibitor to increase the growth of IFN-sensitive viruses in a cell-line of choice represents an approach, which is broadly applicable to research investigating the importance of the IFN response in controlling virus infections and has utility in a number of practical applications including vaccine and oncolytic virus production, virus diagnostics and techniques to isolate newly emerging viruses. Knockout of viral IFN antagonists is also a method of engineering viruses to specifically target cancer cells for oncolytic virotherapy Virus infection triggers the cellular interferon (IFN) response to produce Type 1 IFN's alpha and beta (IFN\u03b1/\u03b2). Secreted IFN\u03b1/\u03b2 can stimulate the JAK-STAT pathway in an autocrine or paracrine manner to activate hundreds of IFN-stimulated genes (ISGs), many of which have antiviral activities that elicit an antiviral state Despite the advantages of disabling a virus's IFN antagonist, it can be difficult to grow such IFN-sensitive viruses to high-titer in tissue culture cells that produce and respond to IFN Inhibitors of the IFN response  were prepared as 10 mM stocks in dimethyl sulfoxide (DMSO) and used at the indicated concentrations. Inhibitors were purchased from Selleck Chemicals except MRT68844 and MRT67307, which were gifts of MRC-Technology and Philip Cohen (University of Dundee) respectively. Cell-lines derived from a variety of mammalian species were utilized: human (A549 and MRC5) monkey (Vero), mouse , rabbit (RK13), dog (MDCK) and pig (PKIBRS2). These cells were obtained from the European Collection of Cell Cultures (ECACC) with the exception of the PKIBRS2 cells, which were obtained from the Institute of Animal Health (UK) 4 units/ml of purified \u03b1-IFN  to activate the IFN signaling pathway and GFP expression from the IFN response (ISRE) promoter. Forty-eight hours post-IFN stimulation GFP expression and cellular cytotoxicity were measured as described above. Each assay was conducted in triplicate and the mean and standard deviation (StDev) determined.The A549/pr(IFN-\u03b2).GFP and A549/pr(ISRE).GFP reporter cell-lines were used to test the effect of IFN inhibitors on IFN induction or IFN signaling. A549/pr(IFN-\u03b2).GFP were seeded into a 96 well plate and media supplemented with a TBK1 inhibitor  or the IKK2 inhibitor (TPCA-1) at the indicated concentrations or equivalent volumes of DMSO. Two hours post-inhibitor treatment cells were infected with a stock of PIV5V\u0394C rich in defective interfering particles (DIs) to optimally activate the IFN induction pathway and expression of GFP under the control of the IFN-\u03b2 promoter Standard plaque assays were conducted in the appropriate cells using a 0.6% (w/v) avicell overlay Eight small molecules that have previously been described to inhibit the cellular IFN response were obtained; four inhibitors that target components of the IFN induction pathway: TBK1 inhibitors BX795, MRT68844, MRT67307 Bunyaviridae family are being developed as attenuated vaccines via NSs knockout Effect of the inhibitors on viral plaque formation was examined using A549 cells infected with recombinant Bunyamwera virus (BUN\u0394NSs), in which the NSs IFN antagonist has been inactivated rendering the virus IFN sensitive The six effective inhibitors were used to examine their effect on BUN\u0394NSs growth kinetics and all six inhibitors significantly improved virus titers . At 48 hWe next sought to determine if two inhibitors targeting different components of the IFN response could further boost BUN\u0394NSs growth if used in combination with each other or to supplement the medium of infected A549/PIV5-V cells. The IKK-2 inhibitor TPCA-1 and JAK1/2 inhibitor Ruxolitinib were tested. However combinations resulted in no further increases in plaque size in A549 cells and in fact a small decrease in plaque size was observed when the inhibitors were used in combination compared to Ruxolitinib or PIV5-V expressing cells alone . One posA limited number of cell-lines have regulatory approval for vaccine manufacture e.g. MRC5 Respiratory Syncytial Virus (RSV) and Influenza are examples of viruses currently being developed as IFN-sensitive attenuated vaccine candidates We also tested two traditional vaccine strains, measles (MeV) Edmonson and the Mumps (MuV) Enders, which have been generated empirically using nonsystematic attenuation methods in vitro. In the initial plaque formation screen the JAK1/2 inhibitor Ruxolitinib was the most effective and hence was taken forward for further study. Moreover, all the results obtained for Ruxolitinib were essentially mirrored with the IKK2 inhibitor TPCA-1 (data not shown). The plaque assays and growth curves performed required incubation with the inhibitor for multiple days. To ensure our results were not affected by loss of activity of the drug, we used the A549/pr(IFN-\u03b2).GFP and A549/pr(ISRE)GFP reporter cell-lines to measure the activity of the drug over time; confirming that the inhibitory effect of both Ruxolitinib and TPCA-1 was stable up to at least 7 days in tissue-culture  the cost of the inhibitor and (ii) the harvested virus stocks will contain the inhibitor which may affect experiments to address both basic science questions and regulatory problems for medical applications in humans, although in this latter regard it is noteworthy that Ruxolitinib is approved for clinical treatment of myelofibrosis in vivo, they may also prove useful in studies designed to investigate the importance of the IFN response in controlling virus infections in animal models.These results provide proof of principle that supplementing tissue-culture medium with IFN inhibitors provides a simple, effective and flexible approach to enhance virus growth in cell-lines of choice. IFN inhibitors targeting different components of the IFN response  significantly increased replication and yield of a variety of viruses; including examples of potential vaccine candidates with disabled IFN antagonists , traditionally attenuated vaccine strains  and wild-type viruses . In addition JAK1 inhibitors have recently been shown to enhance the growth of oncolytic vesicular stomatitis virus (VSV) in cancer cells resistant to oncolysis"}
+{"text": "The genes encoding the E3 ubiquitin protein ligase Parkin (PARK2) and the mitochondrial serine/threonine kinase PINK1 (PARK6) are mutated in clinically similar, autosomal recessive early onset Parkinson\u2019s disease (PD) forms. Over the past ten years, a number of studies in different model systems have demonstrated that PINK1 and Parkin regulate jointly several processes relevant to maintenance of mitochondrial quality, including mitochondrial trafficking and dynamics, mitophagy and biogenesis. By using a combination of approaches of cell biology, confocal imaging and biochemistry in different cell models, we recently showed that loss of protein import efficiency triggers recruitment of Parkin by PINK1 in proximity of the translocase of outer mitochondrial membrane (TOM). We provided evidence that the degradation of specific TOM subunits plays a key role in initiating the autophagic degradation of damaged mitochondria. We also showed that PINK1 and Parkin interact with the TOM machinery on polarized mitochondria. Our results suggests that this interaction modulates the import of the multifunctional mitochondrion-protective matrix enzyme 17beta-hydroxysteroid dehydrogenase 10, which is depleted in Parkin-deficient mice and Parkinson\u2019s disease patients. Electron and confocal microscopy, and calcium imaging approaches used to characterize the endoplasmic reticulum (ER)-mitochondria interface, a compartment previously linked to neurodegenerative processes, revealed enhanced juxtaposition between these organelles, associated with increased ER-to-mitochondria calcium transfer in cells from Parkin-deficient mice and patients with PARK2 mutations. Our current work aims at investigating the relevance of mitochondrial quality control mechanisms regulated by PINK1 and Parkin in different cell types of the central nervous system, to evaluate the contribution of each of them to the physiopathology of autosomal recessive Parkinson\u2019s disease."}
+{"text": "Observation of the kinetics of tissue enhancement after the injection of a bolus of tracer has been used for the analysis of perfusion and related variables. In general, a gradient of concentration in the exchanging vascular compartment between the arterial and venous ends is represented in models via focus on maintaining the detailed balance between the advective and diffusive exchange processes. Conventionally, this is by considering the exchange in an Eulerian framework, based on considering the exchange within each compartment as a separate unit  model ). HereinEight patients (age 63 \u00b1 12 years) underwent first-pass perfusion (FPP) rest and regadenoson stress cardiac MRI (CMR) , followed by invasive coronary angiography. Images were obtained at 4 slice locations  and 3 short-axis slices of the left ventricle for the wall) using a TurboFLASH readout with centric k-space reordering [The results of a representative patient (66 year old man) with history of hypertension, hyperlipidemia, Diabetes Mellitus and known coronary artery disease with prior stents on maximal medical therapy are shown in Figure A novel method combining aspects of TH model and a Lagrangian approach allows quantification of the transit of tracer through myocardial tissue, and may serve to identify physiologically significant coronary artery disease. Larger studies to validate this approach are warranted.NIH R01 HL083309."}
+{"text": "Atherosclerosis, a chronic inflammatory disorder of the arteries, is responsible for most deaths in westernized societies with numbers increasing at a marked rate in developing countries. The disease is initiated by the activation of the endothelium by various risk factors leading to chemokine-mediated recruitment of immune cells. The uptake of modified lipoproteins by macrophages along with defective cholesterol efflux gives rise to foam cells associated with the fatty streak in the early phase of the disease. As the disease progresses, complex fibrotic plaques are produced as a result of lysis of foam cells, migration and proliferation of vascular smooth muscle cells and continued inflammatory response. Such plaques are stabilized by the extracellular matrix produced by smooth muscle cells and destabilized by matrix metalloproteinase from macrophages. Rupture of unstable plaques and subsequent thrombosis leads to clinical complications such as myocardial infarction. Cytokines are involved in all stages of atherosclerosis and have a profound influence on the pathogenesis of this disease. This review will describe our current understanding of the roles of different cytokines in atherosclerosis together with therapeutic approaches aimed at manipulating their actions. Atherosclerosis is now recognized as an inflammatory disorder of medium and large arteries initiated by risk factors such as high plasma cholesterol levels and hypertension in vitro studies using cell culture model systems have made a major contribution in advancing our understanding of the roles of cytokines in the cellular processes associated with atherosclerosis, the major focus of this review will be on the outcome from studies using animal model systems. In particular, two mouse models, the apolipoprotein (Apo) E-deficient mice and the low-density lipoprotein receptor (LDLr)-deficient mice Cytokines are a diverse group of low-molecular weight proteins with over 100 identified so far. Cytokines are clustered into several classes such as the interleukins (IL), chemokines, colony-stimulating factors (CSF), tumor necrosis factors (TNF), the interferons (IFN) and transforming growth factors (TGF) 2Atherosclerotic plaques tend to form particularly at the inner curvatures and branch points of arteries that are often associated with disturbed blood flow, and is augmented by other factors such as high plasma low-density lipoprotein (LDL) concentration, hypertension and toxins from cigarette smoke The activated ECs release a range of chemokines and other cytokines that then cause the recruitment of circulating immune cells, particularly monocytes and T lymphocytes 3C, XC) high [express high levels of CC-chemokine receptor (CCR)-2, believed to be pro-inflammatory in nature and their levels increase in hyperlipidemia) and less frequent Ly6Clow [express CX3C-chemokine receptor 1 and perceived to carry out a homeostatic function) high monocytes involves immobilization of CCL5 and CXCL1 on proteoglycans and P-selectins on ECs Chemokines are a large family of structurally related, chemoattracting cytokines that are divided into subgroups on the basis of the position of the amino terminal cysteine residues  is also associated with reduced macrophage recruitment  and the alternatively activated M2 (thought to be derived from Ly6Clow-monocytes and produces anti-inflammatory cytokines such as IL-10 and TGF-\u03b2) that aid in the resolution of inflammatory responses \u2212/\u2212 model system drives M2 macrophage polarization and inhibits atherosclerosis progression In the arterial intima, monocytes can differentiate to macrophages or dendritic cells (DCs) depending on the cytokine signal received with macrophage colony-stimulating factor (M-CSF) a major facilitator of macrophage differentiation LDL tends to diffuse passively through EC junctions and its retention is aided by interaction of its apoB moiety with components of the extracellular matrix such as proteoglycans Macrophages express pattern recognition receptors (PRRs), such as scavenger receptors (SRs), toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLR), that participate in foam cell formation and/or elicit an inflammatory response against foreign particles or endogenously produced danger signals in vivo; for example, IFN-\u03b3 and TNF-\u03b1 promote this whereas IL-1RA and IL-33 are inhibitory. The formation of foam cells involves dysfunction of a homeostatic mechanism that controls the uptake, intracellular metabolism and efflux of cholesterol by macrophages \u2212/\u2212 mice in vivo and macrophages in vitro by decreasing modified LDL uptake, reducing intracellular content of cholesteryl esters and stimulating cholesterol efflux As shown in 4Cholesterol is toxic to cells and mechanisms exist to maintain homeostasis. For example, derivatives of cholesterol, such as oxysterols, activate liver X receptors (LXRs) that then stimulate cholesterol efflux by inducing the expression of ABCA1 and ABCG1 Defective lipid homeostasis is instrumental in the amplification of the inflammatory response and activation of the immune response Antigen presenting cells, such as macrophages and DCs, are essential for the adaptive immune responses as they engulf and process antigens, and present them on the cell surface in association major histocompatibility complexes (MHC) for recognition by T-cells SMCs also play an important role in atherosclerosis and more advanced lesions are generally covered with a fibrous cap, composed of SMCs and ECM components produced by them, and lipid-rich necrotic core 5The continued inflammatory response ultimately leads to the destabilization of atherosclerotic plaques via the action of pro-inflammatory cytokines. Indeed, studies in mouse model systems have shown that IFN-\u03b3, IL-18, GDF-15 and TWEAK destabilize plaques whereas TGF-\u03b2 causes stabilization , Table 46Inflammation plays a pivotal role in all stages of atherosclerosis: endothelial dysfunction; recruitment of immune cells; modification of LDL; foam cell formation; apoptosis of foam cells; plaque rupture; and thrombosis. The inflammatory response in atherosclerosis is regulated by both the innate and adaptive immune system via the action of cytokines. Our understanding of the roles of such cytokines has recently advanced considerably mainly via studies using mouse model systems  None."}
+{"text": "India\u2019s agricultural output, economy, and societal well-being are strappingly dependent on the stability of summer monsoon rainfall, its variability and extremes. Spatial aggregate of intensity and frequency of extreme rainfall events over Central India are significantly increasing, while at local scale they are spatially non-uniform with increasing spatial variability. The reasons behind such increase in spatial variability of extremes are poorly understood and the trends in mean monsoon rainfall have been greatly overlooked. Here, by using multi-decadal gridded daily rainfall data over entire India, we show that the trend in spatial variability of mean monsoon rainfall is decreasing as exactly opposite to that of extremes. The spatial variability of extremes is attributed to the spatial variability of the convective rainfall component. Contrarily, the decrease in spatial variability of the mean rainfall over India poses a pertinent research question on the applicability of large scale inter-basin water transfer by river inter-linking to address the spatial variability of available water in India. We found a significant decrease in the monsoon rainfall over major water surplus river basins in India. Hydrological simulations using a Variable Infiltration Capacity (VIC) model also revealed that the water yield in surplus river basins is decreasing but it is increasing in deficit basins. These findings contradict the traditional notion of dry areas becoming drier and wet areas becoming wetter in response to climate change in India. This result also calls for a re-evaluation of planning for river inter-linking to supply water from surplus to deficit river basins. Indian summer monsoon rainfall (ISMR) over India contributes approximately 80% of the annual precipitation during June-September (Jun\u2013Sep) . India\u2019s). The hydrologic simulations were performed with a Variable Infiltration Capacity (VIC) model [S1 Text). The model was validated with satellite-based observation from the European Space Agency-Climate Change Initiative (ESA-CCI) soil moisture data [The gridded daily rainfall data (mm/day) from the India Meteorological Department (IMD), for the years 1901\u20132004 at a resolution of 1\u00b0  were useS1 TextC) model  in energure data ,29. The The spatial variability of the mean and extreme of the ISMR exhibit opposing trends. In the present case, rainfall associated with a return period of 50 years  was consWe address the first point with hydrological simulations over entire India and by computing the water yield  sum of . The resTo reconfirm our conclusions, we conducted a trend analysis of the ISMR over water surplus and deficit river basins in India . The majTo investigate the systematic nature and consistency of the opposing trends in the spatial variability of the mean and extreme ISMRs, we selected five regions of equal grid-size from different agro-climatic zones  in the surplus (deficit) river basins strongly contradict the traditional notion of wet (dry) areas becoming wetter (drier) over India. Our conclusion corroborates a study conducted by Greve et al. , who repS1 FigThe spatial variability of the mean does not exhibit a trend pre-1950 (a) and a significant decrease post-1950 (b). The spatial variability of extremes does not exhibit a trend pre-1950 (c) and a significant increase post-1950 (d).(TIF)Click here for additional data file.S2 Fig(a) The spatial variability of the mean monsoonal rainfall (blue), with the black solid line indicating the fitted trend line, and (b) the spatial variability for rainfall extremes (blue) with the black line representing the linear trend. The respective Mann-Kendall trend and associated p values are individually presented for each panel.(TIF)Click here for additional data file.S3 Fig(a) Correlation between the simulated and observed soil moisture from 1979\u20132004. (b) Normalized Root Mean Square Error (nRMSE) for the same period.(TIF)Click here for additional data file.S4 FigTrends in temperature (a), ET (b) and soil moisture (c) over India during 1951\u20132004, respectively. (d) shows a scatter plot of ET and temperature over India. The values inset the figures represent magnitude of the correlation (R) and slope for the respective variables. All the values are significant at 10% significance level.(TIF)Click here for additional data file.S5 Fig(a) Ratio of convective to total precipitation obtained from TRMM for all of India. (b) Trend in the spatial variability of the Indian Summer Monsoon Rainfall  for the stratiform precipitation obtained from MERRA database over the Indian region (blue), where the black line indicates the fitted trend (linear) line. The Modified Mann-Kendall trend is insignificant at the 5% level. (c) is similar to (b) except for the trend in convective precipitation, which is significant at the 5% level. The spatial data obtained from TRMM and MERRA were re-gridded to IMD at a 1\u00b0 resolution using a linearly interpolated technique.(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.S7 Fig(a) The trend in the spatial variability of convective precipitation (blue) during 1951\u20132004 for ERA-20c reanalysis data, where the black line indicates the fitted trend (linear) line. The modified Mann-Kendall trend is significant at the 5% level. (b) is similar to (a) but shows stratiform precipitation, for which the trend is insignificant at the 5% level. Trends in convective precipitation (c) and stratiform precipitation (d) during 1961\u20132004 for JRA-55 reanalysis data. The modified Mann-Kendall trend is insignificant at the 5% level for both convective and stratiform precipitation. The spatial data obtained from ERA-20c and JRA-55 were regridded to a 1\u00b0 resolution (same as the IMD data resolution) using a linearly interpolated technique.(TIF)Click here for additional data file.S8 Fig(a) Spatial correlation for the monsoonal mean and (b) spatial correlation for the seasonal maxima. (c) The trend in the spatial correlation of individual grid points over the given region estimated with a 30-year overlapping moving window for the monsoonal mean. (d) same as (c) but for seasonal maxima.(TIF)Click here for additional data file.S9 Fig(TIF)Click here for additional data file.S1 TextContains complete description of methods and also the Tables.(DOCX)Click here for additional data file."}
+{"text": "The use of medication during pregnancy should be taken with caution, especially because of its implications for maternal and fetal health. The mycophenolate sodium (MFS) is used to avoid possible rejection of transplanted tissues and organs by inhibiting T and B lymphocyte proliferation.To evaluate the effects of maternal immunosuppression by MFS on physiological parameters in rats.The rats were divided into three groups: rats treated with water (CONT=10) rats orally treated with MFS (20mg/Kg) daily for 15 days until a positive diagnosis of pregnancy (MICO-1=10) and rats orally treated with MFS (20mg/Kg) daily for 15 days prior to and during 21 days of pregnancy (MICO-2=10). It was weekly evaluated body weight, blood glucose, and water and food intake (before and during pregnancy). Statistical significance was p <0.05.In the pre-pregnancy period, although there were no changes in body weight values, the continuous treatment with MFS decreased food and water consumption and also increased blood glucose (MICO-2). During pregnancy period, these rats presented a reduction of the body weight, maintaining a mild hyperglycemia level (about 170 mg/dL)The continued use of MFS during pregnancy can be considered toxic, damaging the maternal health, lead to mild hyperglycemia state plus some toxic data (low food and water intake). This study shows that MFS use is not recommended during pregnancy freely and should be replaced by another immunosuppressant."}
+{"text": "One of the challenges facing us in India, translating recent discoveries of chronic disease associated SNPs into clinical domain for prevention, is the lack of knowledge about the frequency of the polymorphism in our population. Hence, using available HapMap data has become a norm. However, it is anticipated that population genomics in India could be different from the HapMap Caucasian population. Relative disease risk prediction based on relevant SNPs, both for personalized medicine and for population genetics, has little value without accurate information of population allele frequencies. We report allele frequency of 384 SNPs directly related to chronic disease risk and metabolic traits in the Indian population.We report the allele in a random sample of 146 individuals and compare them with the data reported in HapMap Caucasian population (n = 112). Genotyping was performed using Illumina golden gate genotyping assay following DNA extraction from saliva. Allele frequencies were determined by direct gene count method.GWAS studies confirmed 384 SNPs to be associated with disease risk (364) of Diabetes Type 1 and 2 (54 & 118 respectively), Coronary artery disease(71), myocardial infarction(9), cardiac failure(24), sudden cardiac arrest(38), atrial fibrillation(9), hypertension(18), obesity(10), metabolic syndrome(2) and stroke(11); or were associated with metabolic traits (20). The master table of their \u2018rs\u2019 id, chromosomes, location and association is presented. Of the 384 SNPs, 44 were not in H-W equilibrium and were omitted. HapMap data were not available for 13 SNPs. We are reporting their allele frequencyon the Indian population for the first time. Of the remaining 307 disease association SNPs, statistically significant difference (p<.05) from HapMap Caucasian population was observed in 53% of them (164 of 307) and the difference of >10% (considered major in population genetics) was found in 42% (130 of 307). Of the 20 metabolic association SNPs, 50% (10 of 20) had statistically significant difference and in all of them it was >10%.We are reporting the largest repository, documenting disease and related SNP and allele frequencies in Indian population. We have also highlighted clear differences with HapMap data and would caution against indiscriminate use of HapMap for bench-to-bedside application of genetic knowledge in our population."}
+{"text": "In 2011, the University of Michigan\u2019s Center of Excellence in Public Health Workforce Studies and the Association of Public Health Laboratories (APHL) assessed the workforce and program capacity in U.S. public health, environmental, and agricultural laboratories  of 105 laboratory directors participated. A laboratorian was defined as a person whose principal work was in a governmental public health, environmental, or agricultural laboratory; positions could be reported as one-quarter fractions of full-time equivalents. For each program area, the director was asked if they had adequate capacity to perform necessary services for that program area. Estimates were categorized as follows: full = 100% capacity to perform; almost full = 75%\u201399%; substantial = 50%\u201374%; partial = 25%\u201349%; minimal = 1%\u201324%; and none. Fifty-six (71%) of the laboratories self-identified as a public health (49), environmental (three), or agricultural (four) laboratory; 23 (29%) self-identified as some combination of these categories; and one did not specify laboratory type.In 2011, a total of 6,656 employees, of whom 5,555 (83%) were laboratorians in one of the eight job classifications identified, worked in the 80 responding laboratories; the remaining 894 employees (13%) were administrative support staff, and 207 (4%) were information technology staff . The disFor those laboratories indicating any capacity in a given program area , more than half reported either no, minimal, or only partial capacity to perform necessary activities in toxicology (65%), agricultural chemistry (80%), agricultural microbiology (80%), clinical chemistry/hematology (68%), and education and training (55%). Conversely, more than 75% of laboratories reported substantial to full capacity in emergency preparedness and response (89%), safety and/or security (91%), bacteriology (91%), administration/operations (86%), molecular biology (92%), quality assurance (83%), serology/immunology (85%), and regulation and inspection (80%); however, fewer than half reported substantial to full capacity in agricultural chemistry (20%), agricultural microbiology (20%), clinical chemistry/hematology (32%), toxicology (35%), and education and training (45%) . SeveralMore than half of laboratories (42 [53%]) anticipated that up to 15% of their workers would retire, resign, or be released within 5 years, whereas 27 (34%) laboratories predicted a loss of 16%\u201325%, 10 (13%) predicted a loss of 26%\u201350%, and one anticipated losing more than 75% within 5 years. The lack of opportunities for promotion and lack of a career path for advancement were the two most common barriers to recruitment; both were reported by 76% of responding laboratories. Other major barriers to recruitment were inadequate salary scale (59 [74%]), hiring policies/procedures (54 [68%]), and complexity of the administrative bureaucracy (49 [61%]). Lack of promotion opportunities and career path for advancement were reported as obstacles to worker retention by 66 (83%) and 64 (80%) of laboratories, respectively, as was inadequate salary scale by 58 (73%) of laboratories.The public health, environmental, and agricultural laboratory workforce is a vital component of the nation\u2019s public health infrastructure. Laboratory capacity is essential for protection against health hazards and provision of essential community services . The 201The lack of many laboratories\u2019 ability to provide training to their staff is a concern because access to continuing education is essential to ensuring a well-trained public health workforce. This might be particularly true for laboratorians because only one quarter of laboratorians have a graduate or professional degree. Laboratory directors and public health, environmental, and agricultural laboratory workers reported lack of opportunities for promotion and a clear career path to advancement as the most common barriers to worker recruitment and retention , which mThe assessment of laboratories\u2019 program area capacity should be based on the Laboratory System Improvement Plan (LSIP) standards, which were developed by APHL and CDC to assess laboratory performance ,8. HowevThe findings of this report are subject to at least three limitations. First, only three quarters of laboratory directors completed the survey; nonresponders might have differed systematically from responders and yielded dissimilar results if they had participated. Second, the questions used to assess program area capacity in the laboratory were subjective, and their interpretation might have varied by respondent. Finally, some subjective questions have objective correlates, such as assessment of equipment quality.What is already known on this topic?The public health, environmental, and agricultural laboratory workforce is a vital component of the nation\u2019s public health infrastructure. Well-trained laboratorians are essential to providing protection against newly emergent diseases and other health hazards through diagnostic testing; reporting and surveillance; chemical, toxicologic, and environmental analysis; emergency preparedness; and provision of other vital services for the community.What is added by this report?Data from a 2011 National Laboratory Capacity Assessment indicate that national public health laboratory capacity needs to improve in several areas to achieve optimal testing and response capacity. Laboratory workers need better access to training and educational opportunities to ensure a well- qualified laboratory workforce.What are the implications for public health practice?Agencies at the local, state, and federal level should collaborate to improve laboratory capacity, including worker training and education, and encourage the development of a greater number and type of available laboratory degree programs.Healthy People 2020 public health infrastructure objective no. 11 (PHI-11) aims to increase the proportion of tribal and state public health agencies that provide or ensure comprehensive laboratory services to support essential public health services (The services . The Nat"}
+{"text": "Juvenile Dermatomyositis (JDM) is the most common idiopathic inflammatory myopathy in childhood, a systemic vasculopathy that usually affects skin and skeletal muscle but also can affect gastrointestinal tract and other organs. Diagnosis is based on Bohan and Peter's criteria and the goals of treatment include control of skin and muscle symptoms and prevention of disease complications. Stepwise aggressive treatment decreases JDM activity and improves long-term outcome.Muscle involvement in JDM can be assessed by electromyography (EMG), magnetic resonance imaging (MRI) and/or muscle biopsy.Muscle biopsy assesses the presence of lymphocytic inflammatory infiltrate, perifascicular atrophy, muscle fibers necrosis and it allows studying the overexpression of major histocompatibility complex (MHC) class I in the sarcolemma and sarcoplasm of the muscle cell. In healthy muscles, there is no MHC class I expression but in inflammatory myopathies there is a distinctive and generalized overexpression, not limited to the affected areas, it appears before the inflammatory infiltrate occurs and it is not modified by immunosuppressive treatment.To assess MHC I overexpression on muscle biopsy of our patients with JDM.Descriptive retrospective review of our JDM patients with muscle biopsy at diagnosis between January 2000 and December 2011. In all cases, muscle biopsy techniques were performed with hematoxylin-eosin, trichrome, oxidative enzymes , neonatal myosin and MHC class I.12 patients were included, 8 of them were girls (66%). All children had cutaneous and muscular clinical features at diagnosis. All MRI were pathological before treatment. EMG was performed in 9 patients, being altered in 8 of them (88%). Childhood Myositis Assessment Scale (CMAS) was done in 6 children with a median score of 30.5/52 (range 12-50/52). We found pathological muscle biopsy in 8 children (66%). Mild endomisial inflammation was found in 5 (41%) patients and moderate inflammation in 4 (33%). No vasculitis was found, but 7 (58%) patients had necrotic muscle fibers in biopsy. Immunohistochemical staining for MHC class I was positive in all cases, even in those children with normal muscle biopsy.MHC class I overexpression is present in muscle biopsy of all our patients with suspected JDM, even those with negative EMG or normal CMAS score. Although it is an invasive technique, muscle biopsy including MHC class I staining should be performed in all patients with suspected JDM in order to achieve more accurate diagnostic and establish an early and aggressive treatment.None declared."}
+{"text": "Many patients die and majority of those who survive remain in a vegetative state2. There is paucity of data on the clinical characteristics and outcome of patients with status myoclonus treated with hypothermia from resource-limited centres in South Asia.Generalized status myoclonus following out of hospital cardiac arrest (OHCA) has been associated with poor prognosisTo study the clinical characteristics and outcome of patients with status myoclonus following out of hospital cardiac arrest and treated with hypothermia.Retrospective chart review of patients surviving > 24 hours following OHCA in an urban community hospital in South India, between January 2006 and December 2012. All patients received therapeutic hypothermia (32-34\u00b0C) for 24 hours. Data on the clinical characteristics of patients developing status myoclonus  and their outcome  were studied in detail. Based on the cerebral performance category (CPC) score at hospital discharge, the neurological outcome of patients was classified into favorable  and unfavorable .Out of the 124 patients surviving > 24 hours, 52 (42%) developed status myoclonus. Baseline and general characteristics were similar in patients with and without status myoclonus (Table Status myoclonus following out of hospital cardiac arrest was associated with unfavorable outcome. Majority of deaths in patients who developed status myoclonus was secondary to WLST, which may indicate self-fulfilling prophecy."}
+{"text": "Data have been retrieved from several databases mentioned in details in the text. Determination and analysis of the structural and functional impact of TAFI and its expression could help elucidate the contribution of the TAFI pathway to acquired hemostatic dysfunction and will form the basis of potential therapeutic strategies to manipulate this pathway. An inhibition of TAFI (e.g. by FXI inhibitors) will offer the therapeutic possibilities to improve the decreased fibrinolysis and increase the efficiency of fibrinolytic therapy in thrombotic disorders including cancer.The data in this paper is related to the research article entitled \u201cThrombin-activatable fibrinolysis inhibitor Thr325Ile polymorphism and plasma level in breast cancer: A pilot study\u201d   Specifications TableValue of the data\u2022in silico analysis of the structural and functional characterization of TAFI and its expression.This data provides a comprehensive \u2022The data are useful for understanding the effect of TAFI variants on its structure and function.\u2022This data may provide insight for determining the role of future drug treatment to inhibit TAFI function especially in cancer cases.11.1Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) represents the molecular link between the coagulation and fibrinolytic pathways TAFI activity is generated during the blood clotting process via binding to thrombin, thrombin\u2013thrombomodulin complex, or plasmin, which in turn cleave TAFI protein at Arg114  into N-terminal activation peptide and catalytic domains, leading to exposure of the active site cleft of activated TAFI (TAFIa) 1.2The plasma concentration of TAFI appears to be under the control of genetic factors and non-genetic factors 1.3in silico analysis predicted these two coding SNPs to be functionally neutral using polymorphism phenotyping (PolyPhen) version 2 and MutPred web-based programs According to several databases, TAFI gene contains multiple variants; all are rare with minor allele frequencies (MAF) of less than 0.001 except two common natural variants rs3742264 and rs1926447 at positions 46073959 and 46055809 with MAF of 0.31 (T) and 0.22 (A), respectively,"}
+{"text": "G protein coupled receptors (GPCR) comprise a large family of transmembrane proteins involved in the regulation of signal transduction through the cell membrane in response to various extracellular stimuli. GPCR have become important targets of many drugs for treatments of very different diseases. During the last decade several fluorescence-based methods have been implemented for the characterization of signal transduction via GPCRs, starting from ligand binding and including several steps leading up to a response on the level of gene regulation. We have proposed the fluorescence anisotropy (FA) and fluorescence intensity (FI) assay to investigate fluorescent ligand binding properties to different GPCRs . The implementations of budded baculoviruses that display G protein-coupled receptors on their surfaces have significantly increased sensitivity and applicability of these assays . The developed novel assay systems opened new possibilities for real-time monitoring of ligand binding to their receptors for understanding their particular kinetic properties. These assays are also compatible for homogenous HTS suitable fo ligand screening. There has been implemented assay systems for receptors of peptides like melanocortin (MC4R) and neuropeptide Y (NPY1R) as well as for receptors of monoamines like dopamine (D1DAR) and serotonin (5-HT1AR)."}
+{"text": "The shoulder joint is the foundation for excellent upper extremity function. It contributes to stability and basic movements like rotation and elevation of the arm. Shoulder fusion should not be accepted even for total palsy, and nerve repair should be recommended as long as an available donor nerve exists.In planning the reconstructive procedure for shoulder function, accurate biomechanical analysis of individual glenohumeral (GH) and scapulothoracic (ST) joint is imperative, especially concerning serratus anterior muscle (SA) function.Priority of nerve repair and selection of donor nerve for shoulder function are the most important key points especially in C5~7, C5~8 and total palsy depending on accompanying reconstruction of elbow and finger function including conventional nerve transfer (NT) and free muscle transfer.Many previous articles of shoulder reconstruction with nerve repair following brachial plexus injuries were concluded from global shoulder motion that combine GH and ST motion, and emphasized only suprascapular nerve (SSN) repair. I emphasized SSN and long thoracic nerve (LTN) repair except in C56 palsy. The axillary nerve (Ax) can be ignored because simple AX palsy does not result in serious paralysis of shoulder function.Postoperative range of shoulder motions following SSN repair, in decreasing order according to individual donor nerve was; phrenic never (PN), spinal accessory nerve (SAN), C5 root and contralateral C7 (CC7 ) root. For LTN repair; the decreasing order of post operative range of shoulder joint movements were intercostal nerve (ICN), PN, SAN, C5 root and CC7 root. PN to SSN and ICN to LTN transfer achieved the most satisfactory outcome in total palsy; however, other combinations of nerve repair and AX repair did not provide significantly better shoulder motion.Dynamic shoulder XP is useful to differentiate between GH and ST motion for pre- and postoperative evaluation.I will introduce our techniques of the representative nerve repairs for shoulder reconstruction."}
+{"text": "Wall shear stress (WSS) may be associated with the onset and development of aortopathy in the presence of bicuspid aortic valve (BAV) . The use of 'aortic atlases' of 3D WSS vectors allows for systematic analysis of WSS differences between large patient cohorts. In this study, a comparison is performed between WSS atlases of BAV patients, BAV patients with aortic dilation, patients with BAV stenosis, and healthy controls with tricuspid valves. The aim is to test the hypothesis that WSS atlases can identify regions of significantly altered WSS that are associated with different expression of BAV and aortopathy.Prospectively ECG and respiratory gated 4D flow MRI was performed in 10 healthy controls, 10 BAV patients, 10 BAV patients with aortic dilation (as defined by aorta diameter > 4 cm), and 10 patients with BAV stenosis (table Figure WSS atlases demonstrate the ability to regionally detect that all BAV patients exhibit significantly elevated WSS compared to healthy volunteers with tricuspid valves.NIH NHLBI grant R01HL115828; American Heart Association Scientist Development Grant 13SDG14360004."}
+{"text": "Staphylococcus aureus (MRSA) clonal complex 398 septicemia in persons who had no contact with livestock. Whole-genome sequencing of the isolated MRSA strains strongly suggest that both were of animal origin and that the patients had been infected through 2 independent person-to-person transmission chains.We describe 2 fatal cases of methicillin-resistant  Staphylococcus aureus (MRSA) clonal complex (CC) 398 is associated with livestock and can spread to humans who have contact with animals . On the basis of these data, a phylogenetic tree was constructed from single-nucleotide polymorphism differences in genome sequences of isolates from the 4 patients and from the isolates obtained during the previous study by using the S0385 complete genome sequence (GenBank accession no. AM990992.1) as reference (tet(M) and czrC determinants (similar to most MRSA strains from clade IIa) and lacked the \u0278Sa3 phage   and the nursing home . Transmission of MRSA CC398 in hospitals and institutions has been reported elsewhere, which underscores its potential to spread through person-to-person contact (In conclusion, the organism implicated in these 2 fatal cases was by all accounts spread from person to person. These findings suggest that this clonal complex can be of high pathogenicity and is readily transmissible among humans."}
+{"text": "Investigators from 4 pediatric hospitals in Canada analyzed the clinical presentation and electrophysiological data of 12 children with hereditary neuropathy with liability to pressure palsies (HNPP), caused by PMP22 gene deletion. Investigators from 4 pediatric hospitals in Canada analyzed the clinical presentation and electrophysiological data of 12 children with hereditary neuropathy with liability to pressure palsies (HNPP), caused by PMP22 gene deletion. Peroneal palsy was the most common presentation (42%) followed by brachial plexus palsy in 25% of their cases. Complete nerve conduction studies were available in 10/12 cases and it demonstrated 3 major patterns: multifocal demyelination at areas of nerve entrapment without generalized demyelinating polyneuropathy (20%), isolated generalized sensorimotor polyneuropathy (20%), combined focal demyelination at the area of entrapment and demyelinating polyneuropathy (60%). All patients had electrophysiological evidence of unilateral or bilateral carpal tunnel syndrome, although it was not always symptomatic. Electrophysiological findings are useful in diagnosis of HNPP, especially in children with heterogeneous clinical presentation. [COMMENTARY. HNPP is the third most common type of hereditary motor and sensory neuropathy . The typ"}
+{"text": "Estonian concentrated HIV epidemic started in August 2000 when rare HIV-1 CRF06_cpx was introduced into the population of intravenous drug users (IDUs). The majority of these HIV-positive subjects are likely co-infected with HCV but the prevalence of HCV and its genotypes during HIV concentrated epidemic in Estonia is largely unknown. The Estonian HIV database collects clinical and laboratory data (including HCV) of HIV-positive patients on medical care. Of 4500 patients on medical care 3500 are entered into Estonian HIV database .Aim: to describe the prevalence of HCV infection and the distribution of the HCV genotypes among HIV-positive subjects infected during HIV concentrated epidemic in Estonia.nd of January 2014 and it comprised subjects diagnosed HIV-positive from 2000.Data for present analyses was extracted from Estonian HIV database on 2In total 2,420 of 3,476 (70%) HIV-positive subjects were HCV antibody positive and 1,184 (64%) were HCV RNA positive. More than half of HCV-positives were men (66%) and the median age was 32 years (inter quartile range 30-36 y). The prevalence of HCV was higher in subjects verified to be HIV-positive between 2002 and 2010 as compared to between 2011 and 2013 . The prevalence of HCV-positivity was equally high in subjects reporting the use of intravenous drugs (88%), the use of other narcotics but intravenous drugs (69%) and persons who have not reported the use of illegal drugs (71%). In total 640 subjects had HCV genotype data available. The dominating genotypes were Ib (53%) and IIIa (36%), however, in recent years the prevalence of genotype Ia is raising (from 2.6% in 2005 to 25% in 2013). The distribution of HCV genotypes between different IDUs and non-IDUs was similar. Altogether 5% of HCV RNA positive subjects  received HCV treatment and all except one admitted the drug usage. Of 59 subjects 48 (81%) received both HCV and HIV therapy.Decreased prevalence of HCV-positive subjects among HIV-positives may suggest a lowered HIV transmission through intravenous route during the last years. The high prevalence of HCV in persons who did not report the use of illegal drugs might indicate under-reported drug usage in this population."}
+{"text": "Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of the endothelial cell-derived tumor Kaposi's sarcoma and of the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. The life cycle of KSHV includes a latent and a lytic/productive phase that both contribute to tumorigenic activity. Major threats for infected tumor cells are attacks of the immune system and the induction of endogeneous cell death programs in response to the virus infection. KSHV opposes these threats for example by hiding from the immune attack by entering the latent infection phase where only few genes are expressed and replication is absent or in the productive phase by the downregulation of major histocompatibility complex class I on the surface of infected cells. Moreover, KSHV uses several different strategies to counteract endogenous cell death programs such as apoptosis and necroptosis.KSHV encodes more than 87 ORFs (open reading frames) and numerous ribosomal-loaded not previously annotated RNAs . ORF actIn another RTCM-based study the effects of all KSHV-encoded genes on the inhibition of p53 were investigated. The tumor suppressor p53 is a major regulatory molecule of apoptosis and cell cycle progression. Three structural proteins namely ORF22 (envelope glycoprotein gH), ORF25 (major capsid protein) and ORF64 (tegument protein) were identified as potent inhibitors of p53 signaling [Finally, viral DNA establishes a pathogen associated molecular pattern (PAMP) that can trigger the host innate immune responses by stimulating production of type I interferons (IFNs). This leads to repression of viral replication and elimination of virus infected cells by apoptosis. Systematic analyses of all KSHV-encoded genes identified the tegument protein ORF52 as a potent inhibitor of this pathway . ORF52 aAltogether, the transfection studies summarized here indicate that KSHV encodes a large repertoire of genes regulating survival of the infected cell in all stages of the viral life cycle Figure . In the"}
+{"text": "The kidneys are known as a target of hepatitis viruses. The renal impairment associated with hepatitis B virus (HBV) could be represented by lesions of glomeruli, or by injury of the renal tubules. Membranous nephropathy is the most common form of glomerulonephritis associated with HBV infection. We aimed to develop a prospective study that evaluated the relation between serum levels of 8-hydroxy-2-deoxiguanosine (8OHdG) and total antioxidant status (TAS) in patients with membranous glomerulopathy associated with HBV infection.The study included a group of 18 patients with chronic infection with HBV and membranous nephropathy with nephrotic syndrome, without renal failure (eGFR >60mL/min/1.73sqm), and a group of 20 patients with chronic infection with HBV without membranous glomerulonephritis. The patients did not receive any treatment for the mentioned diseases before the inclusion in the study. The groups were similar for demographic and nutritional status characteristics. The assessment of 8OHdG, a metabolite of oxidative damage of DNA, was made by ELISA method. TAS was determined by spectrophotometric method.In patients with chronic HBV infection and membranous nephropathy, 8OHdG (ng/mL serum) had higher levels than in patients with chronic HBV infection without renal disease . Serum levels of TAS (mmol/L serum) were significantly lower in patients with membranous glomerulopathy compared with those without nephropathy . A statistically strong negative correlation was determined between 8OHdG and TAS in patients with glomerulopathy associated with HBV infection.The negative association between serum levels of 8OHdG and TAS in patients with membranous nephropathy induced by HBV infection suggests an important role of oxidative stress in the development of renal diseases. The adjustment of imbalance between levels of reactive oxygen/nitrogen species and those of antioxidants in the human body could represent a goal for a better management of renal diseases."}
+{"text": "Platanista gangetica (the Ganges and Indus river dolphin), is the sole surviving member of the broader group Platanistoidea, with many fossil relatives that range from Oligocene to Miocene in age. Curiously, the highly threatened Platanista is restricted today to freshwater river systems of South Asia, yet nearly all fossil platanistoids are known globally from marine rocks, suggesting a marine ancestry for this group. In recent years, studies on the phylogenetic relationships in Platanistoidea have reached a general consensus about the membership of different sub-clades and putative extinct groups, although the position of some platanistoid groups  has been contested. Here we describe a new genus and species of fossil platanistoid, Arktocara yakataga, gen. et sp. nov. from the Oligocene of Alaska, USA. The type and only known specimen was collected from the marine Poul Creek Formation, a unit known to include Oligocene strata, exposed in the Yakutat City and Borough of Southeast Alaska. In our phylogenetic analysis of stem and node-based Platanistoidea, Arktocara falls within the node-based sub-clade Allodelphinidae as the sister taxon to Allodelphis pratti. With a geochronologic age between \u223c29\u201324 million years old, Arktocara is among the oldest crown Odontoceti, reinforcing the long-standing view that the diversification for crown lineages must have occurred no later than the early Oligocene.The diversification of crown cetacean lineages  occurred throughout the Oligocene, but it remains an ongoing challenge to resolve the phylogenetic pattern of their origins, especially with respect to stem lineages. One extant monotypic lineage,  Multiple lines of evidence point to the Oligocene epoch as an important period for the origin and early evolutionary history of crown group Cetacea . This inPlatanista gangetica . The inclusion of Squalodontidae and Waipatiidae in Platanistoidea, as suggested by Currently, phylogenetic studies of Platanistoidea have reached a general consensus about the inclusion three groups (two of which are completely extinct): Allodelphinidae, Squalodelphinidae and Platanistidae , it is both the oldest allodelphinid and among the oldest crown Odontoceti known. The results of our phylogenetic analysis continue to support a monophyletic Platanistoidea, along with traditional sub-clades (including a monophyletic Allodelphinidae), which underscores the importance of Oligocene cetaceans in documenting the early diversification of crown Cetacea.Here we describe t Alaska \u20136. ArktoArktocara yakataga was scanned using Nikon Metrology\u2019s combined 225/450 kV microfocus X-ray and computed tomography (CT) walk-in vault system at Chesapeake Testing in Belcamp, Maryland, USA. Using this vault CT scanner system, we collected CT slices at 0.63 mm, resulting in three-dimensional reconstruction increments of 0.30 mm. We mounted the holotype skull vertically in the vault CT scanner system, with the posterior side down to minimize scanning width. Also, we collected CT scan data for the right periotic (YPM 13408) of Allodelphis prattiArktocara cranium that will be available for viewing and download on the Smithsonian X 3D website (http://3d.si.edu). These 3D files, along with the original DICOM files, are also archived at Zenodo (http://zenodo.org) at the following DOI: 10.5281/zenodo.51363. While the CT data were useful for making 3D models of the holotype, the density of the fossil material prevented the CT scanner from clearly determining internal morphology of the skull, failing to clarify indistinct sutures between skull elements.The holotype of Arktocara yakataga using Notocetus vanbenedeniPhocageneus venustusSqualodon calvertensisWaipatia maerewhenuaZarhachis flagellatorPlatanista gangetica. The stem cetacean taxon Georgiacetus vogtlensis was used as the outgroup. We removed an undescribed specimen (OU 22125), and added 4 allodelphinid taxa (Zarhinocetus errabundus (Goedertius oregonensisAllodelphis pratti and Arktocara yakataga), raising the number of OTUs used in the analysis to 86. We also added codings for four periotic characters (288\u2013291) for Pomatodelphis inaequalisZarhachis flagellator, based on material available at the Smithsonian Institution (see \u2018Specimens observed\u2019). We did not add codings for taxa that we could not directly observe, and therefore some platanistoid taxa were excluded from the analysis, including Huaridelphis raimondiiNinjadelphis ujiharaiAllodelphis woodburneiWe tested the phylogenetic placement of rabundus  GoedertiWe performed a cladistic search in TNT*  using all characters as unordered and equally weighted. We then conducted subsequent statistical support analyses by searching for successively longer trees to calculate bremer decay indices and 100 bootstrap replicates. The complete matrix in .txt format, as well as a description of character states  are avaiFollowing http://zoobank.org/\u201d. The LSID for this publication is: urn:lsid:zoobank.org:pub:0194A593-DBE0-47CA-A41F-04A37931BA2F. The electronic edition of this work was published in a journal with an ISSN, and has been archived and is available from the following digital repositories: PubMed Central, and LOCKSS.The electronic edition of this article conforms to the requirements of the amended International Code of Zoological Nomenclature, and hence the new names contained herein are available under that Code from the electronic edition of this article. This published work and the nomenclatural acts it contains have been registered in ZooBank, the online registration system for the ICZN. The ZooBank LSIDs (Life Science Identifiers) can be resolved and the associated information viewed through any standard web browser by appending the LSID to the prefix \u201cAllodelphis pratti (YPM 13408); Allodelphis sp. ; Goedertius oregonensis (LACM 123887); Goedertius sp. ; Notocetus sp. (USNM 206286); Phocageneus venustus ; Phocageneus sp. ; Platanista gangetica (USNM 23456); Pomatodelphis bobengiPomatodelphis sp. (USNM 360054); Squalodon calvertensis ; cast of Waipatia maerewhenua (USNM 508061); Zarhachis flagellator ; Zarhachis sp. ; cast of Zarhinocetus errabundus (USNM 526600); Zarhinocetus errabundus .Definitions. Crown group Platanista refers to the crown clade arising from the last common ancestor of all lineages descending from Platanista, including two subspecies of Platanista gangetica  because these familial level groupings are not the explicit focus of this study, and we defer to future work that can better substantiate their taxonomic scope and better test their monophyly  was discovered and collected in 1951 by United States Geological Survey (USGS) geologist Donald J. Miller (1919\u20131961), who was mapping what was then the Yakataga District of Alaska (now the Yakutat City and Borough) between 1944 and 1963. Archival notes housed with the specimen at USNM state that Miller found the specimen in the Poul Creek Formation within the then-Yakataga District . Therefore, we delimit the area for the type\u2019s provenance to exposures of the Poul Creek Formation in the Yakutat City and Borough, Alaska, USA, in a grid ranging approximately from 60\u00b022\u2032N, 142\u00b030\u2032W to 60\u00b000\u2032N, 143\u00b022\u2032W , which belongs, based on one equivocal synapomorphy, to the node-based Platanistoidea: width: width of the premaxillae >50% of the width of the rostrum at the antorbital notch (character 51[1]). More convincingly, Arktocara belongs to Platanistoidea based on its affinities to other members of the Allodelphinidae that possess unequivocal synapomorphies of the Platanistoidea (see \u2018Discussion\u2019 for further comments on the relationship of Allodelphinidae within the Platanistoidea). We also note that, for the purposes of this diagnosis, we use a broad definition of Waipatiidae that includes Otekaikea spp. ; an occipital shield bearing a distinct sagittal crest (character 118[1]); length of the zygomatic process as percent of the greatest width of the maxillae across the postorbital processes <30% (character 152[1]); lacking a dorsal condyloid fossa (character 119[0]); and lacking any asymmetry in the vertex (character 98[0]).Arktocara also differs from Waipatiidae and Platanistidae in having: frontals posterior to the nasals and between the premaxillae wider than the maximum transverse width across the nasals (character 95[0]); and lacking an anterior transverse ridge and large tympanosquamosal recess, with middle sinus still inferred to be present (character 144[1]). Arktocara further differs from Waipatiidae in having: a lacrimal that wraps around the anterior edge of the supraorbital process of frontal and slightly overlies its anterior end (character 37[0]); maxilla forming the dorsolateral edge of the internal opening of the infraorbital foramen (character 43[0]); ventromedial edge of the internal opening of infraorbital foramen formed by maxilla and palatine (character 44[1]); a nuchal crest weakly convex anteriorly in dorsoposterior view (character 117[1]); a lateral end of the groove for the mandibular branch of the trigeminal nerve wrapping laterally around posterior end of pterygoid sinus fossa and opening primarily anteriorly (character 148[0]); the angle formed by the basioccipital crests in ventral view between 15\u201340\u00b0 (character 157[1]); and in lacking a premaxillary crest or posterior maxillary crest adjacent to the nasal (character 72[0]).Arktocara differs from all Platanistidae and Squalodelphinidae in having the anterolateral corner of the maxilla overlying the supraorbital process of frontal being thin and of even thickness to parts posteromedial (character 64[0]). Arktocara also differs from all Platanistidae in having: the apex of the postorbital process of frontal projected posterolaterally and slightly ventrally (character 46[0]); the ratio of the greatest width of the premaxillae to the greatest width of maxillae at the level of postorbital processes between 0.49\u20130.38 (character 76[1]); a shallow emargination of the posterior edge of zygomatic process by the sternomastoid muscle fossa in lateral view (character 111[1]); the width of the squamosal lateral to the exoccipital in posterior view as a percent of the greatest width of the exoccipitals <15% (character 112[0]); fossae for the preorbital lobe of the pterygoid sinus present in the orbit (character 134[1]); shallow posterior portion of the periotic fossa of the squamosal (character 151[1]); posteroventral-most point on the basioccipital crest forming a closely appressed flange with a narrow crease separating exoccipital dorsally from the rest of crest (character 156[1]); and lacking a pneumatic maxillary crest overhanging medially (character 65[0]). Finally, Arktocara differs from all Squalodelphinidae in having: a narrower width of the premaxillae at the antorbital notches as a percent width of the rostrum at the antorbital notch (50\u201364%) (character 51[1]).Arktocara differs from all other Allodelphinidae in having: a reduced postglenoid process of the squamosal (character 114[1]); and the posteroventral-most point of the basioccipital crest forming a closely appressed flange separating the exoccipital dorsally from the rest of the crest by a narrow crease (character 156[1]). Arktocara differs from Allodelphis pratti and Goedertius oregonensis in having: both premaxillae extending posterior to the nasals (character 58[1]); and the ratio of the greatest width of the premaxillae to greatest width of the maxillae at the level of the postorbital processes between 0.49\u20130.38 (character 76[1]).Arktocara also differs from Goedertius oregonensis and Zarhinocetus errabundus in having: the width of the premaxillae between 50\u201364% of the width of the maxillae a the level of the antorbital notches (character 51[1]); a uniformly thin anterolateral corner of the maxilla overlying the supraorbital process of the frontal (character 64[0]); length of the zygomatic process of the squamosal \u226430% of the width of the maxillae at the postorbital processes (character 152[1]); lacking a rostral basin (character 50[0]), lacking a posterior dorsal infraorbital foramen placed posteromedially near the posterior extremity of the premaxilla (character 60[0]); lacking a dorsal condyloid fossa (character 119[0]) and having a symmetrical cranial vertex (character 98[0]).Arktocara also differs from Allodelphis pratti and Zarhinocetus errabundus in having: two anterior dorsal infraorbital foramina (character 49[1]); and a shallow emargination of the posterior edge of the zygomatic process by the sternomastoid muscle fossa in lateral view (character 111[1]). Arktocara further differs from Goedertius oregonensis having: a fused lacrimal and jugal (character 39[1]); the apex of the postorbital process of the frontal directed posterolaterally and slightly ventrally (character 46[0]); a triangular or anteroposteriorly widened falciform shaped postorbital process of the frontal (character 47[2]); one posterior dorsal infraorbital foramina of the maxilla (character 59[1]); nuchal crest weakly convex anteriorly in dorsoposterior view (character 117[1]); and the posterior edge of the vomer terminating on the basisphenoid (character 154[0]).Arktocara further differs from Zarhinocetus errabundus in having: the transverse width of the nasal >70% the length of the nasal (character 91[2]); a distinct sagittal crest on the occipital shield (character 118[1]); and in lacking an anterior transverse ridge and large tympanosquamosal recess (character 144[1]).Arktocara displays the following apomorphies: a weakly developed antorbital notch (character 10[0]); straight lateral margin of the right premaxilla posterior to premaxillary foramen (character 56[1]); a U-shaped nasal frontal suture (character 94[2]); and a greatly reduced postglenoid process of the squamosal (character 114[1]).Lastly, Etymology. The species epithet \u2018yakataga\u2019 derives from the Tlingit name for the point of land along the southeast coast of Alaska between modern day Kayak Island and Ice Bay. This point, currently called Cape Yakataga, is located directly southwest of Watson Peak and represents the southeastern boundary of a floodplain drained by the Bering Glacier. The name Yakataga was first published by Anatomical terminology follows Arktocara yakataga (USNM 214830) consists of an incomplete skull, measuring 23 cm in preserved length. The majority of the rostrum is missing, with an asymmetric transverse break approximately 2\u20135 cm anterior to the antorbital notch. The skull also lacks both nasals, jugals, tympanoperiotics, and the right occipital condyle  and deep , with a broadly open and deep mesorostral canal . While there is material missing around the antorbital notch, the posterior margin of the right antorbital notch appears to be real, demonstrating it to be weakly developed, forming an L-shape with the lateral margin of the rostrum . Though In ventral view, there is clearly a fossa for the preorbital lobe of the pterygoid sinus , as well as for the hamular lobe of the pterygoid sinus (fossa anterior to the choanae). Also present are an extremely shallow tympanosquamosal recess for the middle sinus, and a middle pterygoid sinus fossa anterior to the periotic fossa . There iBoth of the premaxillae are symmetrical, and overlie either the maxillae or the frontals for their entire preserved length . In lateOn the vertex, the posterior termination of the premaxilla lies on the frontal as an asymmetrical, spatulate lobe, tapering posterolaterally and bordered medially by frontal and the nasal fossa of the frontal, and laterally the maxilla . There iOnly a small portion of rostral maxilla remains, including part of the maxillary flange on the left side, and just over 5 cm of the body of this element on the right side. In anterior view, the maxilla preserved on the rostrum slopes dorsally from the lateral edge to the premaxillary suture . The preIn ventral view, the hard palate of maxilla curves dorsolaterally from the midline to the lateral edge, where it flattens out on the maxillary flange . No alveIn dorsal view, the frontals are mostly covered by the maxillae, with the exception of exposures on the postorbital processes and the vertex . The posThe frontal-maxillary suture is also indistinct along the lateral edge of the vertex, where the maxilla rises dorsomedially to the edge of the vertex\u2019s tabular surface . The sutMost of the medial margin of the antorbital process is composed of the lacrimal. In dorsal view, a narrow margin of the lacrimal emerges from beneath the maxilla as a thin plate along the lateral and anterior edges of the antorbital process . In ventAllodelphis pratti . For further discussion of the lateral lamina of pterygoid as a platanistoid feature, see discussion in \u201cPlatanistoid systematics.\u201dPlatanistoids bear a bony structure on the ventral side of their skulls: a thin, bony lamina that extends from the ventral surface of the hard palate and runs parallel to the posterior lateral lamina of the pterygoid to finally attach to the alisphenoid medial of the squamosal in the ear region. The holotype of Both of the palatine bones are missing large portions, including the palatine surface, maxillary process, palatal crest, and lateral lamina. However, in ventral view a prominent pterygoid sinus fossa for the hamular lobe is formed by the palatine, anterior to the medial pterygoid lamina and posterior to the palatine groove of the maxilla . These gPlatanista and an undescribed platanistoid USNM 214911  was estimated using the formula created by n weight . It is lic necks . Though Arktocara, or whether it is more broadly observed in other allodelphinids . Also, the missing nasals and palatines suggest that their sutures to adjacent skeletal elements were unfused. We assessed skeletal maturity based on long-established osteological indicators, particularly the fusion of cranial sutures and textural surface of the occipital condyles . Most suArktocara is the sister taxon to Allodelphis, nested within a broader clade of Allodelphinidae, which includes Zarhinocetus and Goedertius. This is the first phylogenetic analysis to include these latter two genera, which were not included in Zarhinocetus and Allodelphis among their allodelphinid sample of Platanistoidea. Our analysis yields robust support for the monophyly of Allodelphinidae, with higher support values  than those recovered for the node-based clade of Platanistoidea  (sensuWaipatia and both species of Otekaikea\u2014Otekaikea species from their definition of Waipatiidae. We recommend defining Waipatiidae more inclusively (both species of Waipatia and Otekaikea).The phylogenetic analysis resulted in 430 most parsimonious trees, all with a score of 1960, consistency index of 0.233 and retention index of 0.631. The strict consensus tree, which was created from the 430 trees, shows a similar topology to the equally weighted analysis of lue <50) . Like Ta0) sensu, yet in Though it is beyond the scope of this study, the incorporation of molecular data into future analyses of odontocete systematics will help to better resolve the relationships among extant cetaceans, and consequently their fossil relatives. See below for further comment on the implications of these results on the systematics of Platanistoidea.Inia, Pontoporia, and Lipotes were more closely related to Delphinoidea than to Platanista  and is slightly overlapped by the pterygoid (though not the maxilla) .Dalpiazina ombonii (Champsodelphis by Longhi (1898), was later reviewed by and given its new genus by  ombonii  . However, in their implied weighting strict consensus, Squalodon was added to Platanistoidea. Allodelphinidae was not included in their analysis. sensu stricto  based on 6 synapomorphies: presence of the posterior dorsal infraorbital foramina of the maxilla (character 59); C-shaped or weakly curved parabullary sulcus (character 169); presence of the articular rim on the periotic (character 186); presence of the anterior spine of the tympanic bulla (character 195); presence of the anterolateral convexity of the tympanic bulla with anterolateral notch (character 196); and presence of the ventral groove (median furrow) of bulla anteriorly (character 212). Arktocara.In contrast to  hectori , both OtGoedertius oregonensis, Ninjadelphis ujiharai, and Zarhinocetus donnamatsonaeIn a broad review of Allodelphinidae, Waipatia maerewhenua + Waipatia hectori + Otekaikea marplesi + Otekaikea huata), Allodelphinidae and a polyphyletic Squalodelphinidae. We note that, for Phocageneus venustus, we followed Waipatia and Otekaikea is consistent with Waipatia, differing from the results in Waipatia maerewhenua and Otekaikea marplesi. Our results are consistent with Squalodelphis fabianii as a basal member of Platanistoidea and an unnamed clade of Notocetus vanbenedeni + Phocageneus venustus as the sister group to Platanistidae. A more detailed coding of Squalodelphinidae in future work, especially one that includes Huaridelphis raimondii, will provide more insight into the relationships among this group.Our phylogenetic analysis herein addresses some of the shortfalls of previous studies by including type genera belonging to all potential platanistoid families that have been presented in recent phylogenetic analyses i.e., . We resoWe diagnose a node-based Platanistoidea by the following synapomorphies: moderately elevated coronoid process (character 33*); premaxillae >65% of width of rostrum at antorbital notches (character 51*); alisphenoidal-squamosal suture coursing along groove for mandibular branch of trigeminal nerve in ventral view (character 147[1]); lateral groove or depression with profile of periotic becoming slightly to markedly sigmoidal in dorsal view (character 166[1]); anteroposterior ridge on dorsal side anterior process and body of periotic (character 167[1]); parabullary sulcus on the periotic weakly to strongly curved and c-shaped ; and ventral surface of the posterior process of the periotic not flat along a straight path perpendicular to its long axis  Of these synapomorphies, the two marked by an asterisk (\u2217) are equivocal across the group, demonstrating character state reversals or independent origins . Two characters are ambiguous and show independent origins (characters 169 and character 191), but we argue remain useful for characterizing this group.Allodelphis pratti, where there is no distinguishable rim lateral to the posterior process and separated by a sulcus , the anterolateral convexity of the tympanic bulla with anterolateral notch (character 196), and the ventral groove (median furrow) of bulla anteriorly (character 212) are all ambiguous characters, represented by two states each across Platanistoidea. All of the latter traits are present in Allodelphis pratti and Zarhinocetus errabundus, with perhaps the exception of the ventral groove of the anterior surface of the bulla in Allodelphis pratti, which could not be determined from the photos of the referred specimen (UCMP 83791) provided by Only one of the six synapomorphies presented by a sulcus . In ZarhSqualodelphis fabianii and an unnamed sub-clade that includes Notocetus vanbenedeni + Phocageneus venustus + Platanistidae. Allodelphinidae in our study is supported by the following synapomorphies: rostral constriction anterior to the antorbital notch (character 9[1]); premaxillae in dorsal view contacting along midline for approximately half of the entire length of the rostrum and partially fused (character 14[3]); buccal teeth entocingulum absent (character 24[1]); greatest diameter of largest functional tooth <3% of greatest width of maxillae at postorbital processes (character 25[2]); angle of anterior edge of supraorbital process and the median line oriented anteromedially (character 35[1]); dorsolateral edge of internal opening of infraorbital foramen formed by maxilla (character 43[0]); posterolateral sulcus shallow or absent (character 57[1]); lack of premaxillary crest or posterior maxillary crest adjacent to nasals (character 72[0]); temporal fossa roofed over by lateral expansion of the maxillae (character 101[1]); palatines partially covered by pterygoid dividing it into medial and lateral exposures (character 121[1]); lateral lamina of palatine (character 122[1]); lateral end of groove for mandibular branch of trigeminal nerve wrapping laterally around posterior end of pterygoid sinus fossa and opening anteriorly (character 148[0]); lack of anterior bullar facet (character 172[1]); elevated caudal tympanic process of periotic with ventral and posterior edges forming a right angle in medial view (character 178[1]); tubular fundus of internal acoustic meatus (character 182[1]) angle between posterior process of periotic and long axis of pars cochlearis \u2264135\u00b0 from dorsal or ventral view (character 189[1]); and ventral surface of posterior process of periotic convex along a straight path perpendicular to its long axis (character 191[2]). Based on the published descriptions and illustrations provided by Allodelphis woodburnei, Ninjadelphis ujiharai, and Zarhinocetus donnamatsonae) each possess all of the allodelphinid synapomorphies presented by our analysis.Our analysis recovered Allodelphinidae as a well-supported sub-clade within a node-based Platanistoidea, rooted in a polytomy with Waipatia and Otekaikea where the palatine is poorly preserved or missing), and a tympanic bulla with elongated and pointed anterior process, among others. Nevertheless, our diagnosis is consistent with Allodelphis pratti where only one premaxilla is separated from the corresponding nasal by a tiny exposure of maxilla, to further \u201cderived\u201d states in Ninjadelphis and Zarhinocetus where the premaxillae are further retracted anteriorly onto the facial region and away from the nasals. However, it is unclear in the more \u201cprimitive\u201d state of Allodelphis whether the lack of contact between the premaxilla and nasal could be a result of diagenetic breakage, or individual variation. Furthermore, speculations on the more \u201cderived states\u201d in taxa such as Ninjadelphis, are based on specimens with incomplete premaxillae. In Goedertius oregonensis, the premaxillae are not separated from the nasals. This condition is likely also true for Arktocara yakataga: although the nasals are missing, the premaxillae directly abut the nasal fossa of the frontal, and therefore would most likely have been in direct contact with the nasals. Further extensive comparative work on allodelphinid taxa  will heAllodelphis pratti, in part due to obstruction by unprepared matrix. However, in Arktocara yakataga, though there is no obvious indication of a postorbital lobe of the pterygoid sinus, the deep and broad fossa surrounding the ventral infraorbital foramen and the sphenopalatine foramen anteromedial of the orbit suggests the presence of a preorbital lobe.Second, Allodelphis pratti was referred to the Platanistidae by Ninjadelphis is the only allodelphinid specimen with an associated scapula, and it is missing the coracoid process. This agreement with Otekaikea huata), the character may still be relevant for diagnosing Platanistoidea . Though the type specimen of Arktocara lacks tympanoperiotics, it is closely allied with Allodelphis pratti, whose periotic shares three more of the platanistoid synapomorphies: presence of lateral groove or depression with the profile of the periotic becoming slightly to markedly sigmoidal in in dorsal view (character 166[1]); anteroposterior ridge developed on anterior process and body of periotic in dorsal view (character 167[1]); and a curved C-shaped parabullary sulcus . Therefore, in the absence of tympanoperiotics associated with new cranial material of Arktocara, we are confident that these elements would share many features with Allodelphis pratti, the sister taxon of Arktocara.Of the 7 supporting synapomorphies for Platanistoidea in our study, none of the unequivocal synapomorphies are preserved and demonstrated on the skull of Arktocara in morphology is Allodelphis pratti , (B) Platanista gangetica (USNM 23456) and (C) USNM 214911, an undescribed platanistoid. This feature (highlighted in red), is a pointed lamina projected anteromedially from the anterior margin of the falciform process (highlighted in blue), posterior to the lateral lamina of the pterygoid and anterior to the posterolateral lamina of the alisphenoid that articulates with the base of the falciform process  USNM 2345 and (C) Click here for additional data file.10.7717/peerj.2321/supp-2Figure S2Goedertius. (A) USNM 335406, (B) USNM 335765, (C) USNM 314421, (D) USNM 13673.Photographs of undescribed platanistoid specimens housed in the Vertebrate Paleontology collections of the National Museum of Natural History, Smithsonian Institution, Washington D.C. All of the skulls are referred in this paper to the allodelphinid genus Click here for additional data file.10.7717/peerj.2321/supp-3Table S1Zarhinocetus errabundus, Goedertius oregonensis, Allodelphis pratti and Arktocara yakataga). Also added were codings for four periotic characters (288\u2013291) for Pomatodelphis inaequalis and Zarhachis flagellator.0, primitive state; 1, 2, 3, derived states; 0/1, a variable between 0 and 1; 1/2 a variable between 1 and 2; 1/3, a variable between 1 and 3; ?, missing character or taxon not coded for this character. Following Click here for additional data file.10.7717/peerj.2321/supp-4Appendix S1Following Click here for additional data file."}
+{"text": "The hyperglycemic condition from dysregulated glucose homeostasis has been defined stress hyperglycemia. Following burn trauma it persists in a hypermetabolic flow phase as a response of burn itself and sepsis. Serial Sequential Organ Failure Assesment (SOFA) score is recommended from American Burn Association for evaluation of organ dysfunction/failure.The aim of this study is to test the relation of serial SOFA score evaluation and probability of critical hyperglycemia during burn injury.-rd,7-th,14-th and 21 -st day after burn injury.This is an observational prospective cohort study. Population is composed of adults hospitalized in ICU of the Service of Burns near University Hospital Center, Tirana, Albania for 5 years(2010-2015).Patients are grouped according glucose values on three categories: Patients with Euglycemia ( 80-120 mg/dL), Moderate Hyperglycemia (121-180 mg/dL) and Critical Hyperglycemia (> 180 mg/dL ).Test characteristics and performance as well as AUC are calculated for SOFA score on the 3The prevalence of Critical Hyperglycemia in adult burn patients is 6.9%. Using the value 6 as the cutoff SOFA scoring for dysfunction/ failure, serial SOFA score evaluation and presence of critical Hyperglycemia have a good correlation. On the 14-th day after burn the values of Area Under the Curve, Positive Likelihood Ratios and Positive Predicted Values (PPV) are the better values as complementary information to clinical assessment Figure .Figure 1In patients with clinical sepsis after severe burns the probability for Critical hyperglycemia is higher after the first week  This tells us that 2 of 5 patients with sepsis after the first week of the illness will demonstrate critical hyperglycemia. Hyperglycemia is a sign of sepsis in severely burned adult patients."}
+{"text": "Critically ill patients frequently suffer from intensive care unit (ICU) acquired weakness (ICUAW). Evoke muscle contraction by electrical muscle stimulation (EMS) may help to prevent their overall strength diminishing by conserving muscle strength and mass.The aim of the study was to investigate the effects of daily EMS-therapy on muscular strength in ICU patients, compared to a protocol based standard physiotherapy.The interventional randomized controlled trial included critically ill patients at high risk for ICUAW selected by SOFA score \u2265 9 and onset of critical illness in less than 72 hours. Randomization was administered to EMS group  or a physiotherapy group (protocol base physiotherapy). EMS-therapy was applied for 20 minutes 7 days/week to 8 bilateral muscle groups by an experienced physiotherapist. Medical-Research-Council (MRC) score for muscle strength and grip strength measured by hand-dynamometer were recorded on the first day patients were adequately awake and on the day of their ICU discharge. Non-parametric tests were performed. Ethic vote (Charit\u00e9 EA 2/041/10).50 patients, 33 males and 17 females with a median age of 52 (10/90) years and a SOFA score of 13 (10/15) at admission where included in the study. Randomization resulted in 21 to 29 subjects for EMS and controls respectively. Time-points of muscle strength measurements were \u201cfirst day being awake\u201d at median day 11 (7/19) and discharge form ICU, median day 26 (17/33). Patient characteristics and time-points of recorded parameters were without significant differences between the intervention (EMS) and control group (data not shown). Overall subjects fulfilled criteria for ICUAW on their first day of being awake and significantly improved their MRC score and grip strength until their ICU discharge. Surprisingly we could not show direct group differences between EMS- and control group for MRC score and grip strength. By focusing separately on the course of strength for EMS- and control group we found an increase in MRC score for both groups between the first and second measurement.Grip strength in nonEMS treated patients rose significantly whilst patients receiving EMS couldn't show significant improvements between measurements.Our patients managed to increase their grip- and general strength levels significantly from their first day of being adequately awake until the day of their ICU discharge. Further subgroup analysis however indicates that EMS therapy may not be more beneficial in increasing grip or MRC-measured strength compared to the standard physiotherapy protocol within our study. The missing grip strength improvement of the EMS group between the first day of being awake and ICU discharge may be attributed to greater muscle strength at time of awakening without significant power to show group differences.DFG KFO 192/2 TP3"}
+{"text": "Respiratory muscle weakness is common in mechanically ventilated patients and impairs liberation from ventilation. Inspiratory muscle training (IMT) might accelerate liberation from mechanical ventilation. We undertook to summarize previously published IMT protocols and the impact of IMT on respiratory muscle function and clinical outcomes.We searched multiple databases using a sensitive search strategy combining MeSH headings and keywords for studies of IMT during MV. Studies were adjudicated for inclusion and data were abstracted independently and in duplicate. Methodological quality was assessed using the GRADE system.n = 5) or after difficult weaning (n = 5); one study implemented IMT within 24 hours of intubation. IMT was associated with greater increases in maximal inspiratory pressure compared with control , I2 = 0%). There were no significant differences in the duration of MV , I2 = 71%) or the rate of successful weaning . The GRADE quality of evidence was low for all these outcomes; risk of bias was high for most studies and summary effects were imprecise and inconsistent. No serious adverse events related to IMT were reported.Eleven studies met the inclusion criteria; of these, six were randomized controlled trials and five were observational studies. A variety of IMT techniques were employed including inspiratory threshold loading (eight studies), biofeedback to increase inspiratory effort (one study), chair-sitting (one study) and diaphragmatic breathing pattern training (one study). Threshold loading was achieved by application of an external device (six studies) or increases in the inspiratory pressure trigger setting (two studies). Most studies implemented IMT in the weaning phase (IMT in mechanically ventilated patients appears safe and well-tolerated and improves respiratory muscle function. IMT was not associated with accelerated liberation from mechanical ventilation. However, because the included studies had important methodological limitations and employed varying methods of IMT, we cannot draw firm conclusions about the effect of IMT on clinical outcomes."}
+{"text": "Twenty one fully sequenced and well annotated insect genomes were used to construct genome content matrices for phylogenetic analysis and functional annotation of insect genomes. To examine the role of e-value cutoff in ortholog determination we used scaled e-value cutoffs and a single linkage clustering approach.. The present communication includes (1) a list of the genomes used to construct the genome content phylogenetic matrices, (2) a nexus file with the data matrices used in phylogenetic analysis, (3) a nexus file with the Newick trees generated by phylogenetic analysis, (4) an excel file listing the Core (CORE) genes and Unique (UNI) genes found in five insect groups, and (5) a figure showing a plot of consistency index (CI) versus percent of unannotated genes that are apomorphies in the data set for gene losses and gains and bar plots of gains and losses for four consistency index (CI) cutoffs."}
+{"text": "This article gives an overview of recent publications and potential indications of Positron emission tomography/ Magnetic resonance (PET/MR) imaging of prostate cancer. Several original research articles showed that a combination of these functional imaging modalities can improve diagnostic accuracy of MR imaging  or [18F] choline has been examined to a large extent during the past years; however, with partly controversial results. A large meta-analysis defined possible indications of PET/CT examinations of the prostate including initial staging of patients with newly diagnosed prostate cancer and high-risk of nodal extension and suspected recurrent prostate cancer after surgery or radiotherapy indicated by a rising PSA-level. Another indication of a PET/CT scan of the prostate might be a history of negative biopsies in patients with a strong suspicion of prostate cancer to plan a focused re-biopsy in carefully selected cases [PET and PET/CT imaging of prostate cancer with the radiotracers C or [18F18F] choline PET/MR imaging in patients with prostate cancer [11C] and [18F] choline was shown that PET and MR image quality was sufficient and without significant differences in the detection of hyper-metabolic lesions and with excellent correlation of standardized uptake values derived from PET/MRI and PET/CT [18F] choline PET/MRI were reported for detection of prostate cancer relapse after external beam radiotherapy [68Ga] labeled prostate-specific membrane antigen (PSMA) ligand. Recent studies demonstrated the technical feasibility of PET/MR imaging with this new tracer and found a superiority of PET/MRI over PET/CT by using this tracer [68Ga] labeled tracer yielded some difficulties and requires further investigation before routine use  choline PET/MR imaging was performed after PET/CT. The images illustrate the combined findings of anatomical sequences together with diffusion-weighted imaging and PET imaging.Figure legends: Images from a patient with biochemical failure after radical prostatectomy  and fromIn conclusion, the results published so far on PET/MRI of prostate cancer are promising and justify further research in this field. It will be necessary to plan and conduct large prospective studies in order to ascertain the additive value of PET/MRI in comparison to the available diagnostic tools in prostate cancer diagnostics."}
+{"text": "Simian foamy virus (SFV) is a retrovirus ubiquitous in non-human primates (NHPs) that can be transmitted to humans, mostly through severe bites. In the past few years, our laboratory identified more than 50 hunters from Central Africa infected with zoonotic SFVs. Analysis of SFV complete sequences obtained from 5 of these individuals had revealed that the env gene was the most variable one. Furthermore, recombinant SFV strains have been recently shown; some of them involved the env gene. This led us to investigate the env gene variability of zoonotic SFV strains, looking especially for possible recombinants. We sequenced the complete or the surface glycoprotein region (SU) of SFV env gene amplified from blood DNA of: 1) a series of 40 individuals from Cameroon or Gabon infected with a gorilla or chimpanzee FV strain; 2) one gorilla and 3 infected chimpanzees living in the same areas than the hunters. All sequences were aligned and analysed by phylogenetic (neighbour-joining and maximum likelihood) and recombinant detection methods . Phylogenetic analyses revealed the existence of two different env variants among both gorilla FV and chimpanzee FV strains. These were present in zoonotic as well as in NHP strains. These variants differ greatly (more than 30% variability) in a 750 bp long region located in the receptor binding domain of the SU; the rest of the gene is very conserved (less than 5% variability among strains from the same species). Within a given variant, protein sequences of the SU are very conserved and stable  which may reflect functional constraint. Recombination analyses highlighted that these variants could have emerged through recombination events."}
+{"text": "Radium-223 is an alpha emitter, licensed in 2013 for treatment of symptomatic bone metastases in metastatic castration resistant prostate cancer. The treatment consists of 6 intravenous administrations and ongoing patient management before, during and after treatment. In our institution, this service is led by the nuclear medicine departmentThe ALSYMPCA trial, published in 2013, demonstrated improved overall survival (14.9 vs 11.3 months) and prolonged time to first symptomatic skeletal event (15.6 vs 9 months) for patients administered Radium-223 vs placeboImaging plays a key role in the selection criteria and response assessment for this new therapeutic modality. We present an educational review of the spectrum of multimodality imaging techniques employed for pre-therapeutic assessment and also for therapeutic response assessment\u2022 A brief overview of the criteria for treatment with radium-223 will be provided\u2022 Examples of CT and MRI scans of patients suitable for treatment, including pre and post therapeutic findings\u2022 Isotope bone scans of patients before and following treatment, demonstrating the effect of radium-223 on skeletal lesions.Radium-223 is an emerging innovative treatment for symptomatic bone metastases from castrate resistant prostate cancer and may well be the standard of care in the future. Cancer imagers should be aware of the suitability criteria for treatment, which will help inform discussions when patients are being considered for this treatment. They should also be aware of the multimodality imaging findings on post therapeutic response assessment studies."}
+{"text": "Multiple epidemiologic studies have consistently reported association between increased coffee consumption and a lowered risk of Type 2 diabetes mellitus. However, the mechanisms behind this finding have not been fully elucidated.We investigate the effect of coffee (caffeinated and decaffeinated) on glucose effectiveness and insulin sensitivity using the stable isotope minimal model protocol with oral glucose administration in healthy men.Fifteen healthy men underwent 5 arms randomized crossover single-blinding (researchers) clinical trial. They consumed decaffeinated coffee, caffeinated coffee (with and without sugar), and controls \u2013 water (with and without sugar) followed 1 hour by an oral glucose tolerance test (75 g of available carbohydrate) with intravenous labeled dosing interpreted by the two compartment minimal model (225 min). One-way ANOVA with Bonferroni adjustment were used to compare the effects of the tested beverages on glucose metabolism parameters.Decaffeinated coffee resulted in 29% and 85% higher insulin sensitivity compared with caffeinated coffee and water, respectively, and the caffeinated coffee showed 15% and 60% higher glucose effectiveness compared with decaffeinated coffee and water, respectively. However, these differences were not significant (p >0.10). In overall analyze (0 \u2013 225 min) there were no significant differences on glucose effectiveness, insulin sensitivity, and glucose and insulin area under the curve between the groups. The beneficial effects of coffee did not seem to act in the short-term (h) on glucose metabolism parameters mainly on insulin sensitivity indices. The benefits of coffee consumption occur in the long-term (yrs.) as has been shown in the reduction of Type 2 Diabetes Mellitus risk in epidemiological studies. The clinical relevance of the present findings is that there is no need to avoid coffee as the drink choice for healthy people.The findings of this study demonstrate that the consumption of caffeinated and decaffeinated coffee with or without sugar has no acute effects on glucose metabolism in healthy men. Further researches, including long-term interventional studies, are needed to fully elucidate the mechanisms behind the coffee effects on reduced risk for Type 2 diabetes mellitus."}
+{"text": "The third and fourth authors, Delphine Magis (DM) and Jean Schoenen (JS), should be noted as contributing equally to this work."}
+{"text": "The creatinine values in Tables S1 Tablem/z), retention time (sec) and abundance (intensity) of 58 metabolites. The information of sex and age on 50 individuals is indicated on top.Plasma collected from marmoset was analyzed for metabolomics by high-resolution mass spectrometry as described in Methods. The mass spectrometry data includes ion mass Click here for additional data file."}
+{"text": "There was an error in the figure legend of Figure 4. Please see the corrected Figure 4 here: The corrected Figure 4 caption reads:Grand-average ERP waveforms for the Grasping Small and the Grasping large conditions. The plots show ERPs time locked to glasses opening.The corrected Figure 3 caption reads:Scalp distribution of ERP differences between Grasping Small and Grasping Large conditions.In the last sentence of the \"Electrophysiological recording and data processing\" section in Materials and Methods, some of the stimulus appearance sites were listed incorrectly. The corrected sentence is: Based on visual inspection of grand average waveforms and amplitude scalp maps, the following ERP components were statistically analyzed: amplitude and latency of P300, namely the positive peak evoked 200\u2013400 ms following stimulus appearance at parietal sites ; amplitude and latency of N400, namely the negative peak occurring at 300\u2013500 ms after object appearance at frontal , fronto-central , and central  sites; and mean amplitude of the sustained negativity observed in 400\u2013800 and 1200\u20132000 time windows at frontal , fronto-central , central , and parietal  sites."}
+{"text": "Malignancies of biliary tract have been rarely reported in HIV disease.We report 3 cases of biliary tract malignancy associated with HIV infection from Prayas Amrita clinic, an NGO based HIV clinic in Pune, India. Two of the cases were diagnosed with gall bladder malignancies (GBM) and the third one had cholangio carcinoma (CC). All presented with advanced stage of malignancy with metastases and had poor prognosis. All were males with median age at presentation being 47 years (range - 46-48 years) They were diagnosed to have HIV for a median duration of 102 months (range: 69-118 months) . Median nadir CD4 count was 77cells/cmm (range: 71\u2013163 cell/cmm). They were on first line ART for median 63 months (range: 41\u201372 months). A patient with GBM was Hepatitis B co infected. Prior AIDS related events of anemia, immune thrombocytopenic purpura and tuberculosis were present in the patient with CC and progressive multifocal leukoencephalopathy was in one of the patients with GBM. Being managed in resource limited setting; the absence of other risk factors is corroborative and lacks evidence.These 3 cases of biliary tract malignancies were seen recently in a relatively short span of time. All were men in late forties, infected with HIV for a long time and had no other known risk factors. This could be a pointer towards changing scenario of malignancies among HIV infected patients associated with prolonged survival."}
+{"text": "Increasing number of patients with post-herpetic neuralgia (PHN) leads to clinical observation of the fact that it worsening the condition of patients with other chronic pain syndromes such as migraine and tension-type headache (TTH).The aim of this study was assessment of cephalgic pain severity and quality of life (QoL) in patients with primary headaches in comparison with those who additionally suffers of PHN.12 patients with PHN and comorbid migraine and TTH  and 14 patients with migraine and TTH only (4 and 10) as controls were assessed for headache pain severity by visual analog scale (VAS) and QoL by short form (SF-36) screening tools.Patients with PHN had worse results of headache pain intensity and QoL vs patients of control group. Headache pain severity in PHN group was 7-8 vs 5-6 in control group, and QoL scoring was lower in PHN group vs control.PHN as the reason of central sensitization leads to further increase of the other chronic pain syndromes, such as primary headaches, elevate the cephalgic pain and decrease the QoL.No conflict of interest."}
+{"text": "Scientific Reports5: Article number: 1448510.1038/srep14485; published online: 09292015; updated: 02022016The original version of this Article contained a typographical error in the Abstract.\u201cShort diffusion distance of few hundreds of nanosecond was also observed in thin films.\u201dnow reads:\u201cShort diffusion distance of few hundreds of nanometer was also observed in thin films.\u201dThis has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Investigators from Washington University St. Louis studied the impact of electroencephalographic monitoring of neonates with Hypoxic Ischemic Encephalopathy (HIE) and their degree of MRI injury and neurodevelopmental outcomes when increasing seizure burden was present. Investigators from Washington University St. Louis studied the impact of electroencephalographic monitoring of neonates with Hypoxic Ischemic Encephalopathy (HIE) and their degree of MRI injury and neurodevelopmental outcomes when increasing seizure burden was present. Investigators performed a randomized controlled trial to investigate the effect of seizure burden on neurodevelopmental outcomes in infants with recognized electrographic seizures versus infants with clinically recognized seizures. Researchers found 15/35 neonates in the electrographic seizure group (ESG) and 20/34 neonates in the clinical seizure group (CSG) to have seizures. The researchers found that the ESG presented with a lower cumulative seizure burden (SB) than the CSG (p=0.02) likely due to faster identification and subsequent treatment of seizures. The investigators found no difference between ESG and CSG groups regarding developmental outcome due to the power of the study. However, analysis of the cohort as a whole indicated that an increasing SB correlated with worsened outcomes on the Bayley Scales of Infant Development III (p=0.03). The investigators also showed that greater SB in the cohort was associated with a worse MRI injury severity. [COMMENTARY. Neonatal seizures are prevalent in infants with HIE . However"}
+{"text": "In the fourth paragraph of the Discussion section, reference #37 and #5 are switched. The paragraph should read as follows: \"Although this study did not identify any IS6110 positives, previous studies have identified the presence of this locus in New World primates [5]. However, the IS6110 mobile element has been found to be homologous in some related soil mycobacteria [37], and targeting this element with PCR has previously produced false-positives [38].\""}
+{"text": "Background: Hypospadias is one of the most common congenital abnormalities in the male which is characterized by altered development of urethra, foreskin and ventral surface of the penis. Androgen receptor gene plays a critical role in the development of the male genital system by mediating the androgens effects.Objective: In present study, we looked for new variations in androgen receptor promoter and screened its exon 1 for five single nucleotide polymorphisms (SNP) in healthy and hypospadias Iranian men.Materials and Methods: In our study, at first DNA was extracted from patients (n=100) and controls (n=100) blood samples. Desired fragments of promoter and exon 1 were amplified using polymerase chain reaction. The promoter region was sequenced for the new variation and exone 1 screened for five SNPs  using restriction fragment length polymorphism technique.Results: The results showed a new single nucleotide variation (C\u2192T) at -480 of two patients\u2019 promoter region (2%). None of the mentioned SNPs were detected in patients and controls groups (0%). Conclusion: This finding indicates that new single nucleotide polymorphism in androgen receptor promoter may have role in etiology of hypospadias and development of this anomaly.This article extracted from Ph.D. thesis. (Nasim Borhani) Hypospadias is the most common congenital malformation of the male external genitalia in which the urethral meatus opens on the ventral side of the penis . It affeAR gene is located on chromosome Xq11-12 and consists of eight exons, in which exon 1 encodes the transactivation domain that activates transcription of several different AR-responsive downstream genes , and in addition, AR gene promoter region was scanned for new variations in hypospadias disease in Iranian population.Impaired signaling through the androgen receptor (AR) leads to failure of urethral fold formation and fusion and consequently leads to hypospadias . The AR am genes , 7. The am genes , 9. ThesPatients and controlsThe patients in this analytical association study refered to the Mofid\u2019s children Hospital  between March 2012 to August 2012. The patients should have criteria including diagnosis by urologist and having no sign of other genetic or congenital disease or genital malformations; (the properties distribution of patients in our study are listed in =100) and control group (n=100) were taken using venoject tube containing EDTA (0.5 M). The controls were selected from healthy males in Shahid Beheshti School of Medicine. The control samples should not have any sign of genetic disease, genital malformations or any addiction. Peripheral blood samples of hypospadic patients (nDNA extraction and polymerase chain reaction (PCR)AR transactivation domain were amplified using the primer pair: 5\u2019TCCAGAGCGTGCGCGAA GTG3\u2019 (sense) and 5\u2019CCGACTGCGGCTGT GAAGGT3\u2019 . Genomic DNA was extracted from peripheral blood of patients and controls using the whole blood extraction kit . Nucleotides -756 to -366 of the AR 5\u2019 promoter region (based on Ensemble.org genome browser) were amplified using the primer pair: 5\u2019TCTCCAAA GCCACTAGGCAG3\u2019 (sense) and 5\u2019ACCGAA GAGGAAAGGGCAGCTC3\u2019 (antisense). Nucleotides +604 to +888 of the Restriction fragment length polymorphism (RFLP) analysisFor transactivation domain genotyping, PCR, RFLP and 8% polyacrylamide gel electrophoresis (PAGE) were used. The RFLP reaction condition was detailed and presented in Promoter region sequencingFor AR promoter region sequencing, PCR products were purified using DNA extraction kit  and then scanned for variations using direct sequencing .Ethical considerationsThe informed consent was obtained from all adult participants (control groups) and from the parents or legal guardians of minors (patients). This study had been reviewed and approved by a certified Ethical Committee in Shahid Beheshti University of Medical Sciences.RFLP resultsThe 285 bp PCR product containing five SNP sites was digested using suitable enzymes; SsiI, PstI, CaiI, SfaNI, and BseG1. The two SNPs rs62636528, and rs62636529 produce gain of sites compared to wild type allele, while rs78686797, rs139767835, and rs145326748 supposed to have loss of sites in digestion with the mentioned enzymes . The SsiSequencing resultsAR gene promoter region was scanned for new variations in subjected samples and a new single nucleotide polymorphism (SNP) was detected in two patient samples (2%)  at position -48oC\u2192T (the normal sequence and two sequences curves with a new nucleotide variation are shown in AR gene is a member of the nuclear receptor superfamily that is located on Xq11-12. This receptor plays a critical role in male sexual differentiation by mediating the biological effects of androgens (AR amount or structure may disrupt this patterning (AR for the first time in hypospadic patients and we found a new single nucleotide polymorphism in two patients at -480 using direct sequencing. There have been many reports on AR promoter sequencing. ndrogens . Early det al scanned AR gene promoter and untranslated region in 44 clinical prostate cancer specimens and 36 normal controls; but they did not find any different sequence variations (et al screened promoter region of androgen receptor gene in 240 men with idiopathic infertility and 30 healthy men and this study did not show presence of any deletions or mutations in infertile or healthy men and they suggested that AR gene promoter mutation are not common in men with idiopathic infertility (AR gene promoter region of 100 healthy men suggested that DNA sequence alterations are rare in the human androgen receptor gene promoter (In 2006, Waltering riations . Likewisertility . Furtherpromoter . et al in which mutation screening of genomic DNA of men with hypospadias did not show any point mutation in AR gene exons (et al reported that the majority of patients with hypospadias did not carry androgen receptor gene mutations. In addition Sasagawa et al suggested that alteration of the AR gene is rare in males with isolated hypospadias, cryptorchidism, micropenis, or idiopathic male infertility (et al reported that none of the studied hypospadic patients in their research had AR gene mutations (AR gene mutation is rare in hypospadic patient (Additionally, we did not find any of mentioned single nucleotide polymorphisms in control and patient groups using PCR and RFLP techniques. This finding may declare that these five polymorphisms are not be involved in hypospadias etiology. These data are consistent with the previous report by Muroya ne exons . Also Hiertility . Furtherutations . Likewis patient , 17. et al it was found that a SNP in the AR gene region was associated with susceptibility to severe hypospadias. They concluded that AR rs5919436 polymorphism may act as a new gene marker for increased susceptibility to severe hypospadias in Caucasians (AR gene with the hypospadias; and suggested that expanded CAG repeat length has a role in modifying the risk and development of hypospadias (In addition, In a recent study by Adamovic ucasians . BesidesAR gene expression in the genital system due to decreasing the transcription machinery affinity for binding toward regulatory elements.In addition, in another study on Chilean population, the CAG and GGN polymorphisms in the AR gene has been investigated and showed that in isolated hypospadic boys, there are longer CAG alleles in their AR gene that might be associated with the development of hypospadias . Taken t"}
+{"text": "One of the most pressing health-related challenges is the worldwide epidemic of type 2 diabetes and associated complications such as nephropathy. Indeed, type 2 diabetic patients account for the majority of individuals with chronic kidney disease requiring renal replacement therapy. This not only suggests inadequacy of current drug therapies but also failure of endogenous protective mechanisms. Stem cells are known to play pivotal roles in repair and regeneration of damaged/dysfunctional tissues. Our initial observations suggested that initiation and progression of type 2 diabetes mellitus is associated with progressive reduction in endothelial progenitor cells in the obese diabetic db/db mice. Thus, the present study was intended to more fully explore the status of components of stem cells in the setting of type 2 diabetic nephropathy and whether the diabetic milieu affects the survivability of these cells.Male 16-week-old obese diabetic db/db mice (and their db/m controls) were used for this study. Accordingly, indices of glycemic status , kidney function  were determined in the context of assessment of components of stem cells in peripheral blood and renal tissue. In addition, we measured apoptotic cell death in components of stem cells.+Ckit+CD31-) mesenchymal stem cells  and endothelial/epithelial progenitor cells  compared to those of db/m controls. Further, kidney cells prepared for experimental groups also showed reductions in components of stem cells. Using annexin V in association with markers of each component of stem cells revealed significant increases in apoptosis for HSC, MSC and EPCs in cells prepared for kidneys of db/db and db/m mice. Collectively, the results suggest that apoptosis of components of stem cells likely contributes to eventual manifestation of renal failure in type 2 diabetes mellitus.The db/db mice showed significant increases in insulin resistance index and hemoglobin A1c in association with marked increase in albuminuria but reduction in creatinine clearance in association with significant increases in apoptotic and necrotic cell death of kidney cells. The peripheral blood cells of db/db mice displayed significant reduction in hematopoietic stem cells (HSC; Sca1The observation of a similar pattern of decline in stem cell components in the peripheral blood and the kidney suggests that monitoring of blood levels of stem cells subsets may be predictive of failure of their renoprotective features. Further, strategies aimed at reducing apoptosis of stem cell components and \u201cempowering\u201d them through genetic modulations could potentially serve as effective strategies to prevent end-stage renal failure in type 2 diabetic patients."}
+{"text": "Chronic kidney disease (CKD) caused by renal fibrosis is an important public health concern. It is therefore necessary to understand the molecular pathogenesis of renal fibrosis in order to develop novel therapeutic strategies. KLF4 is the most extensively studied factor among the various members of the Kr\u00fcppel-like factor (KLF) family of zinc finger-containing transcription factors. Many studies have demonstrated that KLF4 inhibits the activation of myofibroblasts and exerts an inhibitory effect on fibrosis. However, other studies have indicated that KLF4 may promote renal fibrosis. These controversial results suggest that KLF4 may be crucially involved in the development of renal fibrosis, although the underlying mechanism(s) remain unclear. Here, we summarize the recent progress made in understanding the role of KLF4 in renal fibrosis. Together, these findings suggest that KLF4 may participate in the development of renal fibrosis, but that its inhibition of fibrosis is greater than its promotion of the condition, which suggests that KLF4 may serve as a novel therapeutic target for renal fibrosis. Renal fibrosis is characterized by excessive proliferation of fibroblasts and increased deposition of extracellular matrix (ECM), which together lead to extensive scarring (fibrotic tubular and glomerular sclerosis), renal artery stenosis and chronic inflammatory cell infiltration  family consists of 17 zinc finger-containing transcription factors, among which KLF4 is the most extensively studied  is an important participant in a broad spectrum of inflammatory networks that regulate the cytokine activity in renal fibrosis  regulates the expression of VSMC differentiation markers by cooperating with its co-activator, myocardin, or its co-repressor, phosphorylated KLF4 (Wang et al., renal physiological functions and the progression of fibrosis (Chen et al., in vivo models of unilateral ureteral obstruction, a decrease in KLF4 expression was observed (Chen et al., Recently, Chen et al. showed that KLF4 was indeed involved in the regulation of The role of KLF4 in renal fibrosis is complex. For instance, KLF4 can induce the transformation of primary fibroblasts (Rowland et al., Because KLF4 is expressed in kidney cells (Hayashi et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The dynamical fluctuations in the rhythms of biological systems provide valuable information about the underlying functioning of these systems. During the past few decades analysis of cardiac function based on the heart rate variability  has attracted great attention, resulting in more than 17000-publications (PubMed list). However, it is still controversial about the underling mechanisms of HRV. In this study, we performed both linear (time domain and frequency domain) and nonlinear analysis of HRV data acquired from humans and animals to identify the relationship between HRV and heart rate (HR). The HRV data consists of the following groups: (a) human normal sinus rhythm (n = 72); (b) human congestive heart failure (n = 44); (c) rabbit sinoatrial node cells ; (d) conscious rat (n = 11). In both human and animal data at variant pathological conditions, both linear and nonlinear analysis techniques showed an inverse correlation between HRV and HR, supporting the concept that HRV is dependent on HR, and therefore, HRV cannot be used in an ordinary manner to analyse autonomic nerve activity of a heart. Greek Physicians and scientists were the pioneers who measured pulse rate; however, it was not much accurate till the invention of pulse watch in 1707 .The autonomic nervous system (ANS) controls heart rate, hear rate variability (HRV) and breathing. Heart Rate Variability (HRV) analysis is a non-invasive technique used to evaluate the balancing action of sympathetic and parasympathetic branches of the autonomic nervous system , 4,5. OvOver the last 35 years, various linear and non-linear techniques have been developed to extract the valuable information from cardiac interbeat interval time series data, aiming to help clinician for prognostication of illness and assessing malfunctioning of the autonomic nervous system. However, often contradictory results have left clinicians skeptical and there exists no clear consensus about HRV analysis measures . In 1996The main purpose of this study is to identify the relationship of HR with both linear and nonlinear metrics of HRV. The human and animal data sets were analysed under following conditions: (a) human normal sinus rhythm n = 72); (b) human congestive heart failure (n = 44); (c) rabbit sinoatrial node cell (SANC) (n = 67); and (d) conscious rat (n = 11). Both nonlinear and linear methods showed that HRV is primarily dependent on HR. There is an inverse correlation between the HRV and HR: a larger HRV  was correlated with a lower HR, and the vice versa. Such a correlation was observed both in the human data at variant pathological conditions and variant animal species. This study provided support to the concept of a previous study[; (b) humHRV analysis can be done by many ways and a wide range list of techniques explored since 1960 are described in detail by the North American Society of Pacing Electrophysiology and the task force for European Society of Cardiology . This stMeasures included in linear time domain parameters are derived from direct RR interval measurement for standard deviation of all normal to normal RR intervals (SDNN), and from differences of RR interval for root mean square of successive NN interval differences (RMSSD) (RMSSD) . SpecifiIn which \u2018I\u2019 is RR intervals, Where \u2018I\u2019 is RR intervals and \u2018N\u2019 is the total number of RR intervals.The frequency domain measures used in this study included: Very low frequency (VLF), low frequency (LF), high frequency (HF) and total power. VLF is a band of power spectrum range \u2265 0.04 Hz. Normally this measure shows overall activity of numerous slow mechanisms of sympathetic activity. LF is a band of power spectrum ranging between 0.04 and 0.15 Hz. This parameter reflects both sympathetic and parasympathetic function. HF is a band of power spectrum range between 0.15 and 0.4 Hz. Generally this measure reflects parasympathetic function. Total power is a short term estimate of the total power of power spectral density in the range of frequencies between 0 and 0.4 Hz. In this parameter sympathetic activity is a main contributor when its shows overall autonomic activity .m or 30m and m = 2(100\u2013900 data points) will yield statically reproducible and reliable results. He also describe that ApEn can be applied to any system having at least 50 data points. ApEn algorithm counts similar sequences to given sequence of length m, including the sequence itself to avoid natural logarithm of zero within the calculations. As a result, ApEn can sensitive to the size of data. To overcome this, a variant of the ApEn algorithm called Sample entropy (SamEn) [Approximate entropy (ApEn) and sample entropy (SamEn) were used to analyse the nonlinear behaviour of HRV , 13,14.  (SamEn) , which gThe data sets used in the study comprised of both human and animal data and in We used RR-interval time series data of human normal sinus rhythm (n = 72), human congestive heart failure(n = 44), rabbit SANC and conscious rat(n = 11) subjects.In human groups, HRV in terms of SDNN and RMSSD is high in normal sinus rhythm  then in In frequency domain analysis we used Total Power(TP) (high frequency (HF)+low frequency (LF)+very low frequency (VLF)) to analyse RR-interval time series data of human normal sinus rhythm (n = 72),human congestive heart failure(n = 44), rabbit SANC and conscious rat(n = 11). HRV in terms of Total Power in human groups is high in the normal sinus rhythm then conIn nonlinear time series analysis we used Approximate Entropy and Sample Entropy to analyse RR-interval time series data of human normal sinus rhythm (n = 72),human congestive heart failure(n = 44), rabbit SANC and conscious rat(n = 11). In human groups, HRV in terms of Approximate Entropy and Sample Entropy is high in normal sinus rhythm  then conThe baseline cycle length  also varied widely between preparations . In humaIn the Figs Heart rate variability analysis is a non-invasive technique used to assess the cardiac autonomic control under physiological and pathophysiological conditions , 4, 7. TMonfredi et al , used liIn this study, we investigated the relationship of linear (time domain and frequency domain) and nonlinear HRV parameters with heart rate using RR-interval time series data from human and animals. The RR-interval time series comprised of human (72 NSR and 44 CHF subjects) and animal subjects . The research findings indicate that both linear and nonlinear HRV methods showed an inverse correlation between the HRV and HR: a larger HRV  was correlated with a lower HR, and the vice versa. Such a correlation was observed both in the human data at variant pathological conditions and in different animal species. The inverse correlation of nonlinear HRV measures along with linear ones with HR is the salient feature of this study. The outcomes of this study strong the evidence of relationship between HRV with HR and are in line with outcomes of Monfredi and co-authors. It is suggested that in future studies HR should be taken into consideration at which HRV analysis is being performed."}
+{"text": "For the first time, complete genome sequences of four lineage III peste des petits ruminants (PPR) viruses  originated from the Middle East and East Africa are reported here. The availability of complete genome sequences from all four lineages (I to IV) of the PPR virus (PPRV) would greatly help in a comprehensive understanding of the molecular evolution and emergence of PPRV. Phylogenetic analysis of the partial F gene (322\u00a0nt) (Peste des petits ruminants (PPR) is an important infectious viral disease of domestic and wild small ruminants and endemic in the Middle East, Africa, and Asia  (http://(322\u00a0nt)  has defi(322\u00a0nt) , 5. AvaiThe complete genomes of four PPRV isolates from the Middle East, Oman 1983  and UnitPhylogenetic analysis of all the available (at GenBank as of August 2014) complete genome sequences of PPR viruses , including the four viruses sequenced in this study , has grouped them into four genetically divergent lineages that are similar to the phylogenetic study using partial F, N, and H genes. Complete genomes of PPRV isolates  sequenced in this study were confirmed to be of lineage III. Therefore, this study demonstrated the co-circulation of lineages III and IV in East Africa . FurtherKJ867543 (Uganda 2012), KJ867540 (Ethiopia 1994), KJ867545 (UAE 1986), and KJ867544 (Oman 1983).The complete genome of the PPRV isolates have been deposited in GenBank under accession no."}
+{"text": "In this connexion novel radiopharmaceuticals for the noninvasive molecular imaging of early disease states and monitoring of treatment responses in vivo by means of PET/CT, SPECT/CT and PET/MRI are indispensable prerequisites to further advance and strengthen the unique competence of radiopharmaceutical sciences. In the era of personalised medicine the diagnostic potential of radiopharmaceuticals is directly linked to a subsequent individual therapeutic approach called endoradiotherapy. Depending on the \u201cradioactive lantern\u201d (gamma or particle emitter) used for radiolabelling of the respective tracer molecule, the field of Radiopharmaceutical Chemistry can contribute to the set-up of an \u201cin vivo theranostic\u201d approach especially in tumour patients by offering tailor-made (radio)chemical entities labelled either with a diagnostic or a therapeutic radionuclide.The fields of molecular biology, immunology and genetics have generated many important developments that advance the understanding of the induction and progression of oncological, cardiological and neurological diseases as well as the identification of disease-associated molecules and drugs that specifically target diseased cells during therapy. These insights have triggered the development of targeted radiopharmaceuticals which open up a new dimension of radiopharmaceutical sciences in nuclear medicine. Radiopharmaceuticals, also called radiotracers, are radiolabelled molecules, bearing a \u201cradioactive lantern\u201d, and used as molecular probes to address clinically relevant biological targets such as receptors, enzymes, transport systems and others. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) realised in the in vivo and facilitates to predict and monitor successful therapy strategies. The definition of \u201cmolecular probe imaging\u201d is highlighted in detail in this special issue  : \u201cAt the heart of all nuclear imaging, radiopharmaceutical science is the design, synthesis and evaluation of compounds containing suitable radionuclides that can be used in vivo to trace (follow) a particular physiological or biochemical phenomena\u201d [Early-stage noninvasive molecular imaging enables to look at the biodistribution of molecular probes al issue  1]. Ind. Indin venomena\u201d .In fact, according to reports of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) more than 33 million diagnostic nuclear medicine examinations are performed annually worldwide. The annual frequency of diagnostic nuclear medicine examinations and of nuclear medicine treatments in health-care level I countries have thus increased tremendously, from 11 per 1,000 population in 1970\u20131979 to 19 per 1,000 in 1997\u20132007 and for therapeutic nuclear medicine procedures from 0.17 per 1,000 population in 1991\u20131996 to 0.47 per 1,000 in 1997\u20132007 [(i)reasonable pharmacokinetic behaviour adjusted to the physical half-life of the used radionuclide(ii)ability to penetrate and cross biological membranes and permeability barriers(iii)usage of chemical as well as biological amplification strategies (iv)in vivo stabilityavailability of radiopharmaceuticals with high specific activities and To succeed in the design of targeted high-affinity radiopharmaceuticals that can measure the alteration of a respective biological target several aspects need to be considered:et al. have started a project on targeting the cannabinoid receptor subtype 2 (CB2) with a promising 11C-labelled 2-oxoquinoline derivative [11C]KP23. The CB2 receptor has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer\u2019s disease  could be confirmed, the cellular externalisation of the radioactivity was not improved , PET/CT and PET/MRI , or in a therapeutic radiopharmaceutical (then labelled with 131I) for targeted systemic radionuclide therapy (endoradiotherapy) with identical chemical structure. Similarly to the high efficiency of the combination of radiological diagnostics and radiation therapy, this combined in vivo theranostic approach with targeted radiotracers provide the potential to significantly improve the management of many diseases and the application of individually adapted therapy strategies. One contribution at the current basic research front on Folate Receptor Targeted \u03b1-Therapy using Terbium-149 addresses the mentioned in vivo theranostic approach and is described by M\u00fcller C et al. who discuss the potential matching pairs of diagnostic and therapeutic folate receptor (FR)-targeted radiotracers bearing different radioisotopes of terbium  and positron emitters  or particle emitters , respectively. This results either in diagnostic radiopharmaceuticals for SPECT/CT  is used for the treatment of different tumours. EGFR can thus be considered as an ideal biological target for combinatorial diagnostic and therapeutic approaches using corresponding radiolabelled cetuximab conjugates. Here Sihver W et al. summarises the hitherto developed radiolabelled cetuximab conjugates for EGFR-targeted diagnosis and therapy (The neurotensin receptor (NTS1) is an attractive biological target for the molecular imaging and endoradiotherapy of NTS-positive tumours owing to the overexpression in a range of malignancies. One contribution shows an example of a ogenesis  8]. Ano. Ano177L therapy  9]..177Lu-la68Ga]Ga-PSMA-HBED-CC was developed at the DKFZ and is the most promising PET tracer for the imaging of prostate cancer to date and clinical trials are currently going to be initiated. Therefore, novel important preclinical data of [68Ga]Ga-PSMA-HBED-CC and relevant aspects of its radiopharmaceutical good manufacturing practice (GMP)-compliant production are presented in this special issue (68Ga) as well as with the beta-minus particle emitters yttrium-90 (90Y) and lutetium-177 (177Lu) which are clinically relevant for systemic radionuclide therapy   has gained highest clinical impact during recent years. The new PET radioligand [al issue  11]. On. On68Ga]therapy)  12]. . 68Ga]GaThe GMP-compliant production and quality control of radiopharmaceuticals have to conform to all aspects of the relevant EU-GMP regulations and radiation protection rules. Specific guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals has been recently published by the EANM radiopharmacy committee . One repet al. provides information about radiolabelling procedures of NPs or polymers intended for PET imaging and their potential use as drug delivery systems  have been designed and used for various purposes, such as magnetic resonance imaging (MRI), computed tomography (CT) and optical imaging (OI) or simply for improved drug delivery. The question is: What is the ideal nanodimensional architecture usable as drug delivery system or for multimodality imaging by means of PET/CT and PET/MRI? In detail the review article of Stockhofe  systems  15]. A . A et alRadiopharmaceutical Chemistry Between Imaging and Endoradiotherapy covers a broad spectrum of representative internationally recognized research and development projects and nicely shows the complexity of the multidisciplinary field radiopharmaceutical sciences located in between nuclear chemistry, radiochemistry, organic chemistry, bioorganic and -inorganic chemistry, labelling chemistry, medicinal chemistry, radiopharmacology and nuclear medicine. The special issue published in Pharmaceuticals intends to reach and attract rather extended readership including students, PhD students and young scientists and talents from medicinal disciplines such as nuclear medicine, radiology and radiation therapy, but especially from natural sciences such as chemistry, pharmacy, biotechnology, technical engineering and physics who are looking for highly innovative translational research conceptions in radiopharmaceutical sciences.In summary this comprehensive special issue"}
+{"text": "This article also provides supplementary information to the research article, i.e., within-group comparisons between baseline and outcome cortical thickness and subcortical volume measures, between-group tests of performance changes in cognitive benchmark tests (www.cambridgebrainsciences.com [4]), correlation analyses between performance changes in benchmark tests and training-related structural changes, correlation analyses between the time spent training and structural changes, a scatterplot of the relationship between cortical thickness measures derived from the occipital lobe as control region and the chronological order of the MRI sessions to assess potential scanner drift effects and a post-hoc vertex-wise whole brain analysis with FreeSurfer Qdec (https://surfer.nmr.mgh.harvard.edu/fswiki/Qdec [5]).The data and supplementary information provided in this article relate to our research article \u201cTask complexity and location specific changes of cortical thickness in executive and salience networks after working memory training\u201d   Participants could train from home and their progress and compliance was monitored throughout the training time. Eight participants dropped out so the final sample size for both groups was n=20 each . Training-related changes in working memory span and executive functioning as well as in cortical thickness and subcortical volume in regions of interest of cognitive control networks  were assessed. Cortical thickness and subcortical volume indices were derived with the FreeSurfer longitudinal analyses stream 48 healthy participants (19\u201340 years of age) were pseudo-randomly (with the provision to match groups for age and sex) allocated to an adaptive training or an active control group 2.1post-hoc whole brain vertex-wise analyses in Qdec to test for the effects of group (adaptive training versus active control group) and time of assessment effects (baseline versus outcome) on cortical thickness measures. Cortical thickness indices were derived from the T1-weighted anatomical images smoothed with a kernel of 10. Multiple comparisons were controlled with a False Discovery Rate (FDR) of 5%. There were regions on both hemispheres with significant clusters of group effects across time (see We conducted a time see  but no r"}
+{"text": "Thymic epithelial tumors (TETs) are comprised of a spectrum of histologically distinct tumors that also exhibit differences at the molecular level . SurgerySomatostatin receptors are expressed in TETs and can be detected by octreotide scan . PalmierHistone deacetylases (HDACs) regulate gene expression through chromosome remodeling. Belinostat is a HDAC inhibitor that has been evaluated in a phase II trial in patients with advanced TETs after failure of platinum-containing chemotherapy . Among 2Thymic epithelial tumors express insulin-like growth factor-1 receptor (IGF-1R), particularly recurrent or advanced tumors and those with aggressive histological subtypes . CixutumMultiple case reports have described responses to the multikinase inhibitors, sorafenib  and suniDespites preclinical data demonstrating overexpression of epidermal growth factor receptor (EGFR)  and KIT Milciclib, an inhibitor of cyclin-dependent kinase 2/cyclin A complex and tropomyosin receptor kinase A (TrkA) is being evaluated in two phase II studies in patients with recurrent B3 thymoma and thymic carcinoma (NCT01011439 and NCT 01301391).A phase II study is evaluating the role of the mammalian target of rapamycin (mTOR) inhibitor, everolimus in patients with TETs previously treated with chemotherapy. (NCT02049047).In conclusion, although the presence of targetable mutations detected by current techniques of molecular profiling is low, whole genome and exome sequencing has the potential to uncover novel biological targets. Although many trials of targeted agents have yielded disappointing results, the unprecedented activity of sunitinib in thymic carcinoma and the disease stabilizing effect of cixutumumab in thymoma provides an impetus to continue to explore the role of novel biological agents in TETs.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Pulmonary embolism (PE) is a known cause of morbidity and mortality in oncology patients. Whilst much of the literature focuses on the detection of incidental PE in this cohort of patients (approximately 4%), little is written about the rate of positive CT Pulmonary Angiograms (CTPA) when PE is clinically suspected. We wanted to assess the rate of positive CTPA specifically amongst oncology patients with suspected PE in our teaching hospital.We retrospectively analysed all consecutive CTPAs carried out for clinically suspected PE over a 12 month period in all patients under our oncology services.A total of 230 oncology patients had a CTPA to exclude PE and 40 were positive (17.4%). Of the positive CTPAs, most  showed multiple PEs. The commonest cancer patients to undergo CTPA were lung (38), breast (34) and lymphoma (26) patients, and the highest incidence of positive CTPA were in breast (7/34), ovarian (2/9) and pancreatic (2/5) carcinoma. CTPAs carried out in colorectal carcinoma patients had the lowest probability of being positive (1/15).The published rate of positive CTPA for clinically suspected PE in the general population is 15-20%. Our study shows that despite the widely held view that oncology patients are more prone to pulmonary thromboembolic disease, the incidence of positive CTPA is in fact similar to the general population. Our threshold for imaging oncology patients should therefore be the same as in the general population."}
+{"text": "Noninvasive ventilation (NIV) in the management of chronic obstructive pulmonary disease (COPD) patient with acute hypercapnic respiratory failure is considered a first-line therapy. However, higher mortality was shown in patients receiving transition from NIV to invasive mechanical ventilation than in patients receiving invasive mechanical ventilation from the first management. We tried to find parameters associated with early NIV failure in patients presenting to ED with acute exacerbation of COPD.Medical records of 218 patients with acute exacerbation of COPD visiting Asan Medical Center and managed with NIV during their stay in the ED from January 2007 to December 2013 were analyzed.NIV was successful in 191 (87.6%) and 27 (12.4%) failed NIV treatment. Of the variables obtained before NIV treatment, heart rate  and pH  were significant factors associated with early NIV failure. Of the variables obtained after 1 hr of NIV treatment, heart rate  and pH  were still significant.Presence of tachycardia and severe acidosis before NIV treatment, and persistence of tachycardia and severe acidosis after 1hour of NIV treatment predicted early NIV failure."}
+{"text": "Aspiration can cause a diverse spectrum of pulmonary disorders some of which can lead to death but can be difficult to diagnose.The medical records and autopsy findings of 57 consecutive patients in whom aspiration was the immediate cause of death at Mayo Clinic  over a 9-yr period, from January 1 2004 to December 31 2012 were analyzed.The median age at death was 72 years  and included 39 (68%) males. The most common symptom before death was dyspnea (63%) and chest radiography revealed bilateral infiltrates in the majority (81%). Most common precipitating factors for aspiration were depressed consciousness (46%) and dysphagia (44%). Aspiration-related syndromes leading to death were aspiration pneumonia in 26 (46%), aspiration pneumonitis in 25 (44%), and large airway obstruction in 6 patients (11%). Aspiration was clinically unsuspected in 19 (33%) patients. Antimicrobial therapy had been empirically administered to most patients (90%) with aspiration pneumonia and aspiration pneumonitis.We conclude aspiration-related deaths occur most commonly in the elderly with identifiable risks and presenting bilateral pulmonary infiltrates. One-third of these aspiration-related pulmonary syndromes were clinically unsuspected at the time of death. Aspiration is defined as inhalation of oropharyngeal or gastric contents into the larynx and lower respiratory tract Using a computer-assisted search of medical records we identified 57 patients undergoing an autopsy at the Mayo Clinic  over a 9-year period from January 1, 2004 to December 31, 2012 and were identified to have aspiration-related pulmonary disease as the immediate cause of death on postmortem examination. This cohort comprised 1.2% of 4,623 autopsies that included examination of the lungs over this period, Aspiration-related pulmonary syndromes encountered in this cohort included aspiration pneumonia, aspiration pneumonitis and large airway obstruction. Aspiration pneumonia was diagnosed by: 1) clinical and radiologic features of pneumonia  and 2) pathologic findings of aspiration  and acute bronchopneumonia sometimes accompanied by microabscesses and granulomatous inflammation at postmortem examination. Aspiration pneumonitis was diagnosed by: 1) acute onset of respiratory symptoms with new pulmonary infiltrates on chest imaging and 2) pathologic evidence of acute lung injury  combined with the presence of foreign material or foreign body giant cell reaction at postmortem examination. Large airway obstruction was defined as acute respiratory failure related to the presence of large particulate material causing large airway obstruction confirmed on postmortem examination. Patients who died from drowning and amniotic fluid aspiration were excluded. Other forms of aspiration-related pulmonary syndromes including diffuse aspiration bronchiolitis and exogenous lipoid pneumonia were not encountered in this autopsy study. We identified the time of aspiration event based on available medical history as well assessment of clinical course and emergence of new pulmonary infiltrates on chest imaging. The current study was approved by the Mayo Foundation Institutional Review Board .Medical records were examined in detail and the following data were retrieved: age, sex, clinical presentation, risks for aspiration, radiologic findings, events leading up to death, and autopsy findings. We also determined clinician's diagnosis as to the cause of death based on review of all available medical records including clinical notes as well as the clinician diagnoses listed on death certificates. The clinician diagnosis and the type of aspiration-related pulmonary syndrome causing death was assigned based on a review of all available data by consensus of the two authors (XH and JHR).Continuous data are presented as median and range , when appropriate, and frequency, percentages for categorical variables.Of 57 patients with aspiration-related deaths, 39 (68%) were male Table 1.One or more precipitating factors for aspiration were identified in all 57 patients and mainly included depressed consciousness in 26 patients (46%), dysphagia  in 25 patients (44%); 6 patients had two risk factors Table 2.The type of aspiration-related pulmonary syndrome leading to death were classified as aspiration pneumonia in 26 (46%), aspiration pneumonitis in 25 (44%), and large airway obstruction in 6 (11%). All six large airway obstruction cases died within 72 hours of aspiration. Among the 19 aspiration pneumonitis cases in whom the time of aspiration event could be identified retrospectively, 14 (74%) died within 72 hours. In contrast, among 22 cases of aspiration pneumonia in whom the time of initial aspiration event could be identified, only 6 (27%) died within 72 hours.Among 27 patients who suffered aspiration in the hospital were 10 aspiration pneumonia, 14 aspiration pneumonitis and 3 large airway obstruction cases. In the remaining 30 patients with aspiration likely occurring outside of the hospital were 16 aspiration pneumonia, 11 aspiration pneumonitis and 3 large airway obstruction cases.Main symptoms recorded preceding death included dyspnea (63%), decreased consciousness (19%) Table 1.Fifty-three patients (93%) underwent chest radiography, 16 of whom also had undergone chest computed tomography (CT); four patients had no chest imaging available prior to death. Bilateral distribution of parenchymal abnormalities was seen in 44 patients (83%). The predominant radiologic findings were patchy alveolar infiltrates and/or atelectasis in 46 patients (87%); remaining seven patients exhibited mixed patterns of interstitial, consolidative, and ground-glass opacities. These chest imaging findings were relatively nonspecific.During the hospital course, 35 patients underwent invasive mechanical ventilation (non-invasive ventilation in two patients including one with aspiration pneumonia and another with aspiration pneumonitis); 20 patients had aspiration pneumonitis, 14 patients had aspiration pneumonia and, 1 patient had large airway obstruction. Extracorporeal membrane oxygenation was also employed in one patient with aspiration pneumonitis. Bronchoscopy was performed in 16 patients, including one procedure performed at an outside hospital and one patient who underwent the procedure twice. Three of these patients were found to have evidence of aspiration and 12 patients underwent the procedure for clearance of airway secretion; the bronchoscopic inspection was normal in the remaining patient.Staphylococcus aureus , Enterobacter species (two patients), Streptococcus(one patient), Nocardia (one patient), Klebsiella pneumoniae complex coexisting with Enterococcus (one patient), and Candida (one patient with lymphoma). Microbial culture results were available in 14 patients with aspiration pneumonitis , 9 of whom had potential pathogens identified including Staphylococcus aureus , Escherichia coli , Enterobacter species , Klebsiella species (two patients), Citrobacter koseri (one patient) and Streptococcus species (one patient). Antimicrobial therapy had been administered to 23 patients (88%) with aspiration pneumonia and 22 patients (92%) with aspiration pneumonitis, including three in each group treated with antifungal drugs.Microbial culture results were available in 19 patients  with aspiration pneumonia, nine of whom had potential pathogens identified including Aspiration was included among diagnostic possibilities by clinicians at the time of death for 38 patients (67%). Nineteen patients (33%) whose aspiration was clinically unsuspected included nine who died from aspiration pneumonitis, nine with aspiration pneumonia, and one with large airway obstruction Table 3.With the exception of few reported cases, aspiration-related deaths have not been methodically investigated Our data also show that dysphagia related to neurologic disorders comprise the commonest precipitating factor for aspiration-related deaths, followed by depressed consciousness related to sedation. These findings are in agreement with prior studies showing neurologic disorders and sedation to be common precipitating factors for aspiration Dyspnea was the most common symptom recorded for patients in this study and is similar to a prior study describing the presence of this symptom in almost half of 36 aspiration cases confirmed on lung biopsy specimens Aside from large airway obstruction-related death which is very familiar to clinicians According to our data, aspiration pneumonia is the most common type of aspiration-related pulmonary syndrome leading to death. There were more patients with underlying neurological disorders in our study for whom the median age was 72 years old compared to two prior studies Staphylococcus aureus, Enterobacter species rather than anaerobes. This was similar to that previously reported in the literature Our data demonstrated the common isolated pathogens in aspiration pneumonia were Pathogenic bacteria were recovered in a portion of patients with aspiration pneumonitis, a disease entity generally thought to involve aspiration of sterile gastric contents. There are several potential explanations for this finding. Any form of aspiration is likely to include entrance of oral secretions into the lung. Emerging data on human microbiota have demonstrated that multiple species of bacteria can exist in the stomach as well as lungs of healthy individuals Irwin and colleagues Aside from the issue of correctly diagnosing aspiration-related syndromes, our study has some implications on the prevention of aspiration-related deaths. The patients at risk appear to be identifiable such as those with neurologic impairment and dysphagia. Optimal strategies in managing patients identified to be at risk generally require multidisciplinary expertise in maintaining adequate hydration and nutrition while minimizing the risks of aspiration. These options many include tube feeding, oral and bronchial hygiene measures, positioning, antimicrobial and other pharmacologic therapies This study included consecutive patients undergoing autopsy during a nine year period and the diagnostic criteria were based on combined clinical and autopsy findings. We, however, acknowledge that the limitations of this study including the retrospective design which limited the analysis to clinical data available in medical records and autopsy results. There are likely many patients who died from aspiration but did not undergo a postmortem examination and were undiagnosed. There is a selection bias in autopsy studies which tend to enrich for atypical and diagnostically challenging cases. Microbiology data were limited to standard respiratory cultures obtained at postmortem examination and may not have recovered some pathogens such as anaerobic bacteria. Furthermore, aspiration pneumonia and aspiration pneumonitis can sometimes be difficult to distinguish.Aspiration-related deaths most commonly occur in the elderly with identifiable risks and often manifesting bilateral pulmonary infiltrates. In one-third of these patients aspiration as the cause of death was unsuspected by clinicians."}
+{"text": "Natural killer (NK) cells are highly effective in controlling tumour growth, in mice, but have no significant effect in humans. The reason(s) of this phenomenon is(are) unclear.The effects of cancer cells on NK cells during target-effector cell conjugation was investigated utilising standard immunological methods including flow cytometry, chromium release and enzyme-linked immunosorbent assays while gene expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction.We found that this phenomenon was associated with the different susceptibility of human and mouse NK cells to autologous tumour cell-induced NK cell abnormalities (NKCA). The latter includes CD16 down-regulation and NK cell depletion. Induction of NKCA by leukaemia and solid tumour cells was influenced neither by IL2 treatment nor by HLA class I antigen expression, but was abrogated by a 10 day culture. Following a 10 day of PBMCs culture, NK cells became resistant to leukaemia and solid tumor cell induced NKCA but maintained their cytotoxic activity. Actinomycin D restored the susceptibility of long term NK (LTNK) cells to NKCA suggesting that the generation of resistance to NKCA required RNA transcription. TAPI-0, a functional analogue of the tissue inhibitor of metalloproteinases (TIMP) 3 inhibited cancer cell induced NKCA underlying a role for a restricted number of metalloproteinases in the generation of this phenomenon. Finally, we found an association of TIMP3 gene and protein over-expression with the reduced susceptibility of LTNK cells to cancer cell induced NKCA.This study provides evidence that TIMP3 plays a role in the protection of LTNK cells from cancer cell induced NKCA."}
+{"text": "Lohith et al.  recently identified increased metabotropic glutamate receptor 5 (mGluR5) expression in the frontal cortex (FC) of subjects with fragile X syndrome. These results are consistent with postmortem findings in cerebellar vermis and FC of subjects with autism , suggesting that increased mGluR5 signaling is common to multiple autism spectrum disorders. Increased mGluR5 signaling may be associated with reduced phosphorylation of fragile X mental retardation protein (FMRP), which could result in the inactivation of this protein. In the current study, we report on reduced expression of phosphorylated FMRP in cerebellar vermis of adults and children with autism and in FC of adults with autism. Moreoveet al. . Taken t [et al.  suggest  [et al. .Increased mGluR5 expression in autism and FXS is associated with reduced or absent expression of fragile X mental retardation protein (FMRP) ,3 and frr >0.3) we used analysis of covariance (ANCOVA) to co-vary their effects. In none of these cases were significant differences between controls and subjects with autism in phosphorylated FMRP changed by the presence of these covariates. Our new finding of a reduction in phosphorylated FMRP in the cerebellar vermis of children with autism may be associated with increased activity of mGluR5, which could result in dephosphorylation of FMRP, and its subsequent ubiquitination and degradation [We have recently completed a preliminary study of serine 499 phosphorylated FMRP protein levels in the cerebellar vermis in adults (n = 5 controls and 5 adults with autism) and children (n = 3 controls and 4 children with autism), and in the superior frontal cortex in adults (n = 6 controls and 10 adults with autism) and children (n = 6 controls and 8 children with autism). All values were normalized against neuronal specific enolase (NSE) and data were expressed as ratios of phosphorylated FMRP/NSE. We found significant reductions in phosphorylated FMRP/NSE in the vermis of adults and children with autism when compared with controls (Figure\u00a0radation  support ANCOVA: Analysis of covariance; APP: Amyloid beta A4 precursor protein; BA9: Brodman area 9; FMRP: Fragile X mental retardation protein; FXS: fragile X syndrome; mGluR5: Metabotropic glutamate receptor 5; NSE: Neuronal specific enolase; RAC1: Ras-related C3 botulinum toxin substrate 1; STEP: Striatal-enriched protein tyrosine phosphatase.The authors declare that they have no competing interests. SH Fatemi has several patents on the use of Reelin as a diagnostic marker for neuropsychiatric disorders but has not derived any financial gains from these patents.SHF conceived of the study, participated in its design, supervised conduct of all experiments, and contributed to the drafting of the manuscript. OGR, MKY performed western blotting experiments. TDF performed western blotting experiments and contributed to the drafting of the manuscript. All authors read and approved the final manuscript."}
+{"text": "Metabolic reprogramming is one of the strategies adopted by cancer cells to survive hypoxic conditions. Recent findings suggest that hypoxic cancer cells derive the energy that they need through glycolysis using glucose mobilized from intracellular glycogen reserve. Glycogen phosphorylase (GP) is the major rate-determining enzyme for glycogen mobilization in many normal cells under the condition of starvation or physical exercise. The lysosomal alpha-glucosidase (GAA) has also been implicated in glycogen mobilization since deficiency of this enzyme is known to result in Glycogen Storage Disease Type II (Pompe disease). Although a role for GP in the mobilization of glycogen by cancer cells depleted of oxygen had been demonstrated, whether a similar role for GP (and GAA) could be demonstrated under deprivation of both glucose and oxygen is not yet known. This issue is addressed in this study by examining the intracellular level of glycogen in the absence and presence of pharmacological inhibitors of GP and/or GAA.2) in the presence or absence of glucose for 3 hours. The effect of these hypoxic conditions on intracellular glycogen level was examined in the presence and absence of inhibitors for glycogen phosphorylase [CAS 648926-15-2] or lysosomal alpha glucosidase (castanospermine or miglitol).The Hela, HEK293 and HT29 cancer cell lines were subjected to hypoxic conditions  only when cultured cancer cell  were deprived of both glucose and oxygen for 3 hours. The hypoxia-induced lowering of intracellular glycogen was alleviated by the presence of glycogen phosphorylase inhibitor (CAS 648926-15-2) but not alpha glucosidase inhibitor (castanospermine or miglitol). The simultaneous presence of inhibitors for both enzymes did not have a synergistic effect in preventing hypoxia-induced glycogen mobilization as compared to that observed for (CAS 648926-15-2) alone. Hypoxia had no significant effect on both"}
+{"text": "TDP43 is a ubiquitously expressed prevalently nuclear protein involved in RNA splicing, RNA stability and miRNA processing. Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and inclusion body myopathy (IBM) are characterized by TDP43 being depleted from the nucleus and accumulating in cytoplasmic inclusions, which are the pathological hallmark of the disease \u2013 these diseases are also defined as \u201cTDP43 proteinopathies\u201d. Mutations in TDP43 have been found to be causative of a proportion of ALS cases reinforcing the primary importance of this molecule in disease pathogenesis. The pathogenic mechanism by which TDP43 acts is unclear, and both loss of nuclear function (LOF) and gain of function (GOF) mechanisms have been proposed. We here discuss how we used muscle tissue, which provides high quality RNA of patient disease tissue, to investigate the consequences of TDP43 mislocalization. Further, we characterize two novel mouse TDP43 mutant lines, carrying ENU-induced mutations in order to study the effects of TDP43 mutations expressed at physiological levels in the mammalian central nervous system. One mutation (deltaRNA) strongly reduces the RNA-binding capacity of the protein; the second mutation (C-TERM) is in the glycine-rich C-terminal domain where the majority of human pathogenic mutations are found. Our results underline the importance of studying models with physiological expression levels of TDP43 mutations and shed light on the different effects on RNA metabolism caused by the TDP43 loss and gain of function."}
+{"text": "Heart failure (HF) is characterised by alterations in fatty acid and glucose metabolism. We aimed to determine if myocardial lipid is increased in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction (EF), and assess whether it is related to cardiac structure and function.1H MR spectroscopy to quantify myocardial lipid/water (%).25 HFrEF due to dilated cardiomyopathy (DCM), 18 HFpEF  and 28 normal volunteers were prospectively recruited. All subjects underwent cardiovascular magnetic (MR) resonance at 3T for the determination of left ventricular (LV) volumes and function, and cardiac As expected DCM patients had significantly increased LV volumes and reduced EF, whilst HFpEF patients had significantly increased LV mass to end-diastolic volume ratio (LV mass/EDV). Importantly, cardiac lipid was increased in both HFrEF and HFpEF when compared to normal controls , with HFpEF group having the highest level of cardiac lipid (Table This is the first study to demonstrate that myocardial steatosis occurs in both HFrEF and HFpEF and is related to parameters of LV remodeling. This suggests that myocardial lipid may play a role in the pathophysiological processes of LV remodeling in both HFrEF and HFpEF. Cardiac lipid accumulation may be a potential therapeutic target in these conditions.N/A."}
+{"text": "To compare thin section CT characteristics of the early local tumour recurrence after the resection of squamous cell carcinoma (SCC) with those of the stump deformity or granulation tissue.Twenty nine consecutive patients with local recurrence after definitive SCC operation from April 2006 to September 2012 were included. Pre- and post-operative CT from these patients were retrospectively reviewed and compared with those in age- and gender-matched 29 patients with stump deformity or granulation tissue at stump site after the definitive SCC operation, by two chest radiologists.p< 0.001). The univariate analysis showed that the size of soft tissue and the distance between soft tissue and stump site were associated with the predictive factors of local recurrence (p< 0.001). On the receiver operating characteristic analysis, the optimal cut-offs of the size of soft tissue and the distance between soft tissue and stump staples were 6mm and 5mm, respectively.Local recurrence were commonly observed as round/oval shape, peripheral eccentric lesion or central contour bulging lesion on CT, while the stump deformity or granulation tissue were commonly demonstrated as irregular or flat shape, focal wall thickening. The size of suspected soft tissue and the distance between stump staples and suspected soft tissue were significantly different between two groups (median; 19mm and 3mm; 18mm and 0mm, respectively, The proper knowledge of stump recurrence regarding the size and the distance around the stump on CT imaging will help us achieve an early and higher diagnostic rate of recurred SCC."}
+{"text": "Bicuspid aortic valve (BAV) is the most common congenital heart defect affecting 1-2% of the US population. BAV has been associated with progressive secondary pathologies, such as aortic valve calcification, stenosis, regurgitation, aortic root dilatation, and/or aortic aneurysm. However, not all patients exhibit symptoms or develop aortopathy and the exact link between BAV morphology and disease progression is not fully understood. Magnetic resonance imaging (MRI) has been previously used to characterize BAV hemodynamics. However, studies have been hampered by the need for lengthy manual data analysis thereby limiting reproducibility and/or integration into a clinically feasible workflow.This work develops and applies a novel semi-automated technique to characterize geometry and hemodynamics of the aorta and the aortic valve based on 2D bSSFP cine and 4D flow MRI data. The protocol was applied to a cohort of 30 BAV and 30 control subjects. The table summarizes the preliminary analysis  of the demographics of the subject cohort. The analysis was performed at several cross-sectional locations across the ascending aorta (see figure Geometric metrics (summarized in the table) were found to be significantly larger in the BAV subjects than in the control group (preliminary results are summarized in table A semi-automated protocol for the combined analysis of the aortic valve geometry and hemodynamics in the aorta was developed to analyze MRI data obtained with 2D cine and 4D flow MRI. Application of this protocol and a preliminary analysis performed on the subset cohort of 12 BAV and 12 control cases revealed elevated mean velocity, jet angle and forward flow displacement in BAV subjects in the proximal ascending aorta. This study provides a roadmap for comprehensive large cohort assessment of correlations between geometry and hemodynamics associated with BAV disease.NHLBI grant R01HL115828, K25HL119608 and PURA scholarship."}
+{"text": "The prevalence of different biotic processes  and historical contingency due to priority effects are in the focus of ongoing discussions about community assembly and non-random functional trait distributions.We experimentally manipulated assembly history in a grassland biodiversity experiment (Jena Experiment) by applying two factorially crossed split-plot treatments to all communities: (i) duration of weeding (never weeded since sowing or cessation of weeding after 3 or 6 years); (ii) seed addition (control vs. seed addition 4 years after sowing). Spontaneous colonization of new species in the control treatment without seed addition increased realized species richness and functional richness (FRic), indicating continuously denser packing of niches. Seed addition resulted in forced colonization and increased realized species richness, FRic, functional evenness (FEve) and functional divergence (FDiv), i.e. higher abundances of species with extreme trait values. Furthermore, the colonization of new species led to a decline in FEve through time, suggesting that weaker competitors were reduced in abundance or excluded. Communities with higher initial species richness or with longer time since cessation of weeding were more restricted in the entry of new species and showed smaller increases in FRic after seed addition than other communities. The two assembly-history treatments caused a divergence of species compositions within communities originally established with the same species. Communities originally established with different species converged in species richness and functional trait composition over time, but remained more distinct in species composition.Contrasting biotic processes  increase functional convergence between communities initially established with different species. Historical contingency with regard to realized species compositions could not be eradicated by cessation of weeding or forced colonization and was still detectable 5 years after application of these treatments, providing evidence for the role of priority effects in community assembly. A deeper insight into the mechanisms which control community assembly is central to understand ecosystem functioning and the maintenance of biodiversity. Functional diversity, i.e. the extent of trait differences among co-occurring species In natural ecosystems, the importance of biotic processes causing trait convergence and divergence in community assembly is difficult to disentangle because abiotic processes may also cause trait convergence or counterbalance biotic trait divergence In the present study, we used experimental plots of a grassland biodiversity experiment  cessation of weeding after six years (2007), no seed addition,(S6+) cessation of weeding after six years (2007), seed addition (2005),(S3\u2212) cessation of weeding after three years (2004), no seed addition,(S3+) cessation of weeding after three years (2004), seed addition (2005),(S0\u2212) never weeded, no seed addition, and(S0+) never weeded, seed addition (2005).Plots were mown twice per year  and the mown plant material was removed.Species richness, species identities and visually estimated species cover using a decimal scale A trait matrix comprising species mean traits related to spatial and temporal niche dimensions and to strategies of regeneration was compiled for all observed species  based on information in the floristic literature Bray-Curtis dissimilarities n-dimensional trait space occupied by the species in a community n-dimensional trait space n-dimensional trait space Measures of functional trait diversity quantify the distribution of species in a multidimensional space whose axes are defined by functional characteristics. Three components of functional trait diversity were calculated separately: functional richness (FRic), functional evenness (FEve) and functional divergence (FDiv) http://www.r-project.org) including the packages FDnlmeLinear mixed-effects models were applied to test for effects of the experimental factors on the response variables measured in the 5-year study period in the split-split-plot colonization experiment. Block and plot identity, subplot pair  and subplot were treated as random factors in a nested sequence. Although the factors species richness and number of functional groups are nearly orthogonal in the Jena Experiment, the design of the experiment is not completely balanced because it is not possible to vary species richness and functional group number completely independently. Starting from a constant null model the fitting sequence of fixed terms followed the a-priori hypotheses of the biodiversity experiment starting with the number of initially established species (log-linear term), the number of functional groups (linear term), factors for the split-plot variables colonization period (with three factor levels) and seed addition (with two factor levels) and their interactions with the main experimental factors. Finally, a term for the different study years  and its interaction with the previously mentioned experimental factors was entered. The maximum likelihood method was used and likelihood ratio tests were applied to assess the statistical significance of model improvement. The statistical software R  after colonization of new species , Table 2Realized functional evenness (FEve) after colonization declined with an increased number of initially established species , Table 2Realized functional divergence (FDiv) after colonization decreased with an increased number of initially established species , Table 2Average between-community dissimilarity in species composition was highest for communities initially established with a large number of species. Average between-community dissimilarity in functional trait composition did not depend on the initially established plant diversity . BetweenThe average within-plot dissimilarities (between different seed addition \u00d7 colonization period combinations) in species and functional trait composition were smaller than between communities . Within-In spite of sustained efforts to understand patterns of community assembly, the importance of different biotic processes is poorly disentangled so far. We used the opportunity to study biotic processes of community assembly under relatively homogeneous environmental conditions in split-plots of a large grassland biodiversity experiment opened for colonization by new species and removed dispersal limitation through a seed addition treatment Species gain and increase in functional richness (FRic) after the opening of experimental communities for colonization by new species was reduced by a higher number of initially established species and a longer colonization period (shorter duration of weeding). The negative effects of a higher initially sown plant diversity on the spontaneous colonization of new species may be attributable to the lower stability of low-diverse communities even in the absence of weeding Functional richness (FRic), which quantifies the volume of functional space filled by a community, increased in parallel to species gain in sub-plots without seed addition, but the increment of FRic was flattened in subplots with a higher number of initially sown species . The conPrevious studies have reported that experimental communities initially sown with different plant diversity and opened to colonization converged in species richness and functional or phylogenetic composition while keeping different species composition It becomes increasingly apparent that multiple processes are involved in community assembly. A number of recent studies have shown that patterns of functional trait composition depend on environmental conditions and the traits considered Figure S1Between- and within-community coefficients of variation of realized species richness, FRic, FEve and FDiv.(DOC)Click here for additional data file.Text S1Reference list for data on specific leaf area of particular plant species included in the matrix of functional traits.(DOC)Click here for additional data file."}
+{"text": "Pectus Excavatum affects between 1:400 - 1000 live births. Little academic focus has been directed to the anatomical subgroups of this condition. No anatomical classification and subgrouping has been formulated. Current surgical strategies utilize a 'one size fits all' philosophy with variations of the Nuss or Ravitch procedureOur aim was to stratify patients with Pectus Excavatum by providing an anatomical classification that would guide treatment. The novel classification we propose provides a framework for use with current and evolving medical technologiesBetween April 2006 - March 2015, 24 patients  presented to our institute with symptomatic Pectus Excavatum. All presented with symptoms of dyspnoea /fatigue/dysphagia. All patients underwent Prospective evaluation of exercise and anatomical characteristics by: Spirometry; Cardiopulmonary exercise tolerance (CPEX) testing & Non-contrast axial/sagittal CT scan of the thorax & 3D reconstruction. We propose an Anatomical classification based on 2D and 3D CT imaging: Classification A : No depression of manubrium, posterior angulation of sternal bodyClassification B: (1) Horizontal depression of manubrium and sternal body with no angulation (2) Depression of manubrium with posterior angulation of sternal bodyClassification C: Complex asymmetrical torsion of manubrium and body of sternum associated with asymmetrical distortion and depression of rib cage9 patients (38%) had a Type A defect. We recommend this sternal body angulation to be corrected with Ravitch Procedure, Transverse osteotomy and midline screw fixation bar. 14 (58%) patients had a Type B2 defect, which we recommend should be repaired as a Type A defect but elevation of the whole sternum using a transverse screw fixation bar.Our classification provides a framework for evaluation of the pathological anatomy of Pectus Excavatum. This classification has been shown to have utilitarian value in planning surgical strategy. The model will provide opportunities for future development of surgical technique and provides a descriptor that will allow academic discussion"}
+{"text": "The ability to non-invasively establish patency of cerebral spinal fluid (CSF) flow between adjacent central nervous system (CNS) compartments is of importance in the diagnosis and treatment of patients with various areas of CSF flow obstruction. Recent advances in magnetic resonance imaging (MRI) technology allows for real-time magnetic labeling of CSF to directly visualize flow through different compartments.The presence of CSF flow was examined at the aqueduct of Sylvius (AS), the foramen of Monro (FM), the floor of the third ventricle (3rd V), and the foramen magnum (FMag) using a modification of arterial spin labeling (ASL). The studies were compared with clinical information and classified as true positive, true negative, false positive, and false negative based on expectation of patency.A total of 68 flow studies were done on 44 patients. High correlation with true positive was seen at all four sites. No flow was visualized in 25 readings of the AS; in 9 of those cases we expected flow to be present. Table Establishing qualitative patency between adjacent CSF compartments using MRI is possible with a modified ASL technique. This technique has excellent (above 80%) sensitivity, specificity, and negative likelihood ratio in three out of the four regions studied."}
+{"text": "Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing  in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth. Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing  in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth. Forty-five patients from 38 unrelated families with fetal akinesia (9 families), arthrogryposis (13 families) and severe congenital myopathies (16 families) underwent whole exome sequencing (23), targeted sequencing (7) and both (8). Ten of these families were consanguineous. A conclusive genetic diagnosis was achieved in 18/38 families (47%). Autosomal recessive was the most common mode of inheritance (15), however dominant (1), de novo (1) and X linked (1) were also identified. Mutations were found in eight previously known neuromuscular disease genes  and four novel neuromuscular disease genes .RYR1 are associated with the arthrogryposis and fetal akinesia phenotype while missense mutations in RYR1 are associated with central core myopathy phenotype . The study also led to the identification of novel neuromuscular disease genes  involved in sarcomere assembly and muscle dysfunction. [This study highlights the widening spectrum of phenotypes associated with mutations in known neuromuscular genes. For example, null mutations in the COMMENTARY. Fetal akinesia deformation sequence , arthrogryposis , and severe congenital myopathies comprise a very heterogeneous group, both phenotypically and genetically, that present at or before birth . Prior tThis study used a combination of whole exome sequencing and targeted exome sequencing of known neuromuscular genes. Functional studies were done in cases of novel genes when feasible . A previ"}
+{"text": "Heparin is diluted in parenteral nutrition bags and administered over a period of 24 hours with in-line filtration. However, there are no data on heparin stability in parenteral nutrition bags, especially on its compatibility with 50% dextrose mainly present in bags. The aim of our n = 6 per type) were infused over a period of 24 hours with and without in-line filtration. Heparin activity was measured using a chromogenic anti-Xa method in bags just being prepared (references for other measures) and after 24-hour infusion and in effluents at the end of infusion line after 24 hours.We prepared both types of bag: parenteral nutrition bags whose composition was defined in the unit, including sodium heparin (77 UI/ml); and bags containing only sodium heparin diluted in 50% dextrose (193 UI/ml). These bags (Our results show values of heparin activity measured in bags and effluents with and without in-line filtration after 24-hour infusion for both types of bag assessed Tables  and 2. RWe conclude that there is no loss of heparin activity when drug is infused over 24 hours for both types of bag prepared, with and without in-line filtration, showing heparin activity remains stable during this period and there is no interaction of drug with other nutrient components of bags, especially 50% dextrose."}
+{"text": "ECMO is widely used through the world, but is still surrounded by important complications, most of them at the site of the surgical approach.We describe and assess the effectiveness, the feasibility and the security of exclusive percutaneous peripheral veno-arterial ECMO including the distal reperfusion of the homolateral lower limb.It is a monocentric, retrospective and observational study. Twenty nine patients  were implanted between July 2012 and March 2014. The indications for ECMO were acute phase of myocardial infarction (n = 8), post-cardiotomy cardiogenic shock (n = 12), acute myocarditis (n = 1), cardiac rhythm disorders (n = 1), bridge to cardiac transplantation or long-term circulatory support (n = 7). The insertion was performed in hybrid operating room. After puncture of the common femoral artery (CFA) the superficial femoral artery (SFA) was opacifiated. An anterograde 6F introducer was placed in the SFA under fluoroscopic control. The arterial and venous cannulae were then introduced through guide wires placed under fluoroscopic control. The distal perfusion of the homolateral lower limb was performed through a connection between the arterial cannulae and the introducer placed initially. Femoral arterial cannula was surgically removed at the end of the assistance to avoid vascular complications, the others by compression.The mean duration of circulatory support was 9,5 days (from 1 to 52 days). Thirteen deaths occurred (45%). Bleeding of the groin required a haemostasis procedure in two cases only (5%). One external iliac artery dissection  and two acute thrombosis of the oxygenator (one of which was reversible) (5%) occurred. Neither infection, nor lower limb acute ischemia occurred. A percutaneous atrioseptostomy was performed in catheterization room in eight patients who presented an acute pulmonary edema (21%), which all resumed.These results suggest that the implantation of exclusive percutaneous peripheral veno-arterial ECMO is efficient, reproducible and minimally invasive. The pre-positioning of the distal reperfusion should be systematic. Surgical ablation of the arterial femoral cannula is necessary, but complications related to an initial surgical approach could be avoided during the time of assistance."}
+{"text": "Disturbances of cerebral venous hemodynamics define development of child headache. However directed by the diagnosis and subsequent treatment these disturbances are not considered. The absence of diagnostics algorithm and norms of cerebral venous blood flow limits the possibility of timely therapy at children.The studies of headache caused by venous hemodynamics disturbance.600 patients (3-17 years old) who complained of headache have been examined. The data of a blood flow velocity in deep cerebral veins of a brain: in straight venous sinus, vein of Galen, sinuses cavernous defined by Transcranial Color-Coded Duplex.Headache caused by cerebral venous dysfunction notes in 47% of children. The surveyed children had typical headache (100%) of holding apart character in occipital and parietal areas after a dream (69%) ,after physical activity(14%) and a long static pose have been revealed(17%).\u201cVenous\u201d headache at children often can be similar to dizziness. The attacks of headache which are coming to an end with vomiting are revealed at 25% of children. Children also complained of nasal bleeding as a fountain (60%) during a night or day dream (40%), noise in ears (53%), ocular pathology refraction(43%) and expressed vegetative symptoms (80%).We have found clinical signs of the connective tissue dysplasia syndromes at 67% of children.Structural cerebral abnormalities  were revealed at 9% patients of them by MRI .\u201cMarkers\u201d of disturbances in cerebral venous hemodynamics was venous outflow in deep brain veins. The research of parameters of a cerebral hemodynamics was carried out in the conditions of functional rest and after dynamic tests. We suggest modified Valsalva, orthostasis and head-down tilting tests in children .Definition of cerebral venous hemodynamic normal indicators in children of different age groups is very important for identification and treatment of headache with cerebral venous disturbances.No conflict of interest."}
+{"text": "The differential diagnosis of patients in the emergency department who show symptoms of sepsis and suspected pneumonia may be difficult because of the low sensitivity and specificity of supine chest X rays (SCXR) and physical examination.A retrospective assessment of the usefulness of lung ultrasound (LU) in the diagnosis of pneumonia in patients with signs and symptoms of sepsis and respiratory disease.2 groups of patients were considered:Group A: 22 patients with a positive first SCXR (SCXR1) for pneumoniaGroup B: 18 patients with a negative SCXR1 for pneumonia, but who were subsequently diagnosed with pneumonia during their hospital stay following a second SCXR (SCXR2) or CT.Lung ultrasound examination was performed within 24 hours of admission, searching for direct and indirect echographical signs of pneumonia: focal B lines (FBL), pleural effusion (PE) and images of lung consolidation (LC).See table In our observational study, LU showed high sensitivity in the diagnosis of pneumonia:95% in patients already diagnosed using SCXR, and 100 % of early diagnosis of pneumonia in patients whose diagnosis was subsequently confirmed during hospitalization."}
+{"text": "However, full analyses of T cell receptor (TCR) sequences have been difficult because of the inefficiency of T cell cloning, heterogeneity of T cells or the heterodimeric structures of TCRs. Here, we revealed complete landscapes of cancer antigen-specific TCRs using a novel TCR cloning system; hTEC10 -derived peptide vaccine for advanced hepatocellular carcinoma (HCC). The peptide-specific cytotoxic lymphocytes (CTLs) were detected and sorted as single cells from the patients' peripheral mononuclear cells (PBMCs) after in vitro stimulation. cDNAs of paired TCR chains were amplified from the single cells, cloned into retroviral vectors, and transduced in the T cell strain or PBMCs. The avidities of the obtained TCRs were evaluated by comparing antigen-specific cytotoxicities. This system was also applied to the healthy controls and the participants of the Phase I clinical trial of human telomerase reverse transcriptase (hTERT)-derived peptide vaccine for prevention of HCC recurrence after radiofrequency ablation (RFA) therapy.AFP-specific CTLs were induced in 4 patients whose clinical responses were CR , long SD , SD (91 days) and PD (46 days), respectively (long SD is defined as SD over 6 months). Totally, 347 specific TCR clones that consisted of 10 kinds of TCR gene rearrangements  were amplified. The TCRs obtained from the CR patient and the long SD patient possessed higher avidities than that from the SD patient, the PD patient and the healthy controls without HCC. Similarly, we could obtain highly reactive 122 TCR clones consist of 10 different gene arrangements from 3 patients who were treated with hTERT vaccine and prevented from the recurrence until 24 weeks after RFA. These results indicated that the inductions of TCRs with high avidities reflected the good clinical responses, and high-avidity TCR might be retrieved from vaccinated patients with good clinical responses, not from patients with poor responses or healthy individuals."}
+{"text": "The primary aim of this commentary is to describe trauma-related dissociation and altered states of consciousness in the context of a four-dimensional model that has recently been proposed . This model categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and are associated with trauma-related altered states of consciousness (TRASC) along four dimensions: (1) time; (2) thought; (3) body; and (4) emotion. Clinical applications and future research directions relevant to each dimension are discussed. Conceptualizing TRASC across the dimensions of time, thought, body, and emotion has transdiagnostic implications for trauma-related disorders described in both the Diagnostic Statistical Manual and the International Classifications of Diseases. The four-dimensional model provides a framework, guided by existing models of dissociation, for future research examining the phenomenological, neurobiological, and physiological underpinnings of trauma-related dissociation. Putnam  notes suAccordingly, this commentary will review the relevance of each of the four dimensions of consciousness to the theoretical, neurobiological, and clinical underpinnings of trauma-related phenomenology in the context of a four-dimensional model (4-D model) outlining a dissociative and a non-dissociative dimension of each of the four dimensions of consciousness  those that occur within NWC and (2) those that exhibit a dissociative presentation associated with the experience of TRASC. Experiences of NWC and TRASC can be further classified along four dimensions of consciousness: (1) time (reliving flashbacks [TRASC] versus intrusive memories and reminder distress [NWC]); (2) thought ; (3) body ; and (4) emotion  see . It shouThe model makes four predictions: (1) the experience of TRASC will be less common than will be presentations of normal waking consciousness given that states of normal waking consciousness, by definition, are the most common phenomenological state of human beings; (2) TRASC are expected to be less intercorrelated than states of normal waking consciousness as the experience of TRASC is frequently experienced as more \u201ccompartmentalized\u201d; (3) measures of TRASC are expected to be more strongly correlated with other measures of dissociative symptomatology; and (4) experiences of TRASC are predicted to be more specific to an etiology implicating early life adversity and repeated traumatization. Emerging evidence provides support for these predictions  in the context of a subjective past and anticipated future. Accordingly, under normal circumstances, time is experienced as continuously moving forward. However, traumatized individuals often relive their traumatic memories through flashbacks and lack the ability to live in the \u201cnow,\u201d reflecting a key dissociative process associated with TRASC. Such reliving events are in contrast to intrusive memory recall most frequently associated with reminder distress and not involving an altered state of consciousness or a dissociative process but rather represent a state of normal waking consciousness  traumatized individuals with frequent symptoms of emotional numbing and shutdown and (2) traumatized individuals that solely exhibit general negative affect to identify specific maps of bodily sensations and to explore the relation of these maps to the experience of different emotional experience. These findings will then need to be related not only to the underlying neural deficits of emotion processing but also to treatment outcomes. Moreover, investigating how specific neural networks involved in the consciousness of emotion can be directly targeted through the use of real-time fMRI or EEG-based biofeedback in conjunction with pharmacotherapeutic and psychotherapeutic approaches will be an important avenue for future investigation.In summary, this commentary describes a 4-D model that categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and associated with TRASC along four dimensions of consciousness: (1) time; (2) thought; (3) body; and (4) emotion. Conceptualizing TRASC across these four dimensions has transdiagnostic implications for trauma-spectrum disorders involving dissociation and is relevant to efforts to identify key factors related to the development and maintenance of trauma-related symptoms described both in the DSM and the International Classification of Disease. It will be crucial for future research to examine directly these symptoms along each dimension of consciousness and to identify further their neurobiological and physiological underpinnings, and to determine their role in treatment outcome (also see Sar, Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file."}
+{"text": "Background. The current study was designed to reveal possible associations between the polymorphisms of the vascular endothelial growth factor (VEGF) gene (rs2010963) and its receptor, kinase insert domain-containing receptor (KDR) gene polymorphism (rs2071559), and markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Genotyping of VEGF/KDR polymorphisms  was performed using KASPar assays. Results. Genotype distributions and allele frequencies of the VEGF/KDR polymorphisms  were not statistically significantly different between diabetic patients and controls. In our study, we demonstrated an association between the rs2071559 of KDR and either CIMT or the sum of plaque thickness in subjects with T2DM. We did not, however, demonstrate any association between the tested polymorphism of VEGF (rs2010963) and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP, the presence of carotid plaques, or the presence of unstable carotid plaques. Conclusions. In the present study, we demonstrated minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis in subjects with T2DM. Type 2 diabetes mellitus (T2DM) is considered a major epidemic of this century. It is estimated that its prevalence will increase worldwide from 371 million people in 2013 to 552 million people in 2030 . The genotype distributions in both patients with T2DM and controls were in Hardy-Weinberg equilibrium for the KDR gene polymorphism [rs2071559: T2DM  and controls ]. No statistically significant differences in the VEGF rs2010963 and KDR rs2071559 genotype distribution frequencies were observed between T2DM patients and controls.The genotype distributions in both patients with T2DM and controls were in Hardy-Weinberg equilibrium for both VEGF gene polymorphisms [rs2010963: T2DM  between patients with T2DM and controls (32.3% versus 33%). However, the C allele frequency of the KDR rs2071559 polymorphism was significantly lower (p = 0.04) in T2DM subjects as compared to the controls (49% versus 54%).The observed minor allele frequency (MAF) distributions were mostly in agreement with the 1000 Genomes Project data in the European population. The C allele frequency of the VEGF rs2010963 showed no significant difference (Higher VEGF serum levels were demonstrated in subjects with T2DM with the CC genotype (rs2010963) compared to those with other (CG + GG) genotypes . MoreoveThe comparison of atherosclerosis parameters was performed with regard to different genotypes of the VEGF polymorphism rs2010963) upon enrolment. In our study, we did not demonstrate any association between the rs2010963 and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP or the presence of carotid plaques, or the presence of unstable carotid plaques  and CIMT. Variations in the VEGF gene were reported to be weakly associated with CIMT . None ofAdditionally, we also demonstrated an association between the rs2071559 of KDR and the sum of plaque thickness in subjects with T2DM, whereas no association between tested polymorphism of VEGF (rs2010963) and markers of carotid atherosclerosis was demonstrated. The rs2010963 polymorphism of the VEGF gene was not demonstrated to exert a significant influence on the risk of subclinical atherosclerosis manifested by the presence of endothelial dysfunction by brachial artery reactivity and increased CIMT in a series of patients with rheumatoid arthritis . ContrarIn our study, the effect of either rs2071559 of KDR or rs2010963 on VEGF serum levels was demonstrated. These findings are in accordance with our previous studies in which subjects with recent MI history (up to 9 months after MI) were enrolled , 16, 25.In contrast to the minor effect of the rs2071559 of KDR and the absence of the rs2010963 of the VEGF, an association of either rs2071559 or rs2010963 with MI has recently been reported in Caucasians with T2DM , 16, 24.To conclude, in our study we demonstrated a minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis  in subjects with T2DM, whereas we failed to demonstrate an effect of tested polymorphism of the VEGF gene (rs2010963) on markers of carotid atherosclerosis."}
+{"text": "Actinomycosis is a chronic infection due to anaerobic filamentous bacteria (Actinomyces), which occurs mostly in the cervicofacial region as a chronic granulomatous infection. We report the case of Mr KI, 17 years old, without past medical history, presented a painful ulceration on the right side of the chest wall which evolved since 2 months. The onset of symptoms was a nodule which ulcerated after 2 months with extruding yellowish pus. The examination objectified ulcerated and burgeoning lesion in right parasternal region from what came yellowish pus mixed with sulphur granule (A). A painful subcutaneous nodule was noted under the right breast. An examination of the oral mucosa was entirely normal as well as the rest of the physical examination. Histopathologic studies (hematoxylin-eosin staining) revealed the presence of inflammatory cells surrounding basophilic sulfur granules which were composed of a large number of filaments arranged in a radiating pattern (B). The chest x-ray was normal. The chest scan showed an infiltration of the anterior and right lateral wall without bone and lung injury. The results of aerobic and anaerobic culture showed mixed flora. The histopathologic findings led to the diagnosis of actinomycosis of the wall chest. Treatment was based on oral amoxicillin + clavulanic acid (1g + 125 mg 3 times daily). The size of the ulcerative lesion gradually decreased and completely healed by 4 weeks. Then antibiotherapy was continued for four months. No evidence of recurrence of this lesion was found after 24-month of follow-up."}
+{"text": "Eosinophilic esophagitis (EoE) is a chronic/recurrent inflammatory disease of the esophagus characterized by the association between symptoms of esophageal dysfunction and a prominent eosinophilic infiltrate >15/HPF) of the esophageal epithelium 5/HPF of . The nat"}
+{"text": "Evidence of the association of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) with the full range of cardiovascular diseases (CVDs) is limited. We examined their relationship with the first clinical presentation of the 12 most common CVDs in an unselected population-based cohort of men and women.We analysed CArdiovascular disease research using LInked Bespoke studies and Electronic health Records (CALIBER) data, which links primary care and hospital and mortality data in England, from 1997 to 2010. We assembled a cohort of men and women initially free from CVD at baseline and included all patients with PMR and/or GCA (PMR/GCA) diagnosis, matched by age, sex and general practice with up to 10 individuals without PMR/GCA. Random effects Poisson regression analysis was used to study the association between PMR/GCA and the initial presentation of 12 types of CVDs.The analysis included 9776 patients with PMR only, 1164 with GCA only, 627 with PMR and GCA and 105\u2005504 without either condition. During a median of 3.14\u2005years of follow-up 2787 (24.1%) individuals with PMR/GCA and 21\u2005559 (20.4%) without PMR/GCA developed CVDs. Patients with PMR/GCA had lower rates of unheralded coronary death , transient ischaemic attack  and coronary and death composite . No associations were observed for other CVDs or cerebrovascular diseases, and in patients with only PMR or GCA. No evidence of interaction by age or sex was found. Estimates decreased with longer PMR/GCA duration and findings were robust to multiple sensitivity analyses.In this large contemporary population-based cohort the presence of PMR and/or GCA was not associated with an increased risk of CVDs or cerebrovascular diseases regardless of PMR/GCA duration. Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are two chronic inflammatory diseases with similar genetic and acute-phase response patterns that affect predominantly women aged \u226550\u2005years.3The inflammatory nature of the two conditions and presence of clinical or subclinical arteritisBecause one in two patients diagnosed with GCA will also develop PMRIn this longitudinal population-based study of individuals registered in primary healthcare practices with linked information to hospital, registry and mortality data, we examine the association between PMR and GCA and the 12 most common clinical initial presentations of CVD. We also assess whether associations differ according to disease duration, sex, age or presence of other autoimmune diseases.All patients with prospectively recorded PMR and/or GCA diagnosis between January 1997 and March 2010 were identified in the CALIBER  dataset.13\u201316For each patient with PMR/GCA, up to 10 individuals matched on age (\u00b15\u2005years), sex and practice were randomly selected among those who, on their matched inclusion date, had contacted the medical practice within 1\u2005year and had not been diagnosed with the disease (concurrent sampling). At the start of the observation period all patients were \u226518\u2005years old, free of prior CVD and had been registered with their practice for \u22651\u2005year.Patients with recorded diagnosis of PMR and/or GCA were identified from electronic medical records using Read and ICD-10 codes (see online supplementary table S1). Those with supporting information for PMR or GCA diagnosis  or under the care of a rheumatologist within 6\u2005months) were included in primary analyses (see online supplementary figure S1 and table S3). Patients without supporting information for diagnosis were included in sensitivity analyses. Individuals were initially categorised as having PMR and/or GCA (PMR/GCA group) or not having either condition. Because it is uncertain whether the two conditions are different presentations of the same disease, they were then divided into subgroups of those diagnosed only with PMR, only with GCA or with GCA regardless of previous or later PMR diagnosis during follow-up . Patients were further classified into incident and prevalent cases, depending on whether the first recorded diagnosis was made before or after/on study entry.https://www.caliberresearch.org/portal/.Baseline covariates considered were: sociodemographic , cardiovascular , \u22652 prescriptions in the past year , immunosuppressant drug, oestrogen oral contraceptives and hormone replacement therapy), diagnosis with another autoimmune diseases (see online supplementary table S4) and year of study entry. As in previous CALIBER analyses,http://www.caliberresearch.org/portal/.The primary study endpoints were the initial presentation of 12 fatal and non-fatal cardiac and arterial vascular diseases of heterogeneous pathophysiology identified across the four linked data sources in CALIBER: the CPRDFor individuals with PMR/GCA the observation period began on the date on which the patient fulfilled all the study inclusion criteria, or the date of first recorded diagnosis for patients with incident PMR/GCA (see online supplementary figure S2). For individuals without PMR/GCA, it started on the entry date of the matched individual with PMR/GCA. For all patients the study ended on the date of cardiovascular endpoint diagnosis, death, practice deregistration, last practice data collection date or diagnosis of PMR/GCA (for patients who contributed follow-up to both the PMR/GCA and non-PMR/GCA groups).Incidence rates of events per 1000 person-years of follow-up with 95% CIs were calculated in patients with and without PMR/GCA, separately for individuals with prevalent or incident PMR/GCA, and for patients exclusively diagnosed with PMR or GCA. Associations between PMR/GCA and every study endpoint were assessed with random effects Poisson regression accounting for clustering between practices. Missing values of covariates were multiply imputed (see online supplementary text S1). Models were initially adjusted for age and sex, then additionally for cardiovascular factors. To explore possible pathways or mediators of any increase in risk, estimates were further adjusted for: (i) lipid and blood pressure lowering medication; (ii) diagnosis of another autoimmune disease; and (iii) anti-inflammatory and/or immunosuppressant drugs.In secondary analyses: (i) evidence of interactions with sex and age were assessed using Wald tests for interaction; (ii) the relationships with prevalent and incident PMR/GCA were studied; (iii) associations were assessed separately for patients who had only one of the two diseases and for those who had GCA regardless of PMR diagnosis. Furthermore, to examine the association between disease duration and CVD, the follow-up of patients with incident PMR/GCA was split into duration periods . Patients with prevalent disease who had a first diagnosis recorded \u22655\u2005years before study entry were included in the \u22655\u2005year period group. Those with prevalent disease of shorter duration (<5\u2005years) were excluded from this analysis because of uncertainty about exact disease duration.Sensitivity analyses comprised: (i) exclusion of patients with another autoimmune disease; (ii) restriction to patients with \u22656\u2005months of follow-up; and (iii) exclusion of 2\u2005years of follow-up prior to PMR/GCA diagnosis for patients who contributed to the exposed and unexposed groups (to account for delays in diagnosis); (iv) inclusion of patients without supporting information for PMR/GCA diagnosis; (v) exclusion of patients of <50\u2005years of age; (vi) inclusion of first cardiovascular events irrespective of other earlier CVD presentations; (vii) comparison of estimates in the periods before and after the introduction of the pay for performance scheme\u00a0in England ; and (viii) restriction to patients with evidence of active disease (baseline c-reactive protein (CRP) >3.0\u2005mg/mL or elevated erythrocyte sedimentation rate (ESR)).Statistical analyses were done with Stata (V.13.1).Approval was granted by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency and the MINAP Academic Group. We registered the protocol at clinicaltrials.gov (NCT02062021).In total 11\u2005567 patients with PMR/GCA and supporting diagnosis information and 105\u2005504 non-PMR/GCA patients free of CVD were identified . Of patiDuring follow-up, 2272 (23.2%) patients with PMR only, 348 (29.9%) with GCA only, 167 (26.6%) with both conditions and 21\u2005559 (20.4%) without either disease experienced one of the 12 CVDs. The incidence of fatal and non-fatal CVDs was slightly lower in patients with than without PMR/GCA , greater differences being observed for heart failure, PAD and stable angina. The small number of CVD events in the subgroup of patients with GCA limited the power to examine differences in rate ratios between patients with PMR and GCA for some CVDs. However, no evidence of increased risk of CVD was observed for those with a higher number of events (see online supplementary table S8) and for composites endpoints .Exclusion of individuals diagnosed with another autoimmune disease or patients aged <50\u2005years, inclusion of patients with >6\u2005months of follow-up and censoring of follow-up 2\u2005years before the diagnosis of PMR/GCA in patients who contributed to both, PMR/GCA and non-PMR/GCA groups, did not alter the results (see online supplementary table S8 and figure S10). Patterns of association remained unchanged when PMR/GCA individuals were included irrespective of whether disease supporting information was recorded (see online supplementary figure S11). Analyses comparing estimates before and after the introduction of the pay-for-performance system of CPRD, those of first presentation of CVD  and those restricted to patients with evidence of active disease also showed similar patterns of associations (see online supplementary figures S12 and S13 and table S10).This is to date the largest population-based longitudinal study comparing the initial presentation of a wide range of symptomatic CVDs in patients with and without PMR and/or GCA using contemporary data (1998\u20132010). The large sample size, the longitudinal design and the information available allowed examination of associations in individuals with prevalent and incident PMR/GCA, pure and concomitant PMR and GCA, different duration of disease and adjustment for sociodemographic and cardiovascular factors. In contrast to a previous CALIBER study conducted in the same population in which we reported increased rates of the initial presentation of several CVDs in patients with rheumatoid disease (awaiting publication), no evidence of increased risk of any of the 12 CVD presentations investigated was found in the presence of PMR/GCA.This study has several strengths. The longitudinal population-based design provided evidence of temporality and enabled investigation of associations with duration of PMR/GCA since diagnosis. The large sample size allowed conducting separate analyses for patients with incident and prevalent PMR/GCA and pure and concomitant PMR and GCA, and investigation of sex and age interactions. The time period covered 1997\u20132010) provided epidemiological evidence from a population diagnosed and treated in recent years. The analysis of linked electronic health records spanning primary, hospital and disease registry data improved disease and cardiovascular endpoint ascertainment,10 providStudy limitations include the possibility of PMR/GCA misclassification . In our study, PMR/GCA was defined based on recorded physician diagnosis in primary care and hospitals. Information on American College of Rheumatology classification criteria or histology was not available in the dataset for diagnosis confirmation. However, to reduce the likelihood of PMR/GCA misclassification in patients >60\u2005years of age with incident seronegative rheumatoid arthritis or malignancies,There are several possible explanations for the absence of increased risk of CVD observed in patients with PMR/GCA regardless of disease duration. PMR/GCA affects an old population who might die before a detrimental effect of chronic systemic inflammation on the arteries becomes symptomatic.7Discordance with previous studies that found evidence of increased risk of CVD in patients with PMR/GCA could be related to their inclusion of patients with a history of CVDs and/or primarily diagnosed and treated in tertiary health facilities, and to betterThe chronic inflammatory nature of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) and the presence of clinical or subclinical arteritis might lead to an increased risk of cardiovascular diseases (CVDs). However, findings from the few available studies investigating these associations are heterogeneous and inconsistent.In this large, contemporary longitudinal population-based study of patients treated at primary and hospital levels, we examined the associations between prevalent and incident PMR/GCA  and pure  and concomitant PMR and GCA, and the 12 most common clinical presentations of CVDs. Regardless of PMR/GCA disease duration, presence of pure or concomitant PMR and GCA was not associated with an increased risk of CVD. No evidence of interaction by sex or age was found.The study findings suggest that, under current clinical practice targeted to patients with PMR and/or GCA, including early and long-term administration of anti-inflammatory and immunosuppressant drugs to control chronic systemic inflammation associated with PMR/GCA, and management of cardiovascular factors with primary prevention, cardiovascular patient risk is similar to the risk of patients without PMR/GCA.In conclusion, regardless of disease duration, diagnosis of pure or concomitant PMR and GCA was not associated with increased risk of CVDs in a large, contemporary population-based sample suggesting that, within the framework of current clinical practice, these diseases do not represent an important risk factor for CVD."}
+{"text": "The mechanism by which transmyocardial revascularization (TMR) offers clinical benefit is controversial. We hypothesized that TMR ameliorates vasoconstriction in patients with ENDCADThis study was undertaken to demonstrate that transmyocardial laser revascularization in patients with advanced CAD improves results of combined operations CABG+ TMR through reduction of vasoconstrictionWe investigated vessels of coronary microvascular network of patients with ENDCAD and analyzed the histological changes in two groups: in group of patients died after sole CABG (1-st group - 8 heart specimens) and group of patients died after combined operations CABG+TMR (2-nd group - 6 heart specimens).These data are compared with hospital results  in two large groups of patients with ENDCAD: with isolated CABG (1-st group -33 operations) and CABG+TMR (2-nd group - 87 operations), operated in 2011-2012.in all hearts after sole CABG was identified coronary arteriolar vasospasm that decreases coronary and bypass flow and thus increase the probability of thrombi formation. All cases after CABG+TMR revealed vasodilatation in lased areas. Reduction in the occurrence of vasospasm in cases with CABG+TMR can prevent graft and coronary occlusion. High indices of hospital mortality (12.1%) and morbidity(33.3%) in cases with sole CABG can be explained with coronary spasm in patients with advanced CAD. On the other hand, reduced hospital mortality (1.15%) and morbidity (2.3%) in the second group(CABG+TMR) can be explained by laser-influenced vasodilatation of distal coronary bed. Elevated resistance of the coronary bed hinders the effectiveness of the graft and myocardial blood flow(MBF). We suggest, that intraoperative effectiveness of TMR based of denervation, dilatation of microvascular network of the myocardium and intraoperative improvement of perfusion.elevated resistance of myocardial microcirculation(vasoconstriction) in patients with advanced CAD inhibit the effectiveness of the CABG. In cases with TMR effectiveness is most likely due to vasodilatation of vasoconstriction of myocardial microcirculation"}
+{"text": "Therapeutic temperature modulation (TTM) is widely used in the care setting to improve outcomes of patients with traumatic brain injury (TBI). Through fever prevention, both oxygen utilization and caloric expenditure are reduced, so metabolic efficiency can be maximized . HoweverA retrospective review was conducted looking at SICU patients managed with a normothermia protocol, with particular attention paid to the anti-shivering portion of the protocol. Serum magnesium (Mg) levels were assessed prior to initiation of TTM and Bedside Shivering Assessment Scale (BSAS) scores were collected.n = 10 of 20). Serum Mg levels at the initiation of TTM were observed to negatively correlate with the level of shivering, as indicated by the BSAS scoring system (P = 0.02). See Figure Twenty patients receiving TTM for TBI were evaluated (March to October 2013). One-half of the patients maintained targeted BSAS scores <1 for the full duration of TTM (The literature suggests the positive impact of TTM on patient outcomes can be maximized with shivering prevention . Current"}
+{"text": "Ebstein's anomaly consists of varying degrees of tricuspid dysplasia and displacement into the right ventricular (RV) cavity, along with changes in ventricular function predominantly affecting the RV. Measuring alterations in contraction pattern and dyssynchrony may provide insights into ventricular performance in this disease. We sought to quantify right and left ventricular (RV and LV) deformation and dyssynchrony in a cohort of patients with Ebstein's anomaly in comparison with normal controls using cardiovascular magnetic resonance myocardial feature tracking (CMR-FT).Twenty-six patients with uncorrected Ebstein's anomaly and 10 normal controls were prospectively studied. LV and RV global longitudinal myocardial strain (GLSLV and GLSRV) and time to peak strain (TPKLV and TPKRV) were calculated from the 4-chamber cine CMR images. Intraventricular dyssynchrony (IntraVD) was calculated as the difference between the segments with the longest and shortest TPK divided by the global TPK value of the respective ventricle: (IntraVD) = TPKlongest-TPKshortest/TPK global. The ratio of global TPKRV and TPKLV was measured as interventricular dyssynchrony (InterVD).Mean patient age was 28 \u00b1 15 . GLSRV was significantly reduced in patients (-15.7 \u00b1 5.2) as compared to controls , while there was no significant difference in GLSLV or global TPKRV and TPKLV between patients and controls ."}
+{"text": "There are errors in S10 Figmean annual runoff are shown. Statistics describing annual variability in runoff in these scenarios is shown in Table 2 and illustrated graphically for 4FRI scenario in S8 Fig.Effects of increasing (a) pace and (b) extent of thinning treatments of ponderosa pine forests in Salt-Verde watersheds on increases in mean annual runoff (acre-feet/year). In (a) total area thinned is held constant at 301,000 ha   to show influence of increasing the area thinned per year. In (b) duration of thinning treatments is held constant at 25 years  to show influence of increasing the total area thinned across the scenario. In order to illustrate scale effects, only increases in (TIFF)Click here for additional data file."}
+{"text": "Surgical Site Infections (SSI) are the most frequent healthcare-associated infection in developing countries with incidence rates up to 30%. Prevention of SSI is complex and faces multiple challenges, especially in resource limited settings. Since 2013, WHO in collaboration with Johns Hopkins University, has been leading the Surgical Unit Safety Program (SUSP) in 5 African hospitals, one of which is the AIC Kijabe Hospital, a private teaching facility in rural Kenya.The SUSP intervention incorporated a bundle of 6 SSI prevention measures selected as priority by the site leaders  embedded within adaptive work to improve the safety culture. Implementation was achieved with local adaptation and creation of tools for advocacy, training, leadership and front-line staff and patient engagement. SSI surveillance and process measures evaluation reflecting the intervention have been carried out throughout the study period for about 18 months, based upon a WHO protocol using standardized definitions.Preliminary data show that the crude SSI rate significantly decreased from 9.3% (38/406 patients) before to 5% (18/353) post-intervention. Patients receiving post-operative antibiotics decreased from 50% to 26%; hair removal with shaving decreased from 25% to 2% of patients; theatre discipline improved with a drop in the average number of door openings per operation from 55 to 40.Implementation of a SSI prevention bundle and creation of a safety climate was successfully achieved at AIC Kijabe Hospital with tangible reductions in SSI rates and improvement of process measures. Local production of alcohol-based products for surgical hand and surgical site preparation was an innovative approach to overcome availability and cost barriers. Engagement of senior staff coupled with structured management of patient safety programs helped inculcate these concepts into the local culture and practice and are crucial for the long term sustainability.None declared."}
+{"text": "Quantitative MR myocardial strain analysis is typically performed using rectilinear or Cartesian grid tagging, and regional contractility is visually assessed by the deformation of the grid1. However, it is difficult to visually isolate circumferential and radial components of displacement and strain from parallel straight lines on short axis images. This study evaluates the potential of a polar coordinate tagging system2 for quantification of circumferential myocardial displacement in a variety of clinical conditions.33 subjects including 12 patients with congenital heart disease (CHD), 11 with cardiomyopathy (CM) and 10 healthy volunteers (HV) underwent cardiac SSFP cine and myocardial tagging in the mid-ventricular short axis plane with grid tags (line separation 5-7 mm), circular tags (5 mm separation) and radial tags . Visual assessment of circumferential and radial displacement was performed by two observers for each of the six mid short axis segments. Scores were assigned for: overall tag quality , strain , confidence in the findings  and ease of interpretation . Quantitative analysis of global and segmental circumferential strain was performed using a semi-automated tool previously described3.Healthy volunteers Figure  had the Polar tagging has advantages for the visual and quantitative assessment of myocardial strain. Compared to rectilinear tagging, radial tags are easier to interpret for isolation of circumferential and radial components of myocardial motion. Overall tag quality, strain, confidence in assessment and ease of interpretation of the image were highest in healthy volunteers, second highest CHD patients and lowest in CM patients.n/a."}
+{"text": "We consider parks in a landscape context (including surrounding 30 km) and evaluate both mean and inter-annual variation in 25 biologically relevant climate variables related to temperature, precipitation, frost and wet day frequencies, vapor pressure, cloud cover, and seasonality. We also consider sensitivity of findings to the moving time window of analysis . Results show that parks are overwhelmingly at the extreme warm end of historical temperature distributions and this is true for several variables . Precipitation and other moisture patterns are geographically more heterogeneous across parks and show greater variation among variables. Across climate variables, recent inter-annual variation is generally well within the range of variability observed since 1901. Moving window size has a measureable effect on these estimates, but parks with extreme climates also tend to exhibit low sensitivity to the time window of analysis. We highlight particular parks that illustrate different extremes and may facilitate understanding responses of park resources to ongoing climate change. We conclude with discussion of how results relate to anticipated future changes in climate, as well as how they can inform NPS and neighboring land management and planning in a new era of change.US national parks are challenged by climate and other forms of broad-scale environmental change that operate beyond administrative boundaries and in some instances are occurring at especially rapid rates. Here, we evaluate the climate change exposure of 289 natural resource parks administered by the US National Park Service (NPS), and ask which are presently (past 10 to 30 years) experiencing extreme (<5 Recent scientific reviews of the US National Park Service (NPS) suggest the agency needs to manage its parks for changing climatic and ecological baselines in a landscape context Climate change is a principal factor driving the imperative for progressive management aimed at achieving a specified \u2018desired future condition\u2019 (DFC) Recommendations to both scale up and consider changing baselines n\u200a=\u200a289), including a 30 km buffer around each park\u2019s boundary Our analyses were performed for all natural resource parks considered by the NPS Inventory & Monitoring Program\u2019s landscape dynamics monitoring project, NPScape (2 at the Equator and 2000 km2 at 70\u00b0N latitude) for each month \u00d7 year, 1901\u20132012. Although this dataset is spatially coarse, at least relative to the size of some parks , it offers for all NPS geographies the highest spatiotemporal resolution of observed climate over the 20th and 21st centuries. We selected for analysis monthly averages of daily temperature , percentage cloud cover, and vapor pressure (haP), as well as total monthly precipitation (mm) and monthly frequencies of frost days  and wet days (rain days per month). We used the monthly climate variables to calculate a series of biologically meaningful variables, including 19 standard bioclimatic variables Gridded climate data were obtained from the Climatic Research Unit (CRU) high-resolution time series version 3.21 (TS 3.21) Although correlations exist among some of these variables, we include the full suite in our analysis because the relevance of individual climate variables can vary dramatically by park resource . As such, the elimination of certain variables due to high statistical correlations would adversely restrict the value of these analyses for park interpretation. Furthermore, the data presented here are percentiles calculated from HRV (see below), not the raw climate variables. Hence, whether variables are correlated is not simply a question of correlation at one point in time; it is a complex question of how sensitive correlations are across the entire 1901\u20132012 period of analysis, interacting with the moving time window of summarization.For each biologically relevant variable, over the entire time series (1901\u20132012), we used three moving windows  to calculate a series of running means and standard deviations (SD). Hereafter we refer to these as \u2018moving window means\u2019 and \u2018moving window standard deviations\u2019. These statistical distributions are what we use to estimate HRV. For example, with the 10 year window, we calculated the mean and SD for 103 windows  to create the HRV distribution. The three windows were designed to encompass both near- and long-term management and planning considerations, as well as important climatic periods and cycles. In the NPS, many implementation plans have short horizons (<10 years), while strategic plans forecast out 10 to 20 years th percentile for the most recent 10 year moving window of annual mean temperature signifies that the value of this climate variable during this time period was greater than 90% of all annual mean temperature 10 year moving window values). Hereafter we refer to these estimates as \u2018recent percentiles\u2019.For each variable, moving window size, and summary statistic , we calculated the area-weighted mean for each park, based on the spatial intersect of park areas of analysis with the CRU lattice. Using processing logic contained in the NPScape climate grid analysis toolset We then averaged the recent percentiles of the most recent 10, 20, and 30 year moving windows and computed the maximum difference in percentile (max \u0394) among windows; this resulted in \u2013 for each park, variable, and summary statistic \u2013 both an overall measure of recent climate change exposure with respect to HRV, and an estimate of how sensitive that measure was by comparing the different moving window sizes. Note that our measure of variability (moving window SD) does not reveal any information regarding extreme events, such as droughts, heat waves, and storms, which can also impact park resources An example of these steps with annual mean temperature (Bio1) is shown for Grand Canyon National Park . In thisth percentile (low) or greater than the 95th percentile (high), and all intervening percentiles as \u2018average\u2019. We tallied the total number of temperature and precipitation variables that met either of these conditions and categorized each park as extreme low or high on temperature and precipitation if at least one variable in each class was low or high. Parks were considered \u2018mixed\u2019 if they possessed low and high estimates of temperature, or low and high estimates of precipitation. Then, considering only the low and high variables, we calculated the maximum value of their max \u0394\u2019s to provide a maximum estimate of sensitivity to window size. Given the thresholds used to define \u2018extreme\u2019, the maximum possible value for max \u0394 is 15%.Given the number and complexity of variables considered in our analysis, we performed two multivariate analyses in an effort to produce more integrated summaries of recent percentiles. Principal component analyses were used to identify a small set of uncorrelated axes for each combination of summary statistic  and measure (mean percentile and max \u0394 percentile). We also conducted a threshold-based classification analysis of mean percentiles, on both the moving window mean and SD, to characterize which parks were extreme on their annual, monthly, or quarterly temperature  or precipitation  variables. In this classification analysis, as well as in other evaluations of individual climate variables, we define \u2018extreme\u2019 as either less than the 5For a subset of parks spanning the contiguous US, we conducted another sensitivity analysis using local weather station data to examine the degree to which CRU results differ from those obtained using direct climate observations. For local station data, we identified 18 United States Historical Climatology Network stations located within park boundaries that similarly span the 1901\u20132012 period of analysis Lastly, as part of the CRU-based classification analysis, for each climate variable  we used a Monte Carlo simulation to test whether the number of extreme parks was significantly different than random expectations. To conduct this test, we first randomly selected 100000 samples of size 289 from a uniform distribution  to develop a sampling distribution of the expected number of extreme parks under the null hypothesis . Using that sampling distribution, we then computed the probability of obtaining the observed number of extreme parks for each climate variable.th percentile in 99% of parks), while recent percentiles associated with the annual number of frost days (Frs12) are correspondingly quite low  are greater than the 95th percentile), with low sensitivity to moving window size (125 parks (43%) have a maximum difference in percentile that is less than 5%). This general pattern holds for parks from the Pacific Islands to Alaska to the East Coast of the US.Focusing on two common climate variables, annual mean temperature (Bio1) and annual precipitation (Bio12), geographic distributions of recent percentiles are illustrated for moving window means  and stanth to 75th percentiles and 233 parks (81%) are within the 5th to 95th percentiles. Hence, only 56 parks (19%) are extreme (<5th percentile or >95th percentile) with respect to annual precipitation.Corresponding results for annual precipitation  are rathth to 75th percentiles and 275 parks (95%) are within the 5th to 95th percentiles. Annual precipitation is similar: 188 parks (65%) are within the 25th to 75th percentiles and 277 parks (96%) are within the 5th to 95th percentiles. Hence, only about 10 parks are extreme with respect to either annual mean temperature or annual precipitation, and these parks differ between the two variables  triggered by any one of the temperature  or precipitation  variables, most parks are presently dominated by extreme high temperatures (235 parks (81%) are higher than the 95th percentile), and \u2013 independent of temperature \u2013 some also by either extreme high precipitation (78 parks (27%) are higher than the 95th percentile) or low precipitation (43 parks (15%) are lower than the 5th percentile)  . Excludicentile) .The number of parks that are extreme high or low on each temperature or precipitation variable considered in the classification analysis are reported in th percentile) or low (<5th percentile) on temperature or precipitation variables , Bio1 and 10 , and Bio11  Management and planning decisions will be greatly informed by an overall assessment of vulnerability that integrates the present climate change exposure analyses with others that consider both the sensitivity and adaptive capacity of park resources to climate change a priori knowledge of how major climate drivers have changed in recent time. For resources influenced by climate variables that are presently well within the bounds of HRV, parks might decide that limited funding should be redirected to study other resources that are sensitive to variables approaching the limits of HRV. Parks might also decide to monitor variables with recent extreme percentiles to assess rates of change and detect when and where they become \u2018novel\u2019 with respect to 1901\u20132010 HRV. Beyond applications related to monitoring and management, results offer park interpreters scientific information that may be translated and communicated to the public.Our measures of climate change exposure support broad-scale vulnerability assessments in the NPS, but they also help individual parks understand and interpret which of their major climate drivers are beginning to approach the limits of 1901\u20132012 HRV. Such insights facilitate discussion of how climate change may impact diverse park resources and values , which are often sensitive to different measures of exposure, but they are not intended to replace more detailed analyses required for site-level management and planning within park boundaries. Many parks are in areas of complex topography and indeed this heterogeneity has important implications for climate adaptation In approaching the 100-year anniversary of its creation in 2016, the NPS is poised to enter its next century of natural resource stewardship and science. The new century brings new challenges in terms of stewarding park resources in the face of environmental drivers that operate beyond park boundaries. Climate change further challenges us to develop new, ecologically viable desired conditions to guide the preservation of park resources in this new era of change. While such challenges remain paramount, more integrative research and education in the climate and landscape arenas will contribute to solutions.Appendix S1Mean percentile and maximum difference in percentile (in parentheses) for moving window means: annual mean temperature (Bio1), mean diurnal range (Bio2), isothermality (Bio3), temperature seasonality (Bio4), maximum temperature of the warmest month (Bio5), and minimum temperature of the coldest month (Bio6).(PDF)Click here for additional data file.Appendix S2Mean percentile and maximum difference in percentile (in parentheses) for moving window means: temperature annual range (Bio7), mean temperature of the wettest quarter (Bio8), mean temperature of the driest quarter (Bio9), mean temperature of the warmest quarter (Bio10), and mean temperature of the coldest quarter (Bio11).(PDF)Click here for additional data file.Appendix S3Mean percentile and maximum difference in percentile (in parentheses) for moving window means: annual precipitation (Bio12), precipitation of the wettest month (Bio13), precipitation of the driest month (Bio14), precipitation seasonality (Bio15), precipitation of the wettest quarter (Bio16), precipitation of the driest quarter (Bio17), precipitation of the warmest quarter (Bio18), and precipitation of the coldest quarter (Bio19).(PDF)Click here for additional data file.Appendix S4Mean percentile and maximum difference in percentile (in parentheses) for moving window means: mean annual percentage cloud cover (Cld1), cloud seasonality (Cld4), vapor pressure of the warmest quarter (Vap18), annual number of wet days (Wet12), number of wet days of the warmest quarter (Wet18), and annual number frost days (Frs12). NA\u2019s associated with Frs12 indicate that the variable is undefined .(PDF)Click here for additional data file.Appendix S5Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: annual mean temperature (Bio1), mean diurnal range (Bio2), isothermality (Bio3), temperature seasonality (Bio4), maximum temperature of the warmest month (Bio5), and minimum temperature of the coldest month (Bio6).(PDF)Click here for additional data file.Appendix S6Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: temperature annual range (Bio7), mean temperature of the wettest quarter (Bio8), mean temperature of the driest quarter (Bio9), mean temperature of the warmest quarter (Bio10), and mean temperature of the coldest quarter (Bio11).(PDF)Click here for additional data file.Appendix S7Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: annual precipitation (Bio12), precipitation of the wettest month (Bio13), precipitation of the driest month (Bio14), precipitation seasonality (Bio15), precipitation of the wettest quarter (Bio16), precipitation of the driest quarter (Bio17), precipitation of the warmest quarter (Bio18), and precipitation of the coldest quarter (Bio19).(PDF)Click here for additional data file.Appendix S8Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: mean annual percentage cloud cover (Cld1), cloud seasonality (Cld4), vapor pressure of the warmest quarter (Vap18), annual number of wet days (Wet12), number of wet days of the warmest quarter (Wet18), and annual number frost days (Frs12). NA\u2019s associated with Frs12 indicate that the variable is undefined .(PDF)Click here for additional data file."}
+{"text": "Here we review zebrafish modeling for two broad groups of inherited conditions that each share genetic and molecular pathways and overlap phenotypically: neurodevelopmental disorders such as Autism Spectrum Disorders (ASD), Intellectual Disability (ID) and Schizophrenia (SCZ), and neurodegenerative diseases, such as Cerebellar Ataxia (CATX), Hereditary Spastic Paraplegia (HSP) and Charcot-Marie Tooth Disease (CMT). We also conduct a small meta-analysis of zebrafish orthologs of high confidence neurodevelopmental disorder and neurodegenerative disease genes by looking at duplication rates and relative protein sizes. In the past zebrafish genetic models of these neurodevelopmental disorders and neurodegenerative diseases have provided insight into cellular, circuit and behavioral level mechanisms contributing to these conditions. Moving forward, advances in genetic manipulation, live imaging of neuronal activity and automated high-throughput molecular screening promise to help delineate the mechanistic relationships between different types of neurological conditions and accelerate discovery of therapeutic strategies.Zebrafish are a unique cell to behavior model for studying the basic biology of human inherited neurological conditions. Conserved vertebrate genetics and optical transparency provide  Therefore these genes may be associated with earlier onset cases of CMT, which can occur anywhere between birth and adulthood  is a large gene and mouse Shank3 knockout models exhibit variable phenotypes depending on whether a mutation is expressed in a predominant isoform . Because brain regions mediating human cognitive symptoms may lack parallels in zebrafish, modeling has focused on embryonic development and disorder comorbidities  that still allow testing of etiological theories for these developmental disorders. These studies have paved the way for comprehensive functional assessments that link cellular- and circuit-level phenotypes to changes in behavior.CHD8 mutations  was shown to have a dose-dependent affect in producing macrocephaly (knockdown) and microcephaly (overexpression) that supports a role for KCTD13 copy number variants causing head size phenotypes  interacts with canonical and non-canonical Wnt signaling and zdisc1 morphants and mutants exhibit disorganized axon tracts at larval stages that can be rescued by activating Wnt signaling  mutants, recapitulating a mutant mouse Cntnap2 model and suggesting that in the absence of cntnap2ab larvae fail to maintain inhibitory neuronal populations. This inhibitory decrease was shown to increase seizure susceptibility in \u2212/\u2212cntnap2ab mutants by applying a GABA receptor antagonist  signaling in Fragile X Syndrome  knockout models in mice, a zebrafish fmr1 knockdown model showed behavioral deficits that were ameliorated when treated with an mGluR inhibitor  and shank3a exhibit hyposensitivity with concomitant neuronal cell death and morphological changes in skin innervating sensory neurons  knockdowns and sodium channel, voltage gated, type II, alpha (scn1lab) knockouts display hyper-excitable phenotypes that are characterized by extended or disorganized swimming with epileptiform-like activity in the brain , HSP, SMA or spinal muscle atrophy (SMA), ALS, as well as some forms of CATX which have phenotypic and mechanistic overlap , a molecular motor for transporting microtubule-mediated cargo, have been reported in both CMT2  encoding atlastin-1 cause an early onset form of HSP  are the primary cause of axonal degeneration in Charcot-Marie-Tooth Neuropathy (CMT2), and MFN2 has been implicated in the fusion and transport of mitochondria in neurons , and early lethality by 1 year of age  cause a spectrum disorder classified as Costeff syndrome and includes optic atrophy, ataxia, extra pyramidal dysfunction, and increased urinary excretion of 3-methylglutaconic acid  morphants show decreases in PC progenitors while cwf19-like 1 (cwf1911) morphants show disruptions in overall hindbrain morphology  mutations that cause Spinocerebellar ataxia type 13  mutations rarely covert carrier cells into cancer cells unless in a p53 mutant background (Kaufman et al., It is also common, though not necessarily well-represented in the literature, for knockout models to lack phenotypes. In a zebrafish study that generated mutant lines with 32 distinct lesions in 24 genes, most of the mutants exhibit a wild-type phenotype (Kok et al., in situ hybridization data and determine the relative enrichment of gene expression in brain regions and spinal cord (Figure Both developmental and degenerative diseases are associated with dysfunction in specific regions of the CNS Figure . None-th0 mutant models of inherited neurological disorders (Jao et al., 0 mutants (Bernier et al., 0 generation. Combined with a large repertoire of behaviors that develop within 5 days of fertilization and diverse transgenic lines for rapid screening of cellular phenotypes, F0 CRISPR zebrafish mutagenesis promises to contribute significantly to our understanding of genetic variation linked to nervous system disorders.Because of the large number of rare mutations linked to inherited nervous system diseases, an important frontier for disease modeling is strategies that leverage to make stable Fin vivo or create conditional mutant alleles, several groups have also recently pioneered the use CRISPR/Cas9 for more sophisticated genome engineering. One novel strategy effectively \u201cenhancer traps\u201d a gene of interest by replacing the last exon with an engineered last exon encoding the C-terminal end of the coding sequence in frame with a cleavable p2A sequence followed by a fluorescent reporter (Li et al., Shank3 autism model, rescuing the mutant Shank3 protein in the adult was sufficient to rescue social interactions and excessive grooming but not anxiety and repetitive motor behaviors (Mei et al., To model specific patient missense mutations and to better understand the basic biology of disease genes by tagging them in vivo calcium imaging with genetically encoded calcium indicators- (GECIs; Chen et al., The development of approaches that enable monitoring of behavior-relevant neural circuits in the intact larvae will be a boon for modeling inherited neurological disease (Ahrens et al., In addition to genetic screens, due to their small size and their tendency to absorb drugs added directly to the water, zebrafish larvae are uniquely amenable for high-throughput drug screens (Rihel et al., The continued expertise and innovations of zebrafish genetic and developmental tools will continue to make zebrafish an attractive neurological disease model. Going forward, combining standard assays that allow comparisons across models with newer approaches would be ideal to enable a better understanding of the molecular, cellular, and systems-level groupings of these neurological conditions. Finally, zebrafish will certainly contribute to consortia of research groups that use multiple animal models for discovering essential molecular to circuit level mechanisms underlying neurological disease.RAK conducted all meta-analyses, made all figures and wrote introductory and developmental disorder sections and conducted extensive edits to coordinate sections. AJA wrote the bulk of the neurodegenerative section with the exception of the ataxia section that was written by EB. DMJ wrote comorbidity section that centered on GI distress in developmental disorders. QY wrote the lessons learned section. JED conceived the scope of the review, wrote frontiers section and helped RAK to conduct extensive edits to coordinate sections.This work was supported by support from the National Institutes of Health Institute of Mental Health R03MH103857 to JED and from the Institute of General Medicine, an IMSD graduate fellowship from parent grant R25GM076419 to DMJ.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To examine both migraine and pulmonary hypertension (PH) we developed a hypoxic mouse model. Under hypoxic conditions (four weeks at 10% O2) mice develop typical symptoms of PH, characterized by an increased muscularization of arterial blood vessels in the lung. The vessel remodeling can be prevented by the chronic application of 5-HT2B receptor antagonists. We found that hypoxic mice also develop increased sensitivity towards the 5-HT2 receptor agonist meta-Chlorophenylpiperazine (mCPP). In contrast to the control group (normoxic mice kept at 20% O2) at low doses of 1 \u00b5g / kg body weight, mCPP triggers plasma protein extravasation (PPE) in the dura mater in hypoxic mice. Dural PPE is a quantifiable indicator of migraine-like events in animal models.The sensitization towards mCPP may coincide with structural remodeling processes in arterial blood vessels of the dura mater, possibly exhibiting similarities to vascular alterations in the lung. A prerequisite in the investigation of vascular alterations in the dura mater is a thorough understanding of the normal organization of dural vasculature in mice and of the extent of its normal biological variance.Histological examinations of the length of dural vessels were performed to quantify and statistically analyze inter- and intraindividual differences.Interindividual differences: The arteriole total lengths are 15% far from the arithmetic mean.Intraindividual differences: The difference in the length of arterioles represents 12% of the total length of the arterioles.On the basis of these results examinations of dural vessel of hypoxic mice can be investigated.No conflict of interest."}
+{"text": "Patients with repaired tetralogy of Fallot (TOF) frequently have right bundle branch block. However, the contribution of cardiac dyssynchrony to dysfunction remains controversial. To better understand this phenomenon and ultimately study therapies, we developed a method to quantify left (LV), right (RV) and inter-ventricular cardiac dyssynchrony using standard cine CMR.30 patients with repaired TOF  and 17 healthy controls  underwent cine CMR. Patients were imaged twice to assess inter-test reproducibility. Circumferential strain vs time curves were generated with a custom feature tracking algorithm for 12 LV and 12 RV segments in 4-7 slices encompassing the ventricles. For each segment, the temporal offset (TO) of the strain curve relative to a global reference curve derived from the controls was calculated and expressed as a percent of the cardiac cycle. The intra-ventricular dyssynchrony index (DI) for each ventricle was computed as the standard deviation (SD) of the TOs (more dyssynchrony increases the SD). The inter-ventricular DI was calculated as the difference in median RV and median LV TOs. Regional dyssynchrony was quantified in 3 LV  and 3 RV  regions using median TOs.Compared to controls, patients with repaired TOF had a greater LV, RV and inter-ventricular DI Figure . The grePatients with repaired TOF suffer from left, right and inter-ventricular cardiac dyssynchrony which can all be quantified from standard cine CMR with good inter-test reproducibility. Future studies need to determine whether these patients may benefit from resynchronization therapy.This work was supported by a National Institutes of Health (NIH) Director's Early Independence Award (1DP5OD012132-01), and NIH grant number KL2 RR033171 from the National Center for Research Resources and the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH."}
+{"text": "The correct legend is given below. The article has since been corrected and reposted in the issue.In Figure 1 of the article \u201cPulmonary Fibrosis in Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis: A Series of 49 Patients and Review of the Literature\u201d,Representative high-resolution computed tomography showing typical features of the 3 major patterns of PF associated with AAV. Predominantly basal, subpleural reticular pattern with macrocystic honeycombing lesions in usual interstitial pneumonia (A). Centrilobular and paraseptal emphysema predominating in the upper lobes (B). Ground-glass opacities in a patchy distribution in nonspecific interstitial pneumonia (C), and reticular subpleural changes in the lower lobes, associated with few microcystic lesions suggesting honeycombing (D) in combined pulmonary fibrosis and emphysema syndrome."}
+{"text": "Solanum lycopersium L.) is the most widely grown vegetable in the world. It was domesticated in Latin America and Italy and Spain are considered secondary centers of diversification. This food crop has experienced severe genetic bottlenecks and modern breeding activities have been characterized by trait introgression from wild species and divergence in different market classes.The tomato  using a custom-made Illumina SNP-panel. Most of the 175 successfully scored SNP loci were found to be polymorphic. Population structure analysis and estimates of genetic differentiation indicated that landraces constitute distinct sub-populations. Furthermore, contemporary varieties could be separated in groups  that are consistent with the recent breeding aimed at market-class specialization. In addition, at the 95% confidence level, we identified 30, 34 and 37 loci under positive selection between landraces and each of the groups of commercial variety . Their number and genomic locations imply the presence of some extended regions with high genetic variation between landraces and contemporary varieties.Our work provides knowledge concerning the level and distribution of genetic variation within cultivated tomato landraces and increases our understanding of the genetic subdivision of contemporary varieties. The data indicate that adaptation and selection have led to a genomic signature in cultivated landraces and that the subpopulation structure of contemporary varieties is shaped by directed breeding and largely of recent origin. The genomic characterization presented here is an essential step towards a future exploitation of the available tomato genetic resources in research and breeding programs.The online version of this article (doi:10.1186/1471-2164-14-835) contains supplementary material, which is available to authorized users. Solanum lycopersicum L.) was probably domesticated in Mexico from wild species that originated in the Andean region, although other hypotheses have been also put forward  for each K value. (JPEG 723 KB)Additional file 7: Figure S1: Estimation of the optimum number of clusters. Estimation of the optimum number of clusters of tomato accessions according to the analysis of variance of the log-likelihood values  of the genotypes based on STRUCTURE and CLUMPP analyses. (XLSX 52 KB)Additional file 9: Table S8: Pairwise estimates of Fst and Nei\u2019s standard genetic distance (Dst) between predefined groups or between groups of tomato accessions as inferred by the Bayesian analysis implemented in the STRUCTURE software. (XLSX 16 KB)Additional file 10: Table S9: Heterogeneity in F-Statistics among loci. (XLSX 11 KB)Additional file 11: Table S10: Candidate loci under positive selection between landraces varieties and the different market-classes of contemporary varieties. (XLSX 10 KB)Additional file 12: Table S11: Marker names and their genomic information. (XLSX 22 KB)"}
+{"text": "Circulating strains cluster geographically and belong to at least 5 distinct clades. Mastomys natalensis) is the only known reservoir of LASV. Most human infections result from zoonotic transmission. The very diverse LASV genome has 4 major lineages associated with different geographic locations. We used reverse transcription PCR and resequencing microarrays to detect LASV in 41 of 214 samples from rodents captured at 8 locations in Sierra Leone. Phylogenetic analysis of partial sequences of nucleoprotein (NP), glycoprotein precursor (GPC), and polymerase (L) genes showed 5 separate clades within lineage IV of LASV in this country. The sequence diversity was higher than previously observed; mean diversity was 7.01% for nucleoprotein gene at the nucleotide level. These results may have major implications for designing diagnostic tests and therapeutic agents for LASV infections in Sierra Leone.Lassa virus (LASV) is endemic to parts of West Africa and causes highly fatal hemorrhagic fever. The multimammate rat ( Arenaviridae), the etiologic agent of LF (Lassa fever (LF) belongs to a group of viral hemorrhagic fevers characterized by a febrile syndrome and high case-fatality rates , a natural host and reservoir of this pathogen  and high-density resequencing microarrays to detect LASV and amplify fragments of NP, GPC, and L genes. The obtained amplicons were sequenced and compared with previously published sequences from Sierra Leone to obtain a more complete and updated picture of the strains circulating in this country.Mastomys sp. were further identified down to species level by using molecular methods as described previously . Thirteen locations were selected for study in the LF-endemic region of eastern Sierra Leone. The geographic coordinates of the sampling locations and details of rodent trapping methods are available in the online Technical Appendix . Traps wRNA from 10 mg of spleen of each rodent was extracted with TRIzol following the manufacturer\u2019s recommendations. The samples were stored at \u201380\u00b0C.RNA were reverse-transcribed by using the SuperScript III Reverse Transcriptase kit (Life Technologies) according to the manufacturer\u2019s instructions, and RT products were stored at \u201320\u00b0C. Specific oligonucleotide primer pairs were used for the PCR targets of interest  at finalThe resequencing pathogen microarray (RPM) analysis was conducted by using Tropical and Emerging Infections microarrays . The RPM-TEI microarray enables detection of 84 biothreat agents, including all lineages of LASV (http://tree.bio.ed.ac.uk/software/figtree).We conducted the sequence alignment using the MUSCLE algorithm implemented in the MEGA 6.0 software package ; Cricetomys sp. (3 [1.4%] rodents); and Mus sp., Praomys sp., and Hylomyscus sp. (1 [0.5%] rodent each).We collected 681 small mammals during the field survey. Of these, we analyzed 214 for this study on the basis of RNA availability at the time of the study Table 2.We screened all samples for LASV by RT-PCR using pan\u2013Old World arenavirus (OWA) primers .In addition, we screened a randomly selected subset of 51 samples , Largo (8 samples), Bumpeh (7 samples), Ngiehun (4 samples), Koi and Yawei (3 samples each), Taiama (2 samples), and Saama (1 sample) . No LASVAll positive samples came from multimammate rats, which is considered the sole vector species for LASV  was closely related to that of strains from Barlie . In another example, 1 GPC sequence originating from Liberia (523) clustered with Sierra Lone clade A sequences. In some cases , such unusual clustering patterns may be explained by cross contamination or mislabeling of the samples. They also might result from relative proximity of all sampling sites and inadvertent anthropogenic transfer of rodents. Massive population movements that occurred in Sierra Leone during the 1991\u20132002 civil war could contribute to the process of mixing multimammate rat subpopulations carrying different LASV strains  most likely originated from the Yawei village area because they cluster closely. A few other human isolates  for which no location information is available also clustered with Yawei isolates on the basis of GPC and L sequences, suggesting their origin in the same area. These sequences were obtained in 2002 from United Nations peacekeepers stationed in this part of Sierra Leone (Recent epidemiologic data show that LF was detected in 10 of 13 districts in Sierra Leone, which suggests that the infection is much more common that previously recognized (Molecular characterization of isolates from a wider geographic area of the country is needed to fully understand the diversity of the LASV strains in Sierra Leone and its impact on disease distribution and risk. Such information would be useful for developing efficient viral detection technologies, for example, enabling design of PCR primers and antibodies specific for a broad range of LASV types. These diagnostic tests are extremely relevant to disease surveillance and monitoring and evaluation of interventions to prevent primary LASV infection in humans. More extensive information about sequence diversity affecting the antigenicity of the virus or the function of its RNA-dependent RNA polymerase may help in the development of vaccines and antiviral drugs. It will also lead to deeper understanding of the biology and pathogenesis of LASV.Rodent trapping procedures; coordinates of sampling locations; and list of all analyzed samples."}
+{"text": "Figure S1 is incorrect. Please view the correct The seventh sentence of the second paragraph of the Discussion section is also incorrect. The correct sentence is: Only sample 74 had a serine (S), polar neutral, at position 429, while the other samples had phenylalanine (F), which is neutral and hydrophobic.Figure S1Average temporal distribution of precipitation and suspected or confirmed dengue cases.(TIF)Click here for additional data file."}
+{"text": "To summarize a first stage of research on implementation of a peer leader suicide prevention program by testing the utility of a method for tracking and reporting each school's success in retaining and preparing Peer Leaders.Peer leader programs that prepare opinion leaders to spread healthy practices through their social networks reduce high-risk sex behaviors and show promise in preventing adolescent substance use and suicidal behavior. However, knowledge of implementation processes is very limited. To address this limitation, we drew on the Stages of Implementation Completion (SIC) framework to measure a key phase of peer leader implementation.40 high schools were randomly assigned to either immediate Sources of Strength (n = 20) or waitlist (n = 20). The schools were underserved by mental health services and over-represented by youth at high risk for suicide . In the 20 implementing schools, 656 students (18-71 per school) received Peer Leader (PL) training. Adult mentors facilitated PL meetings to reinforce program concepts and help PLs plan and execute activities to spread healthy coping practices. Using a framework derived from the Stages of Implementation Completion (SIC), school reports of PL meeting dates/attendance were codified as indices of school success in retaining and preparing PLs. Surveys with 5,712 students showed wide school-level variation in success of PLs in reaching their classmates with the prevention concepts. In analytic models examining predictors of school-level exposure, a higher proportion of student population trained as PLs and greater retention of PLs predicted higher population exposure to the prevention program, congruent with diffusion of innovations theory, whereas frequency of meetings did not.Identified an efficient method (derived from the SIC) for assessing a school's success in preparing/retaining peer leaders. This approach shows promise in providing schools actionable data to increase impact of peer-led programs.NIH R01MH091452."}
+{"text": "Although the in vivo anti-tumor efficacy of cannabinoids is mimicked in continuously cultured cancer cells in vitro, cannabinoid potency for direct elicitation of apoptosis in cancer cells is far lower, indicating that other mechanisms (perhaps other cell types within the tumor) are involved in vivo. We have recently obtained evidence that: 1) CB2 agonists mediate inhibition of primary tumor growth and metastasis in vivo, 2) significant infiltration of TAMs occurs within the developing tumor in this murine model, 3) administration of a CB2 agonist increases populations of pro-inflammatory M1 macrophages  in both the primary tumor and in the spleen of tumor bearing mice, and 4) a concurrent increase in the proportion of CD8+ cytotoxic T lymphocytes is also observed within the primary tumor upon CB2 agonist treatment.In human breast cancers, tumor infiltration by tumor associated macrophages (TAMs) correlates with multiple markers of poor prognosis: higher tumor macrophage counts are associated with higher tumor grade, higher tumor vascular density, and reduced overall survival. TAMs sesentation. Recent"}
+{"text": "Acute aortic dissection is the most common life-threatening vascular disease, with sudden onset of severe pain and a high fatality rate. Clarifying the detailed mechanism for aortic dissection is of great significance for establishing effective pharmacotherapy for this high mortality disease. In the present study, we evaluated the influence of biomechanical stretch, which mimics an acute rise in blood pressure using an experimental apparatus of stretching loads in vitro, on rat aortic smooth muscle cell (RASMC) death. Then, we examined the effects of azelnidipine and mitogen-activated protein kinase inhibitors on mechanical stretch-induced RASMC death. The major findings of the present study are as follows: (1) cyclic mechanical stretch on RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch on RASMC induced c-Jun N-terminal kinase (JNK) and p38 activation with peaks at 10 min; (3) azelnidipine inhibited RASMC death in a concentration-dependent manner as well as inhibited JNK and p38 activation by mechanical stretch; and (4) SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) protected against stretch-induced RASMC death; (5) Antioxidants, diphenylene iodonium and tempol failed to inhibit stretch-induced RASMC death. On the basis of the above findings, we propose a possible mechanism where an acute rise in blood pressure increases biomechanical stress on the arterial walls, which induces RASMC death, and thus, may lead to aortic dissection. Azelnidipine may be used as a pharmacotherapeutic agent for prevention of aortic dissection independent of its blood pressure lowering effect. With the rapid progress of population aging in most developed countries, the number of patients with atherosclerosis has remarkably increased; this is becoming an extremely serious problem requiring urgent attention It is well recognized that aortic dissection occurs when a small tear generated in the inner aortic wall extends along the wall of the aorta and causes blood to flow between the layers of the tunica media and adventitia of the aorta, forcing the layers apart. Despite the pathophysiological interpretation, the detailed mechanism for aortic dissection still remains unclear. Various efforts have been recently made to clarify the possible reasons for aortic dissection. Collins et al. reported that progressive loss of smooth muscle cells is observed in the specimens of acute aortic dissection characterized by aortic medial degeneration Azelnidipine has been approved for the treatment of patients with hypertension and is extensively used in developed countries In the present study, we used an experimental apparatus of stretching loads in vitro that can simulate sudden increases of blood pressure and observed RASMC death induced by biomechanical stretch. Furthermore, we investigated whether azelnidipine inhibited stretch-induced VSMC death. The effect of azelnidipine on changes in intracellular signaling by biomechanical stretch was also examined to provide a possible mechanism by which azelnidipine may be used as a pharmacotherapeutic agent for the prevention of aortic dissection independent of its blood pressure lowering effect.The study design was approved by an ethics review board of guidelines for the use of laboratory animals of Nara Medical University (No. 11011) and this study conducted in accordance with the guide for the Care and Use of Laboratory Animals as adopted and promulgated by the United States National Institutes of Health.2 in a humidified incubator. RASMCs were used for experiments between the third and sixth passages. The cells were cultured in collagen I-coated (70 \u00b5g/cm2) silicon chambers . When the cell confluency in culture was estimated to be 70\u201380%, the medium was replaced with unsupplemented DMEM. The cells were further cultured for 24 h and then subjected to cyclic mechanical stretch  for a given time period using the computer-controlled mechanical Strain Unit . After cyclic stretch, the medium was replaced with DMEM-containing 0.1% FBS. For western blot analysis, a portion of the RASMCs were lysed immediately after stretch stimulation and lysate proteins were collected in the manner described earlier RASMCs were isolated from the thoracic aorta of 8-week-old male Sprague\u2013Dawley rats by enzymatic digestion, as previously described Materials were purchased from Wako (Kyoto) or Nacalai Tesque (Kyoto) unless stated otherwise. Azelnidipine (CS905) was from Daiichi Sankyo, Inc (Osaka). The antibodies used for western blot analyses were as follows: anti-phospho-SAPK/JNK (Thr183/Tyr185) antibody and anti-phospho-p38 MAP kinase (Thr180/Tyr182) antibody were purchased from Cell Signaling Technology, while ECL and ECL plus systems were purchased from GE Healthcare. Collagen I was purchased from Nippon Meat Packers, Inc. (Osaka). All chemical compounds were dissolved in dimethyl sulfoxide (DMSO) at final concentration less than 1% except for special notification.t-test was used to determine significant differences in multiple comparisons. A P value<0.05 was considered to be significant.All experimental values were expressed as mean \u00b1 standard deviation. Analysis of variance along with subsequent Student\u2019s The effect of cyclic mechanical stretch on the viability of RASMCs was firstly examined by measuring MTT reduction and LDH released. The effects of cyclic mechanical stretch on the activation of JNK and p38 (members of MAP kinases family proteins) were assessed by western blot analysis . RASMCs In order to clarify the possible mechanisms of how cyclic mechanical stretch influences cell death, the following two experiments were undertaken.The effects of azelnidipine on cyclic mechanical stretch-induced activation of JNK and p38 in RASMCs were firstly examined and the results are shown in It has been reported that azelnidipine has the effects of anti-inflammation and antioxidant in mouse aneurysmal models The major findings of the present study are as follows: (1) cyclic mechanical stretch of RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch of RASMCs induced JNK and p38 activation with peaks at 10 min; (3) azelnidipine, a calcium channel blocker, inhibited the activation of JNK and p38 by cyclic mechanical stretch in a concentration-dependent manner; and (4) azelnidipine and JNK or p38 inhibitors protected against stretch-induced RASMC death; (5) Antioxidants, DPI and tempol failed to inhibit stretch-induced RASMC death.In this work, we recall the assumption that acute biomechanical stretch applied to cultured VSMCs in vitro simulating a sudden increase in blood pressure resulted in VSMC death that led to aortic dissection. As shown in Azelnidipine is a calcium channel antagonist (blocker) that has been applied extensively to the treatment of patients with hypertension all over the world. In the present study, we found that azelnidipine inhibited RASMC death induced by cyclic mechanical stretch . Under tAmong MAP kinases, JNK and p38 were recognized to be related to cell death or apoptosis We have reported in the previous study that p38 and JNK are oxidative stress sensitive In conclusion, azelnidipine inhibited RASMC death induced by acute cyclic mechanical stretch (originating from a simulated increase in blood pressure in vitro). JNK and p38 in RASMCs were activated by cyclic mechanical stretch; however, the activation was inhibited by azelnidipine. Similar to azelnidipine, pharmacological inhibition of JNK and p38 activation by mechanical stretch suppressed cyclic mechanical stretch-induced RASMC death. It is expected that the mechanism of acute aortic dissection will be clarified from further study of the fate of VSMCs by acute cyclic mechanical stretch. Azelnidipine may be an alternative candidate for prevention of acute aortic dissection independent of its blood pressure lowering effect."}
+{"text": "PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53 and ATP7B genes. Ten genetic modifications were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. PGR gene polymorphisms\u2019 impact on ovarian cancer risk was specific only for the group of the BRCA1 mutation carriers, which proves the difference in the modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of ATP7B gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in three out of four groups. Cumulative risk analysis revealed 3 unfavorable variants that significantly increased the risk of developing ovarian cancer, and also two favorable genotypes which protected against ovarian cancer.Single nucleotide polymorphisms modulate the risk of developing ovarian cancer during lifetime. In this study we analyzed 12 polymorphic variants and 2 deletions in Survival analysis for carriers of favorable versus unfavorable genotypes emphasized the importance of regulation of the cell cycle and active transport of xenobiotics during paclitaxel/cisplatin chemotherapy. The unfavorable variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors."}
+{"text": "Scientific Reports5: Article number: 1007210.1038/srep10072; published online: 07082015; updated: 08262015The Acknowledgements section in this Article is incomplete.\u201cRM acknowledges the Academy of Finland for support within the FiDiPro scheme.\u201dshould read:\u201cRM acknowledges the Academy of Finland for support within the FiDiPro scheme. We acknowledge financial support of the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of the University of Potsdam.\u201d"}
+{"text": "Hemorrhage in association with microvascular obstruction (MVO) is a new independent predictor of adverse remodeling following acute myocardial infarction (AMI), occurring in ~35% of patients presenting with STEMI , 2. HoweMyocardial hemorrhage was induced in a porcine model of AMI by direct intracoronary injection of collagenase (col) . AnimalsAt day 1, low T2* values in the infarct region confirmed the presence of myocardial hemorrhage in the collagenase groups 2 and 3  whereas group 1 was non-hemorrhagic. Infarct size was significantly greater in group 3 compared to group 1 at all time points  beyond the effects of the initial ischemic insult. Thus, hemorrhage actively contributes to the tissue remodeling processes during infarct healing. A mechanistic view of the consequences of hemorrhage post-AMI will potentially lead to better management and care of the high-risk STEMI patient population.We acknowledge funding support from the Heart & Stroke Foundation of Canada, GIA award #000334, and the D+H Sunnybrook Research Institute (SRI) Summer Student Program."}
+{"text": "Efficient neutralization of HIV is a primary goal both for therapeutic and prophylactic HIV vaccines based on induction of neutralizing antibodies (NAbs) , 2. NeutAnti-HIV IgG antibodies 2F5 and 2G12, switched back to IgM isotype, showed increased avidity and neutralization efficacy . It woulin vivo in a highly specific way either by secondary immunization with protein antigens or in response to immunization with the newly formed ICs (Rheumatoid factor (RF) is an autoantibody which specifically binds Fc region of IgG , 11. Aparmed ICs , 11. Newrmed ICs .The level of RF was significantly higher in some of HIV-infected individuals compared to control groups \u201322. RFs in vivo? Measurements of RF level both in long-term non-progressors Can neutralization-enhancing RF antibodies (NeRFa) be induced after repeated immunization of humans with recombinant gp120 glycoprotein?(ii)Will the power of gp120 immunogen design \u201331 combi(iii)Could NeRFa help to improve the efficacy of previous  and futu(iv)Might induction of NeRFa be a future promising method not only against malaria as suggested in Ref. , but alsStudies , 17 haveRepeated immunization with gp120 glycoprotein might lead to prolonged induction of neutralization-enhancing RF antibodies with a potential to be explored for finding the ways to extend lives of HIV-infected individuals and to stop current HIV pandemic.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In the United Kingdom (UK), major trauma networks became operational in April 2012. Based at Queen Elizabeth Hospital Birmingham (QEHB), supported by the Ministry of Defence and University of Birmingham, the National Institute of Health Research Surgical Reconstruction and Microbiological Research Centre (SRMRC) is one of the few 24/7 UK trauma research centres. Having demonstrated success in delivering time critical studies, collaboration with West Midlands Ambulance Service (WMAS) has resulted in transferring research to the scene of injury, demonstrated by the success of The Brain Biomarker After Trauma Study, \u2018Golden-Hour.\u2019Specialist WMAS staff supported by the Midlands Air Ambulance were trained for \u2018Golden-Hour\u2019 enrolling patients with a traumatic brain injury (TBI) or an Injury Severity Score (ISS)>8. Operating Procedures and consumable packs were developed allowing sampling without delaying patient care. Blood samples obtained by WMAS within one hour of injury are passed at handover to QEHB for processing. A 24/7 research team based at QEHB ensure support and sample transfer from WMAS and are responsible for consequent sampling and consenting.Introducing a 24/7 SRMRC team into both pre-hospital and hospital settings has swiftly embedded research into routine trauma care. Whilst \u2018Golden-Hour\u2019 continues, enrolment remains ahead of predicted target with over 500 samples collected and recruitment continues to improve rapidly as WMAS staff become familiar with the protocol. The study has proved the concept allowing future collaboration and grant applications, potentially resulting in further innovations for the under-researched trauma population.Delivering research pre-hospital within one hour of injury requires a highly motivated team but is achievable. Effective integration between pre-hospital and research teams are paramount for any study to succeed. As trauma care evolves and research infrastructures within trauma networks improve, there is vast potential for further engagement with the goal of delivering evidence based pre-hospital trauma care."}
+{"text": "We report the complete sequences of two West Nile virus strains (FDA-Hu02 and NY99) used for the formulation of CBER/FDA RNA reference reagents and lot release panels for use with nucleic acid technology testing. Flavivirus, family Flaviviridae) is the most widely extended arbovirus in the world. WNV transmission involves a bird-mosquito enzootic cycle that can infect humans, horses, and other vertebrates who act mainly as dead-end hosts. WNV appeared for the first time in the Americas in the United States in 1999 and since then it has disseminated extensively within the country and also to other countries on the continent (West Nile virus (WNV)  and NY99 (obtained from an infected flamingo in 1999). Cell culture supernatants from the second passage of the NY99 strain and third passage of the FDA-Hu02 strain in Vero cells were used for total RNA extraction using the QIAamp Viral RNA minikit (Qiagen). Reverse transcription reactions, PCR amplification, sequencing of overlapping PCR products, and sequence analysis were performed as described previously .The total lengths of the genomes of the WNV NY99 and FDA-Hu02 strains are 11,029 and 11,030 nucleotides (nt), respectively. The isolate FDA-Hu02 showed 20 nucleotide mutations plus one insertion at position 10,497 compared to prototype NY99; 5 mutations resulted in amino acid substitutions. We found no differences between the nucleotide sequences of the original NY99 isolate (AF196835) and the NY99 isolate cultivated and sequenced in our laboratory. Phylogenetic analysis classified FDA-Hu02 as belonging to genotype WN02, whereas strain NY99 is the prototype of the NY99 genotype (AY646354 and KM083619, respectively.The complete sequence of the WNV strains FDA-Hu02 and NY99 have been submitted to the GenBank under the accession numbers"}
+{"text": "Cardiovascular magnetic resonance (CMR) has expanded its role in the diagnosis and management of congenital heart disease and acquired heart disease in children. However, there are limited studies evaluating the role of cardiac magnetic resonance in delineating the anatomy of coronary arteries along with assessment of first pass myocardial perfusion in children. The purpose of this study is to evaluate the extensive use of CMR for delineating coronary anatomy, evaluating first pass myocardial perfusion and late gadolinium enhancement in children with acquired and congenital heart disease.Retrospective review of 37 consecutive CMR Whole Heart T2 Prep coronary angiography studies of patients with congenital and acquired heart disease. The subjects had CMR from December, 2013 to September, 2014. Results of first pass myocardial perfusion study (at rest and with adenosine stress) and myocardial inversion recovery for delayed myocardial enhancement imaging were also reviewed.The median age at the time of CMR was 11 years with range of 3 months to 25 years; 26 male and 11 female subjects. The origins and proximal course of coronary were well demonstrated by CMR in 92% (34/37) of the cases. Five patients (13.5%) had multiple coronary artery aneurysms related to Kawasaki disease (Cardiac magnetic resonance imaging can reliably evaluate the coronary anatomy, first pass myocardial perfusion defect and myocardial scar in diverse group of children with acquired and congenital heart diseases.None."}
+{"text": "Obesity is a risk factor for cardiovascular disease and mortality. Studies in both obese humans and murine models of obesity have identified changes in left ventricular (LV) mechanics , which manifest prior to global changes in cardiac function (ejection fraction) and may represent early markers of cardiovascular disease. These data are generally acquired under resting conditions, which could mask subtle differences in the early stages of disease. We sought to evaluate LV mechanics under inotropic stress conditions with the hypothesis that mechanical deficiencies with obesity would be exacerbated under stress conditions and revealed at earlier stages of disease.C57BL/6J mice were randomized to either a high-fat or control diet  for varying time intervals (n=7-10 subjects per group per time point). At each interval, LV mechanics were quantified under baseline (resting) and stress conditions (40 \u00b5g/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) on a 7T Bruker ClinScan. Three short-axis and 1-2 long-axis slices were acquired with 11-20 frames per cardiac cycle. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used to compare interactions between time and group with Benjamini-Hochberg adjustments for multiple comparisons.Under rest conditions, reductions in LV peak strains Fig  were obsDifferences in left ventricular mechanics in obese mice are exacerbated under inotropic stress conditions. Compared to evaluation at rest, stress CMR demonstrated a broader array of mechanical dysfunction (changes in systolic strain rates and torsion in addition to peak strains) and revealed these differences at earlier time points (16-22 vs. 42 weeks). A deficit in circumferential peak systolic strain rate at peak stress was the earliest observed marker of obesity-induced ventricular dysfunction. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions in order to fully elucidate the presence of ventricular dysfunction.This work was supported by a Ruth L. Kirschstein National Research Service Award (T32 HL91812); an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the NIH (P20 GM103527); the University of Kentucky Cardiovascular Research Center; the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR000117). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources."}
+{"text": "Individuals with short bowel syndrome (SBS) have reduced intestinal absorptive capacity and many require home parenteral nutrition (PN) support. One of the common causes of SBS is secondary to intestinal resections in the management of Crohn\u2019s disease (CD). Complication rates and survival in SBS secondary to CD on PN versus other etiologies remains unknown.To determine whether patients with SBS secondary to CD versus SBS secondary to other etiologies on home PN, have increased risk of hospitalizations and complications including central line associated bloodstream infection (CLABSI) and venous thromboembolism and whether there is a difference in overall survival between groups.This is a multicentre prospective cohort study using the Canadian Home Parenteral Nutrition (HPN) Registry on individuals with defined SBS separated into two cohorts: 1) Patients with SBS secondary to Crohn\u2019s disease vs. 2) Patients with SBS secondary to other aetiologies . Patient characteristics and clinical factors are presented as mean (standard deviation) for continuous variables and as frequency (percentage) for categorical variables. Comparison between groups (SBS CD vs SBS other) were performed using 2-sample t-test for continuous variables and Chi-square or Fisher exact tests when appropriate for categorical variable. Survival probabilities will be estimated using the Kaplan-Meier method.The study included a total of 379 patients with short bowel syndrome on home PN. There are 170 (45%) patients with SBS secondary to CD and 209 (55%) patients with SBS from other secondary causes. The average age of those with CD is 52 and 65% female patients. The average age of those with other causes of SBS is 56 with similar percentage of female patients (65%). There were significant differences in baseline medications with higher use of immunosuppressant therapy  in those with CD. There was no significant difference in total number of hospitalizations, hospitalizations related to PN and CLABSI.Individuals with SBS secondary to CD do not appear to be at increased risk of central line infections or hospitalizations compared those with SBS from other causes.NoneNone Declared"}
+{"text": "A decrease in SUV max of more than 60% in the primary tumour was identified as optimal cut-off value for predicting major pathological response and performed better than computed tomography morphologic partial response measured by a size reduction of the primary tumour of more than 30%. The same result was observed for prediction of prognosis.The authors must be congratulated on systematically assessing the role of fluorodeoxyglucose-positron emission tomography and computed tomography in predicting pathological response and prognosis of locally advanced non-small cell lung cancer (NSCLC) after neoadjuvant chemoradiotherapy . IntegraRelevant differences were identified for the subgroup of T3-4N0-1 patients compared to N2 positive patients and a decrease of <60% of SUVmax was found as an indicator of poor prognosis, particularly in N2 patients. The analysis was focused on metabolic and imaging response in the primary tumour, whereas lymph node status was analysed pathologically.Previous analyses of well-designed prospective trials looking at pre-treatment metabolic tumour volume only showed conflicting results on the impact on 5-year survival rates , whereasIn the current treatment landscape, the presented data will be challenged by several issues. Particularly, the details of pathologic reporting after neoadjuvant treatment are crucial to ensure comparability of trials. In 2020, the \u2018International Association for the Study of Lung Cancer\u2019 (IASLC) has reported a multidisciplinary recommendation for pathologic assessment of lung cancer resection specimens after neoadjuvant treatment . The autThe integration of immunotherapy in neoadjuvant treatment algorithms  will leaIn summary, innovative neoadjuvant combination schemes have the potential to substantially change staging algorithms in NSCLC. The paper by Tanahashi and colleagues provides relevant confirmatory reference data on the impact of metabolic response on pathologic response rates and 5-year survival rates after neoadjuvant chemoradiation therapy."}
+{"text": "Recent events in the world, wars, pandemics, have once again raised the issue of the need for competent human resources in global public health (GPH). In Georgia, there are master\u2019s degree programs in public health where global health is mostly offered as an elective or core course of the curriculum. University of Georgia (UG) is involved in the ERASMUS + project in GPH (BACE). UG initiated to create new GPH Master Program, which will be response towards local, regional and international challenges and demand.Main objective of developing GPH program was to address and meet national and international global health education needs and challenges. The aim of the study was to identify evidence-based prerequisites for the MPH in GPH (UG). We conducting document review based on the GPH competency model (GPHCM) and evaluated: 1) GPH & MPH programs of the top 20 world university ranking (THE/2022); 2) CUGH associated programs; 3) Georgian MPH programs; 4) Georgian education documents ); 5) Main directions of career development in global health. In addition, interviews with national experts were conducted  using the Delph method.Study found that depending on the scope and content of the program, prerequisites for obtaining MPH in GPH varies. In addition to English competence and a high GPA, working or research experience or interviews or additional exams or other are required. In Georgia, there is no adopted GPHCM, but GNQF allows the establishment of MPH in GPH. UG new Master program (120 ECTS) will include 99 ECTS core (including research practicum & thesis) and 21 ECTS elective courses based on 6 domains of GPHCM. The program will mostly focus on population health management at a global level.Study findings suggest any undergraduates with appropriate conditions could be eligible for admission to the UG (MPH in GPH).\u2022\u2002UG admission prerequisites for Health Science undergraduates: National entrance exam, English proficiency B2, working experience and motivation letter.\u2022\u2002UG additionally admission prerequisites for Health Science undergraduates: basic knowledge epidemiology and medical terminology (if credits available or test)."}
+{"text": "Pregabalin is an analogue of gamma-aminobutyric acid (GABA). Recent reports suggest illicit pregabalin use may be increasing among youth, however its addictive potential has not been well established (1).Drug seeking behavior and chronic drug use are associated with defcits in glutamate clearance and activation of postsynaptic glutamatergic receptors (2). Based upon multiple studies, we compare here the addiction and misuse risks of pregabalin with those of traditional psychoactive substances (3).Users of pregabalin were identified from 1st January 2019 to 31 December 2019 in Oran Addictology service, at west Algeria. The aim of the study was to establish the addictive potential of pregabalin and to compare the addiction risks of pregabalin with traditional psychoactive substances in west Algerian population. Clinical diagnosis was established according DSM-5 diagnosis criteria.A total of 92 cases of pregabalin abuse or dependence were identified. The principal population at risk consists of patients with other current or past substance use disorders, for the most part opioid and multi-drug users, the age group were between 17-38 years old, mostly single men. The mean daily dose of pregabalin was 1200 mg. Almost all patients experienced withdrawal symptoms when pregabalin was discontinued.The misuse of pregabalin often leads to abuse and dependence, mostly in the context of multiple drug addiction, especially in youth population."}
+{"text": "Currently, Buprenorphine maintenance therapy (BMT) is an evidence-based treatment in retaining patients who are dependent on opioids. However, factors influencing retention are often measured objectively. Studies on patient\u2019s perspectives on take home BMT in developing countries are limited.This study examines the potential factors influencing treatment compliance in the early phase of Buprenorphine maintenance treatment from the patient\u2019s perspectiveParticipants (n=89) who were initiated on BMT were recruited and followed after six weeks. A semi-structured interview was conducted with 62 patients who remained in treatment and 24 patients who dropped out of the studyBased on the semi qualitative analysis some of the factors which facilitated the patient\u2019s retention in treatment were: (1) Effectiveness in blocking withdrawal symptoms (2) effectiveness in reducing their cravings and controlling their opioid use (3) decreased fear of withdrawal and/or missing doses(4) improvement in the quality of life(5) patient-related factors like family support (6) effectiveness of the treatment program. Around nine percent of patients reported family support as the reason for retention, which is not noticed in other studies. Barriers reported by the patients while on medication were: (1) negative effect experienced with medication (2) program related difficulties like distance, unavailability (3) major life event interrupting the treatment (4) patient-related factors like low mood, financial constraints.Understanding factors associated with barriers to treatment provide insights into preventable factors that contribute to premature drop out from BMT and to improve clinical practice, policy decisions, or future research."}
+{"text": "Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures.To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations.The study was based on data extracted from a database consisting the results obtained previously in a three pillars complex health survey. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk.Interestingly, the rs121909567 (SERPINC1) SNP was not present in the general population, however the risk allele frequency was 1.4% among Roma, which might suggest a founder effect in this minority. The risk of VTE was higher among depressive Roma subjects who carried the risk variant of rs2036914 ; however, not for the general subjects. The joint presence of high level of LDL-C and rs2066865 increased the VTE risk only among Roma . A multiplicative interaction between rs8176719 and cancer was identified and higher for the Roma population . The VTE risk increased in the Roma population  but was higher in the general population  as a result of the multiplicative interaction between CAD and rs2036914 (F11).rs121909567 (SERPINC1) was confirmed as a founder mutation in the Roma population. As a result of higher genetic load and GxE interactions, the minority Roma population is at higher risk of VTE than the general Hungarian population.\u2022\u2002Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE.\u2022\u2002A marginalized and segregated Roma community could need due attention for the prevention and control of CVDs."}
+{"text": "Oculo-auriculo-vertebral spectrum (OAVS) is a rare condition characterized by the involvement of the first branchial arches.To investigate the ear abnormalities of a sample of patients with OAVS.The sample consisted of 12 patients with OAVS seen at the Clinical Genetics Unit, UFCSPA/CHSCPA. The study included only patients who underwent mastoid computed tomography and with normal karyotype. We performed a review of its clinical features, giving emphasis to the ear findings.Nine patients were male, the ages ranged from 1 day to 17 years. Ear abnormalities were observed in all patients and involved the external (n=12), middle (n=10) and inner ear (n=3). Microtia was the most frequent finding (n=12). The most common abnormalities of the middle ear were: opacification (n=2), displacement (n=2) and malformation of the ossicular chain. Agenesis of the internal auditory canal (n=2) was the most frequent alteration of the inner ear.Ear abnormalities are variable in patients with OAVS and often there is no correlation between findings in the external, middle and inner ear. The evaluation of these structures is important in the management of individuals with OAVS. Branchial arch disorders comprise several developmental anomalies including the oculo-auriculo-vertebral spectrum (OAVS), also known as Goldenhar's syndrome, or hemifacial microsomy OMIM 164210)2104, 5, The origin of the OAVS is unclear, but it is a complex and heterogeneous condition. Two pathophysiologic mechanisms have been proposed for the OAVS: a reduced blood flow, and focal hemorrhage in the development region of the first and second branchial arches around 30 to 45 days of pregnancy, in the blastogenesis periodAlthough external ear anomalies have been described in OAVS patients - to the point of being inclusion criteria - middle and especially inner ear alterations have received little attention in the literatureThe sample comprised 12 patients with the OAVS seen at the Clinical Genetics Unit, UFCSPA/CHSCPA. The inclusion criteria were alterations in at least two of the following bodily regions: oro-cranial-facial, ocular, auricular, and vertebral, according to Str\u00f6mland et al.'s criteria (2007)p<0.05 were considered statistically significant. The institutional review board approved this study (Opinion no. 581/08 of 25/01/2008).The registries of patients were reviewed to gather clinical data and the results of diagnostic tests . Fisher's exact test (bicaudate) was applied to compare the frequencies were found. The software was the PEPI program. Values of There were 9 male and 3 female subjects. The ages at the first visit ranged from 1 day to 17 years (10 were aged 1 year or less). Most of these patients were referred from the pediatrics unit (n= 7); two others were referred from the plastic surgery unit, one from the cardiology unit, one from the otorhinolaryngology unit, and one from the pediatric surgery unit. Eight subjects had two of the inclusion criteria, three subjects had three, and one had four. All subjects had ear anomalies, affecting the external ear n= 12), the middle ear (n= 8), and the inner ear (n= 3). Microtia was the most frequent finding - it was observed in all cases (ranging from grades I to IV). It was mostly unilateral, to the left, and grade III. Four patients had bilateral microtia (33%). The most common middle ear anomaly was opacification (n= 2), and displaced (n= 2) and malformed ossicular chains (n= 2). Agenesis of the inner ear canal (n= 2) was the most frequent inner ear anomaly. The most common finding in the temporal bone was a non-aerated mastoid (n= 5). Additional alterations in other organs or systems consisted of low height (n=4), craniofacial anomalies (n= 11), ophthalmologic anomalies (n= 2), esophageal/ pulmonary anomalies (n= 6), cardiac anomalies (n= 7), abdominal anomalies (n= 4), skeletal anomalies (n= 6), and cerebral anomalies (n= 5) , the mid.Figure 1External ear malformations in OAVS patients ranged from slightly dysmorphic to absent ears (or anotia - the most severe form of microtia)Because the ossicles of the ear develop from the dorsolateral terminations of the cartilage in the first (Meckel's cartilage) and second (Reichert's cartilage) branchial arches, anomalies of these structures are often found in the OAVS. Anomalies in the stapedial and tympanic tensor muscle suggest that these structures originate from the first and second branchial archesAlthough external middle ear anomalies are well known, inner ear alterations are rarely observed; these anomalies vary widely and range from mild to severePoorly pneumatized mastoid antrumEnlarged cartilaginous portion of the Eustachian tube lumen and absence of the cartilaginous lateral lamina of the Eustachian tubeLengthened mastoid antrumPreauricular appendages and pitsEar anomaliesAtresia/stenosis of the outer ear canalUndeveloped tympanic membraneMicrotia/anotiaIncomplete development of the tympanic cavityImmature and malformed ear ossiclesAbsent oval and round windowAbsence of the tympanic tensor muscleAbnormal path of the facial nerve and absence of the chorda tympani nerveDistorted and hypoplasic cochleaAbsence of the cochlear aqueductImmature vestibular system and absence/fusion of semicircular canalsDisplaced endolymphatic ductWidened vestibular aqueductAbsent/abnormally coursing facial nerve canalSmall, wide, and/or duplicated inner ear canalAgenesis of the inner ear canalDuplicated inner ear canalThe frequency of these anomalies in our sample (25%) was similar to previously reported rates (27% to 36%)As mentioned above, the most frequently reported ear anomalies in the OAVS are external and middle ear abnormalities. Thus, secondary conductive hearing loss predominates in these patientsSurgery is difficult because of the complexity of this condition and the number of factors that may affect the outcome of surgical therapy. On the other hand, hearing loss is generally unilateral in the OAVS; the majority of patients develop speech, and their level of hearing enables them to be socially active. However, patients with bilateral mixed profound hearing loss or pure sensorineural hearing loss required more advanced forms of treatment, such as cochlear implants or bone anchored hearing aidsEar anomalies are frequent and varied in OAVS patients; often there is no correlation among external, middle, and inner ear findings. Therefore, it is important to assess these structures using radiologic methods (such as computed tomography of the mastoid) when managing patients with OAVS."}
+{"text": "Autoimmune diseases of central nervous system (CNS) are wide spread in children. In some cases, mental disturbances in such patients are barely noticeable in the beginning, which hinders early detection of risks in the child\u2019s mental development.The study focuses on comparative analysis of the structure of mental disorders in pediatric patients with autoimmune diseases of CNS.Research includes two cases: girls aged 14 and 16, one with acute disseminated encephalomyelitis (ADEM), disease onset at 4 years and 11 months, and another with multiple sclerosis (MS), disease onset at 5 years and 5 months. The following methods were used: analysis of patient\u2019s medical record, interview with neurologists, pathopsychological assessment.Common features in both cases: 1) organic brain disorders; 2) patients do not demonstrate intellectual deterioration, can master regular school curriculum; 3) detected mental disturbances reflect risks for mental and personality development. Specific features: 1) the patient with MS demonstrates polymorphism of mental disorders, while the patient with ADEM \u2014 homogeneity of mental disorders; 2) main problems of the patient with MS are related to self-regulation, which makes the general picture similar to pseudo-frontal syndrome; the patient with ADEM has major neurodynamic disturbances, which has similarity to psychoorganic syndrome; 3) predictors of personality disorders detected in case of MS determine the negative prognosis for mental development.The delineated features evidence for further psychological study of CNS autoimmune diseases and formulation of criteria for clinical psychological assessment. These patients need to be monitored by psychologists to prevent personality disorders.No significant relationships."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-80366-2, published online 21 January 2021Correction to: The original version of this Article contained an error in the Methods section, regarding ethical approvals. The data of three patients included from Hino hospital were not covered by the original ethical approval, which read:\u201cThis study was approved by the institutional review board, and the requirement of written informed consent was waived because of the study\u2019s retrospective design .\u201dThese patients provided their consent separately and an additional ethical approval was issued by the IRB of Hino Municipal Hospital. Additional information on the approval for study execution by the other participating centres was also included in the corrected version. The approval statement now reads:\u201cThis study was approved by the institutional review boards of Keio University School of Medicine Ethics Committee , National Hospital Organization Tokyo Medical Center , Saiseikai Utsunomiya Hospital , Japanese Red Cross Shizuoka Hospital , Inagi Municipal Hospital (dated 23/06/2020), Hiratsuka City Hospital , and Hino Municipal Hospital IRB (dated 24/03/2021). The requirement of written informed consent was waived because of the study\u2019s retrospective design.\u201dThe original Article has been corrected."}
+{"text": "Hydrocephalus is reported in approximately one-tenth of neurosarcoidosis patients. However, data on clinical characteristics and outcome are lacking. In this retrospective study, we present 11 patients with neurosarcoidosis and hydrocephalus on neuroimaging. Median age was 52\u00a0years and seven were female (64%). Presenting symptoms consisted of headache in 8 out of 11 (73%), vertigo in 5 (46%), gait abnormalities in 4 (36%), diplopia in 2 (18%) and decreased visual acuity in 1 (9%). Cranial imaging showed obstructive hydrocephalus in 10 (91%) and non-obstructive hydrocephalus in 1 (9%) out of 11, obstruction occurred at the level of the fourth ventricle in 6 out of 10 (60%). Treatment consisted of glucocorticoids in all the patients with additional methotrexate or azathioprine in 6 (55%) and infliximab in 1 (9%) patient. Neurosurgical intervention was performed in 10 out of 11 (91%) patients. Treatment led to remission, improvement or stabilization of disease in 9 out of 10 (90%) of patients. One patient died due to cerebral herniation despite neurosurgical decompression and CSF shunting. Median modified Rankin scale score at last follow-up was 2 (range 0\u20136). A systematic review and meta-analysis of studies on hydrocephalus due to neurosarcoidosis identified 36 patients that compared to our patients had a lower median age at onset and a higher mortality. Acute obstructive hydrocephalus due to neurosarcoidosis is a potentially fatal medical emergency requiring neurosurgical intervention and initiation of immunosuppressive therapy. If patients survive the initial phase, the outcome is generally favorable. Sarcoidosis is an inflammatory disorder that can involve multiple organ systems . InvolveWe retrospectively reviewed all case records from adult patients that were seen between June 2015 until June 2020 at the Neurology Department at the Amsterdam University Medical Centers a tertiary referral center for neurosarcoidosis. We included patients diagnosed with (1) neurosarcoidosis  and (2)Detailed history and neurological examination were retrieved from patient files in an electronic database including presenting symptoms, age of onset of symptoms, results of ancillary investigations and data on treatment and treatment response and outcome of hydrocephalus in neurosarcoidosis.A literature search was performed in PubMed using the following terms: (\u201csarcoidosis\u201d [MeSH Terms] OR sarcoid* [tiab] OR \"Neurosarcoidosis\" [Supplementary Concept] OR neurosarcoid* [tiab]) AND . We included articles written in English describing one or more adult patients that were published in the last 25\u00a0years. The search was followed by a manual search in the reference lists of the publications found. The study conforms with the World Medical Association Declaration of Helsinki, 7th revision 2013 Fortaleza. Ethical approval is not required in the Netherlands for a retrospective study with anonymized patient data such as used in our study.Between June 2015 and June 2020, 303 patients were analyzed because of suspected neurological involvement of sarcoidosis at our outpatient department or clinical department. Of these, 153 patients (50%) were diagnosed with neurosarcoidosis  had a history of sarcoidosis of which one had a history of neurosarcoidosis-associated myelitis (9%) and three used immunosuppressive therapy at symptom onset. Presenting symptoms were headache in eight (73%), vertigo in five (46%), abnormal gait in four (36%), diplopia in two (18%) and decreased visual acuity in one patient (9%). Time from symptom onset of hydrocephalus-related symptoms to first neurological evaluation was 15\u00a0weeks (interquartile range 3\u201338). Abnormalities on neurological examination included nystagmus and impaired consciousness each in four (36%), papilledema and ataxia each in two (18%) and bilateral sixth nerve palsy in one patient (9%). Neurological examination showed no abnormalities in two patients (18%). Median time from onset of symptoms to diagnosis of neurosarcoidosis was 4 months (range 0\u201334). Other organ systems involved were lymph nodes in four patients (36%), lungs in three (27%) and eyes, liver and bones, respectively, in one patient.Serum angiotensin-converting enzyme (ACE) was analyzed in five patients and was elevated in none of them, soluble Interleukin 2 receptor (sIL-2R) was evaluated in two patients and was elevated in both. Cerebrospinal fluid (CSF) analysis was performed, commonly after external ventricular drain placement, in nine and showed an elevated leukocyte count in eight (89%) patients and elevated total protein in five (56%). One patient had a normal CSF analysis. CSF oligoclonal bands were present in the one patient in which they were tested.Results of cranial imaging were re-evaluated for all patients [ten magnetic resonance imaging (MRI) and one computed tomography (CT)] and showed hydrocephalus in all. The hydrocephalus was non-communicating/obstructive in ten patients and communicating in one. Obstruction was at the level of the fourth ventricle in six patients (60%), the foramen of Monro in three (30%) and the cerebral aqueduct in one 10%). In one patient, there was tonsillar herniation due to the obstruction hydrocephalus  was performed in seven patients with no history of sarcoidosis, and showed abnormalities suggestive of sarcoidosis in all of them. Biopsy was performed in all patients. Leptomeningeal biopsy was performed in one patient and showed non-caseating granulomas (definite neurosarcoidosis), lymph node biopsy was performed in eight patients and showed non-caseating granulomas in seven (probable neurosarcoidosis) and was inconclusive in one (possible neurosarcoidosis), in one patient liver biopsy was performed and showed non-caseating granulomas (probable neurosarcoidosis). In the patient with possible neurosarcoidosis, chest CT was highly suggestive of sarcoidosis.Fluor-18-deoxyglucose positron emission tomography (The median follow-up was 23.5\u00a0months (interquartile range 3\u201350\u00a0months). Immunosuppressive treatment was initiated in all 11 patients and consisted of corticosteroid pulse therapy in 7 (64%), corticosteroid maintenance therapy in 9 (82%) and second-line therapy, methotrexate or azathioprine, in 4 patients (36%). Neurosurgical intervention was performed in 10 out of 11 patients (91%) and consisted of external ventricular drain placement followed by ventriculoperitoneal shunt in 3 (30%), ventriculoperitoneal shunt in 5 (50%), ventriculostomy in 3 (30%) and cyst fenestration in 1 patient (10%). All but one patient were treated both with immunosuppressive agents as well as a neurosurgical intervention. Of these ten patients, three underwent neurosurgical intervention prior to immunosuppressive treatment, three received immunosuppressive treatment prior to neurosurgery and in four, neurosurgical and immunosuppressive treatments were initiated simultaneously. Medication was changed during follow-up due to insufficient response to initial therapy, side effects or a relapse of symptoms during follow-up in 5 out of 11 patients (45%). One patient had multiple relapses of symptoms. The relapse of symptoms of neurosarcoidosis was recurrence of hydrocephalus in four (80%) and meningitis without hydrocephalus and myelitis each in one patient (20%). Treatment changes included restarting or increasing the dosage of corticosteroid maintenance therapy in three (80%), corticosteroid pulse therapy in three (60%) and initiation of second-line therapy in five . Third-line therapy (infliximab) was started in one patient (20%). Two patients underwent a second neurosurgical intervention because of failure of CSF shunt or ventriculostomy.Neurological examination at the end of follow-up was available in ten patients and focal neurological deficits were present in only one patient and were attributable to sarcoidosis-associated myelitis. Outcome of neurosarcoidosis at last follow-up was classified as remission in two (18%), improvement in five (45%) and stable disease in three (27%). One patient (9%) died following cerebral herniation as a result of the hydrocephalus. Median modified Rankin scale (mRS) score at last follow-up was 2 (range 0\u20136).Literature review yielded 95 articles of which 46 were assessed for eligibility based on title and abstract. Of these articles, five consisted of case series of neurosarcoidosis patients that included patients with hydrocephalus but did not report clinical characteristic, ancillary investigations, treatment and outcome of this subgroup \u201342. The 18FDG-PET. These investigations can help ascertain a potential biopsy site outside of the central nervous system. Histopathological evidence of non-caseating granulomas is necessary for a diagnosis of probable or definite neurosarcoidosis [Our study shows that hydrocephalus is a rare but potentially fatal manifestation of neurosarcoidosis that requires a combination of neurosurgical intervention and immunosuppressive treatment. In the absence of a positive history of (neuro)sarcoidosis, the differential diagnosis of acquired hydrocephalus is diverse and includes among others inflammatory, (post-) infectious, (post-)hemorrhagic and (post-)traumatic disorders and intracranial tumors such as colloid cysts or malignancy , 43, 44.coidosis .Presenting symptoms of hydrocephalus in neurosarcoidosis are (sub)acute and related to increased intracranial pressure. Hydrocephalus in neurosarcoidosis is often non-communicating and caused by obstruction of the outflow from the fourth ventricle or of the cerebral aqueduct due to a chronic meningitis. Acute obstructive hydrocephalus can be fatal and an emergency neurosurgical intervention such as CSF shunting, ventriculostomy or decompression should be considered in all patients. Corticosteroid treatment in adjunct to neurosurgical intervention should be strongly considered in all patients. Intensification of immunosuppressive treatment is required in case of a relapse of symptoms, as a persistent or recurring granulomatous chronic meningitis can lead to an additional site of obstruction or shunt failure through obstruction of the CSF shunt . AlthougAs compared to our case series, the mortality was higher (9% versus 22%) and more patients had a diagnosis of definite neurosarcoidosis (10% versus 58%) in the review of the literature. The difference in mortality may be explained by publication bias as multiple articles reported on patients with sudden death. A previous review of the literature found an even higher mortality of 75% in patients with neurosarcoidosis who presented with seizures and had hydrocephalus . HoweverThis study has several limitations. First, patients evaluated were referred to our tertiary center. This may introduce selection bias leading to overestimation of the impact of hydrocephalus in neurosarcoidosis. Second, the retrospective design of our study resulted in heterogeneous assessment of disease activity as well as missing data in some patients. This prohibits drawing firm conclusions regarding outcome and treatment effect. Third, as mentioned above there might be publication bias regarding hydrocephalus in neurosarcoidosis. Nevertheless, our retrospective single-center cohort study and systematic review provides valuable information on a rare disease as hydrocephalus in neurosarcoidosis.In conclusion, hydrocephalus due to neurosarcoidosis is a medical emergency as onset is often (sub)acute and the hydrocephalus is obstructive in nature. Initiation of treatment should be prompt and include both neurosurgical interventions to lower intracranial pressure and immunosuppressive therapy to reduce granulomatous inflammation. If patients survive the initial phase outcome is generally favorable."}
+{"text": "Broad-range metagenomic cell-free DNA testing (Karius\u00ae) can identify a variety of pathogens from a single blood sample to help in diagnosis of deep seated and bloodstream infections. Few studies have evaluated the impact of Karius testing on clinical decision making when compared to more conventional diagnostic methods.We performed a retrospective cohort study of adult patients who had Karius tests at University of Iowa Hospitals and Clinics between 01/2020 and 10/2021. Chart review was conducted to obtain patient characteristics and clinical course including patient age, immunocompromising conditions, involvement of Infectious Disease (ID) consultant, reason for the test, and final diagnosis. Results of the Karius tests and conventional tests were compared for concordance. Clinical impact and change in management due to Karius testing were determined using previously established criteria outlined by Hogan et al.:239-245)Out of 26 patients who had Karius testing, 20 patients (77%) had an immunocompromising condition, the most common of which was hematologic malignancy . Twenty-four patients (92%) had received a formal ID consultation prior to the test. The most common finding prior to testing was the presence of pulmonary infiltrates on imaging . Karius testing was positive in 18/26 cases (69%). Organisms detected by Karius and conventional testing were concordant in 9/18 cases (50%). Karius test result had a positive clinical impact in 3 cases (12%), an indeterminant impact in 1 case (3%) and no impact in 22 cases (85%). Reasons for a positive impact are as follows: 1 case with initiation of antituberculosis therapy due to earlier diagnosis of tuberculosis, 1 case with de-escalation of antifungal therapy based on negative Karius results, and 1 case of clearance for urgent lung transplantation based on negative Karius results in the setting of mobile echo density on echocardiogram in the absence of other stigmata of endocarditis.The impact of Karius testing on patient management appears limited. Further studies will be needed to identify patient populations or disease factors in which this testing have clinical impact.All Authors: No reported disclosures."}
+{"text": "Death at home is preferred by most people and has become a key indicator of the end-of-life care quality; however cultural attitudes about death and dying may vary by race and ethnicity. This study describes racial and ethnic variation in place of death among Medicare beneficiaries aged 50 years and older who died in 2018 with a dementia diagnosis  and without a dementia diagnosis . Among those with dementia, 60% died at home, with the highest percentage for non-Hispanic white (62%) beneficiaries, followed by Black/African American (55%), Hispanic (61%), Asian American/Pacific Islander (58%), and American Indian/Alaska Native (58%) beneficiaries. Among those without dementia 61% died at home, with the highest percentage for non-Hispanic white (60%) beneficiaries, followed by Black (57%), Hispanic (65%), Asian American (65%), and American Indian (60%) beneficiaries. Among those who died at home, about half without dementia received hospice care compared to the majority with dementia."}
+{"text": "Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (The online version contains supplementary material available at 10.1007/s13311-022-01237-4. Despite decades of research, there remains a significant unmet need for effective treatments for amyotrophic lateral sclerosis (ALS). The reasons are manifold, but two key considerations have emerged . First, SOD1) gene (SOD1-ALS) ., 24.Pre-The date of emergence of clinically manifest ALS will be defined as the date when the participant first experienced the relevant clinical symptom or, in the absence of symptoms, the date when neurological examination first detected evidence of UMN and/or LMN signs indicative of ALS, whichever is sooner.SOD1 genetic testing to determine or confirm their SOD1 variant. Recognizing the complexities of predictive genetic testing and the potential for emotional, psychosocial, legal, and financial implications [In the ATLAS study, participants undergo centralized ications , 29\u201331, SOD1 result and anticipating or learning about a NfL level increase, additional counseling is available as needed throughout the study. Genetic counseling will be performed by qualified individuals as per local standard clinical practice; acknowledging that exact qualifications for providing genetic counseling differs around the world [During screening for enrollment in Part A of the study, genetic counseling sessions are required before a DNA sample is collected for testing and at the time that the results are communicated. These sessions, which focus primarily on genetic testing, also include in-depth discussions about NfL \u2014 specifically, the uncertain but potential implications of above-threshold NfL levels for the risk of imminent clinical disease. Given the potential for continued psychosocial and emotional impact, especially after receiving a positive he world . In addiSOD1 variant genetic analysis results and their NfL levels \u2014 is paramount. If disclosed, positive SOD1 test results and elevated NfL levels could be used in discriminatory ways, with potential implications for both the study participant and their biological relatives in many spheres of life, including finances, insurance , eligibility for educational and recreational activities, family planning, and employment status [The protection of participants\u2019 privacy \u2014 in particular, their t status , 33, 34.SOD1 variant carriers in the Pre-fALS study. The utility of this critical observation from the Pre-fALS study underscores the importance and value of high-quality natural history data in advancing therapy development for rare diseases [The ATLAS study incorporates unique design elements to evaluate whether presymptomatic initiation of tofersen can delay the emergence of clinically manifest ALS and/or reduce the loss of clinical function over time. ATLAS is the first interventional trial in ALS that uses neurofilament as an enrichment marker for study eligibility and a trigger for initiation of study treatment. The design of ATLAS was built upon the premise that elevations in NfL precede the emergence of clinically manifest ALS, as observed in rapidly progressive diseases .ATLAS has the potential to aid in the identification and understanding of early markers of disease activity beyond NfL. The collection of CSF (at baseline for Part A and prior to every dose in Parts B/C/D) and urine/blood  will enable the identification of other potential fluid markers of disease activity. Similarly, comprehensive electromyography (EMG) at screening for Part A and Part B may inform the timing of NfL elevation relative to the emergence of EMG abnormalities and the relative sensitivity of these two biomarkers. Through these biomarker assessments, ATLAS will help to inform the conduct of presymptomatic trials in other subsets of the ALS population.SOD1 variants is continuously evolving due to limited reporting and heterogeneity across carriers. To account for this, an independent Mutation Adjudication Committee was formed to adjudicate eligibility of non-protocol-defined SOD1 variants based on the most up-to-date information at the time. The use of clinically manifest ALS as a primary endpoint is not without challenges, given potential perverse incentive to receive open-label tofersen in Part C; it is for this reason that we have established an independent EAC to confirm the emergence of clinically manifest ALS.A list of variants associated with high/complete penetrance and rapid disease progression was defined in the protocol based on the totality of information ascertained in the literature, genetic databases, and clinical experience. However, characterization of Pre-fALS study, ATLAS aims to take into account two key considerations: (1) when and how participants are informed of their genetic risk, and (2) how participants\u2019 privacy, especially regarding their SOD1 genetic variant and NfL biomarker status, can be protected. For both study sites and participants alike, education, training, and resources are essential to help address these concerns. Specifically, the ATLAS study has implemented genetic testing and counseling processes along with firewalls and strategies to protect participant privacy in the context of a clinical research study.Recognizing the potentially serious and life-long implications of positive genetic testing results on study participants and their families, the study also necessitated the development of a supportive infrastructure to inform, support, and protect prospective participants. Informed by experience from the SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease through elevated plasma NfL. Recognizing that therapeutic intervention in earlier phases of ALS has the potential to yield the greatest clinical benefit, ATLAS, together with data from the VALOR study and its open-label extension study, will inform the optimal timing of treatment initiation in SOD1-ALS. As the first interventional trial in presymptomatic ALS, ATLAS has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS and other neurodegenerative diseases.The ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of Supplementary file1 (PDF 536 KB)Supplementary file2 (PDF 589 KB)Supplementary file3 (PDF 545 KB)Supplementary file4 (PDF 599 KB)Supplementary file5 (PDF 535 KB)Supplementary file6 (PDF 616 KB)Supplementary file7 (PDF 553 KB)Supplementary file8 (PDF 580 KB)Supplementary file9 (PDF 553 KB)Supplementary file10 (PDF 629 KB)Supplementary file11 (PDF 563 KB)Supplementary file12 (PDF 563 KB)Supplementary file13 (PDF 619 KB)Supplementary file14 (PDF 598 KB)Supplementary file15 (PDF 600 KB)Supplementary file16 (PDF 571 KB)Supplementary file17 (PDF 545 KB)Supplementary file18 (PDF 625 KB)Supplementary file19 (PDF 562 KB)Supplementary file20 (PDF 527 KB)Supplementary file21 (PDF 527 KB)Supplementary file22 (PDF 607 KB)Supplementary file23 (PDF 329 KB)Below is the link to the electronic supplementary material."}
+{"text": "The emotional, behavioral and psychosocial effects of chaotic environments following wars and armed conflicts in terms of exposure to trauma and displacement is well recognized. School-age children who are directly exposed to or witnessed negative effects of armed conflicts show an array of emotional and behavioral problems.Our study aimed to examine the mental health conditions of children living in war and conflict zones and attending primary schools in Agdam.The study sample comprised of 617 children , residing in the conflict areas in the southwestern of Azerbaijan. The children were evaluated with the previously validated Azerbaijani version of the Strengths and Difficulties Questionnaire (SDQ) Teacher Form.About a third of children (32.7%) had abnormal total scores, and a fifth (21.4%) were in borderline range. The SDQ subscale scores included emotional problems (19.4%); conduct problems (20.3%), hyperactivity/inattention (12.2%), peer relationship problems (31.1%), and pro-social behavior difficulties (13.1%). As a result, externalizing problem scores were higher in males (p<.001) and internalizing problems in females (p<.05). Due to correlation analysis, age is negatively and significantly related with externalising (p<.05), internalising (p<.01), and total difficulty (p<.05) scores.The findings of the study show that more than half of the children living in the war zone in Azerbaijan suffer from mental health problems and highlight the need for child mental health services and family supports in the region.No significant relationships."}
+{"text": "Inflammatory Bowel Diseases (IBD) are increasing globally with westernized countries experiencing a dramatic increase in cases of ulcerative colitis and Crohn\u2019s disease. The corresponding rise in the comorbidities of anxiety and depression are linked to inflammation and microbiome dysbiosis; impacting the gut-brain axis (GBA). Another facet of the GBA are the tryptophan metabolites serotonin (5HT) and kynurenine (Kyn). 5HT and Kyn are metabolites implicated in anxious behaviours and memory deficiencies with dysbiosis influencing metabolite production. In inflammatory conditions, upregulation of Kyn impacts brain homeostasis as Kyn has both positive and negative brain metabolites. As disease outcomes are tied to the severity of depression/anxiety, characterization of the behavioural and tryptophan metabolite profile of an IBD model can allow us to develop better IBD therapies.To characterize the anxiety and memory phenotype with corresponding assessment of tryptophan metabolites 5HT and Kyn across tissues of interest in an spontaneous colitis model.-/-) lack the protective mucin 2 layer in the distal colon, allowing for direct contact between the gut contents and the gut epithelial layer. Over time this contact results in the development of spontaneous colitis. Muc2-/- n=12 per sex were compared to C57Bl/6 mice for behaviour and tryptophan metabolites across brain, colon and serum. Open Field Test and Light/Dark tests were used to assess anxiety levels, Novel Object and Radial Arm maze were performed to assess memory deficits. Mice underwent one anxiety and one memory test and were euthanized following their last maze. Enzyme-linked immunosorbent assay (ELISA) assessment of 5HT and Kyn were performed on brain, colon and serum samples. T-tests were performed and graphs created using PRISM (v9.4.1).Mucin 2 knockout mice (Muc2-/- mice had decreased anxiety (p=0.0113) compared to C57Bl/6 wild type mice in the light/dark maze. Muc2-/- displayed no significant differences in novel object preferences or the number of memory errors in novel object recognition test and radial arm maze respectively. Serum kynurenine was found to be significantly elevated (p=0.0444) in Muc2-/- mice. The sex factor has to be mentioned here in the results not in the conclusions.Muc2-/-and wild-type mice with depressed anxiety responses and heightened serum kynurenine, however the implications of these findings require further investigation. Understanding how inflammation is driving behavioural alterations can provide pathways to ameliorate the behavioural comorbidities in IBD patients suffering from anxiety of memory deficits.IBD is increasing globally and problems with mental health is often comorbid. Within our model we were able to show that behavioural and biochemical differences do exist between our Muc2None Declared"}
+{"text": "There is a need for improved communication in assisted living communities (ALCs) for staff and family caregivers of persons with dementia. This study is a cluster randomized trial in 10 ALCs  of a PC education (PCEAL) program for dementia care providers facilitated by hospice nurse educators. Baseline, 3- and 6-month data was collected for documentation of advance care planning (ACP) discussions. The PCEAL program had a moderate effect on ACP discussions at the 3-month follow in the treatment (N=17) compared to the control group (N= 6) . The findings indicate that the PCEAL program potentially improves ACP discussions with family members of persons with dementia. We will discuss recommendations for tailoring the PCEAL program to include other direct and administrative staff and to elicit the perspective of families about quality of communication."}
+{"text": "We evaluated the concordance of lymphoproliferative disorder (LPD) diagnoses made initially at Kamuzu Central Hospital (KCH) with a limited immunohistochemistry panel and telepathology consultation with University of North Carolina (UNC) at Chapel Hill and second review at UNC with an extensive immunohistochemistry panel available.The prospective KCH Lymphoma Study in Lilongwe has been enrolling patients with LPDs since 2013. Diagnoses are made by pathologists in Malawi and supported by US pathologists and Malawian clinicians at weekly telepathology conferences. Diagnostic tissue blocks are sent quarterly to UNC for secondary review and further confirmatory studies. Concordance of diagnosis from primary to secondary review was scored as: exact match (level 1), differences in granularity of the diagnosis (level 2), a change in classification but not in treatment (level 3), and a change to the diagnosis that would have altered the treatment course (Major Discordance). Cases with insufficient tissue for review at UNC were excluded from concordance evaluation.Three hundred eighty-eight adult patients were enrolled (June 2013-May 2019). Three hundred twenty-seven tissue blocks were sent to UNC for review and 292 LPDs diagnostic samples had sufficient quality for concordance review. The five most common LPDs were diffuse large B-cell lymphoma , Burkitt lymphoma , classical Hodgkin lymphoma , Multicentric Castleman disease , and low grade non-Hodgkin lymphoma . Level 1, 2 and 3 concordance represented 175 (60%), 49 (17%) and 50 (17%) cases, respectively, and a Major Discordance was identified in 18 cases (6%).With a limited, selected immunohistochemistry panel and telepathology consultation, 94% of cases were accurately classified in real-time, leading to appropriate therapy. The evaluation of concordance provides a measure of quality assurance of the telepathology program, confidence in diagnoses for involvement in interventional trials, and useful data for understanding the epidemiology of LPDs in Malawi."}
+{"text": "Osteoporosis is common amongst elderly patient populations and is associated with significant morbidity and mortality. We aimed to assess whether national clinical guidelines regarding the identification, assessment and management of osteoporosis and fragility fracture risk were being adhered to on a female later life psychiatry ward. We then aimed to improve the detection and treatment of osteoporosis amongst this patient cohort and subsequently conducted a re-audit of adherence to relevant clinical guidelines.In July 2021, the electronic health records of the 20 most recently discharged patients from a female later life psychiatry ward were reviewed. The proportion of patients who appropriately received FRAX screening, DEXA scanning and pharmacological management of osteoporosis and fragility fracture risk was recorded. The results were compared to standards identified in national clinical guidelines from the National Institute for Health and Care Excellence (NICE) and the National Osteoporosis Guideline Group (NOGG). In addition, the proportion of patients who had FRAX scores communicated to their general practitioners on discharge was recorded. Recommendations were made based on audit findings, and several changes to ward processes were implemented including incorporating fracture risk scoring in a structured ward round template and displaying information posters about osteoporosis in clinical areas. A re-audit was completed in February 2022 using the same methodology as baseline to re-assess adherence to the audit standards.All included patients were female and aged >65 years, and therefore eligible for consideration of fragility fracture risk according to NICE guidelines. 88% (15/17 patients) of those without pre-existing osteoporosis had FRAX scores calculated during their admission on re-audit compared to 50% (8/16 patients) at baseline. 73% (11/15 patients) had FRAX scores communicated to their GP on discharge at completion of the audit cycle compared to 25% (2/8 patients) at baseline. At completion of the audit cycle 10% (1/10 patients) with intermediate fragility fracture risk received measurement of bone mineral density during admission while 30% (3/10) had this recommended to their GP on discharge. None of the high-risk patients (n = 4) were started on bisphosphonate therapy.On completion of the audit cycle, we found excellent compliance with national guidelines regarding the identification of osteoporosis and fragility fracture risk, which demonstrates the feasibility of considering this aspect of physical health in the setting of a later-life psychiatry ward. Areas for improvement include the assessment and management of patients identified as having intermediate or high risk of osteoporosis and fragility fractures."}
+{"text": "We used canonical correlation (n=424) to examine the relationships between a set of physical function measures  time, stair climb time and stair climb power) and a set of cognitive measures (Trail Making Test B (sec), Digit Symbol Substitution Test (DSST), the Montreal Cognitive Assessment, and California Verbal Learning Test). Canonical correlation derives synthetic variables comprised of linear combinations within each set of variables  that maximize the correlations between synthetic variables. The FSST was most strongly correlated with the cognitive synthetic variable (- 0.42). The DSST score was the cognitive measure most strongly correlated with the physical synthetic variable (0.48). It is notable that only the timed cognitive and physical tests are inter-associated"}
+{"text": "The rural areas of southwestern Indiana are challenged with insufficient healthcare workers in the long-term care industry. The University of Southern Indiana (USI) Geriatric Workforce Enhancement Program (GWEP) is collaborating with state agencies to address shortages in licensed administrators, activity professionals and social service designees. These roles, vital in the nursing facility, hold educational requirements through the Indiana State Department of Health (ISDH) and the Indiana Professional Licensing Agency (IPLA). USI gerontology faculty addressed workforce challenges in five phases: 1) Evaluation of state educational requirement and comparison to current USI gerontology courses; 2) Development of new coursework to support state requirements; 3) Expansion of preceptor pool; 4) Proposal to state agencies; 5) USI curriculum modifications. Faculty evaluated the educational and training requirements for these roles and compared the requirements with current courses. Preceptors were needed for students\u2019 field experiences; a preceptor pool was developed through funded training. The requirements and course alignment were included in the program proposal to the state agencies. Upon ISDH, IPLA and University New Program Development Committee approval, additional instructors were recruited. Results of this initiative include a: 1) Fully approved and launched Administrator-in-Training (AIT) residency embedded in curriculum at undergraduate and graduate level; 2) Fully approved Activity Professional Certificate Program; 3) Pool of 10 certified preceptors; and 4) Onset of the social service designee certificate program. This collaborative partnership developed between USI, ISDH and IPLA ensure state agency requirements are met academically for students entering the long-term care workforce."}
+{"text": "Scientific Reports 10.1038/s41598-021-86979-5, published online 01 April 2021Correction to: The original version of this Article contained an error. In the Materials and methods section, under the subheading \u2018Study design\u2019, the approval number of the Ethics Committee was incorrect.As a result,\u201cThe study was conducted with the approval of the Ethics Committee of Nagoya University Hospital and enrolled in the jRCT (CRB4180004).\u201dnow reads:\u201cThe study was conducted with the approval of the Ethics Committee of Nagoya University Hospital .\u201dThe original Article has been corrected."}
+{"text": "Photobacterium damselae subsp. piscicida (Pdp) causes photobacteriosis in fish and important financial losses in aquaculture, but knowledge of its virulence factors is still scarce. We here demonstrate that an unstable plasmid (pPHDPT3) that encodes a type III secretion system (T3SS) is highly prevalent in Pdp strains from different geographical origins and fish host species. We found that pPHDPT3 undergoes curing upon in vitro cultivation, and this instability constitutes a generalized feature of pPHDPT3-like plasmids in Pdp strains. pPHDPT3 markers were detected in tissues of naturally-infected moribund fish and in the Pdp colonies grown directly from the fish tissues but were undetectable in a fraction of the colonies produced upon the first passage of the primeval colonies on agar plates. Notably, cured strains exhibited a marked reduction in virulence for fish, demonstrating that pPHDPT3 is a major virulence factor of Pdp. The attempts to stabilize pPHDPT3 by insertion of antibiotic resistance markers by allelic exchange caused an even greater reduction in virulence. We hypothesize that the existence of a high pressure to shed pPHDPT3 plasmid in vitro caused the selection of clones with off-target mutations and gene rearrangements during the process of genetic modification. Collectively, these results show that pPHDPT3 constitutes a novel, hitherto unreported virulence factor of Pdp that shows a high instability in vitro and warn that the picture of Pdp virulence genes has been historically underestimated, since the loss of the T3SS and other plasmid-borne genes may have occurred systematically in laboratories for decades.The marine bacterium  Photobacterium damselae subsp. piscicida (hereafter dubbed Pdp), a bacterium of the family Vibrionaceae, was first isolated in 1963 from natural populations of white perch (Morone americana) and striped bass (Morone saxatilis) affected by an unknown bacterium in the Chesapeake Bay  ) were used. TSA-1 plates supplemented with Cm5 + Kan50 and sucrose (15% [wt/vol]) were used to select double mutant colonies containing the kan gene plus the cat gene.The coding sequence of each of the two rivative . Two fra plasmid  was inse plasmid . The catPdp. The high in vitro instability of pPHDPT3-like plasmids warns that the picture of Pdp virulence genes has been historically biased and underestimated. The realization of the prevalence of plasmids encoding the T3SS and additional genes in Pdp will surely change our view of this pathogen from now on.This study provides evidence that pPHDPT3 plasmid constitutes a novel, hitherto unreported virulence factor of"}
+{"text": "Describe the progress of developing and monitoring global physical activity policy from the 1990s through the release and implementation of Global Action Plan for Physical Activity-GAPPA;Present findings of a systematic review of instruments for physical activity policy analysis;Describe the methods and progress after 1-year implementation of the Global Observatory for Physical Activity-GoPA! physical activity policy inventory;Present the preliminary findings and lessons learned after 1-year implementation of the Global Observatory for Physical Activity-GoPA! physical activity policy inventory.Physical inactivity is one of the most important factors contributing to global morbidity and mortality, but despite both importance and the recent launch of a WHO action plan, public health policy around physical activity remains poorly developed and monitored.Description of the problemPhysical inactivity accounts for as many as 5 million deaths per year globally but has yet to be addressed effectively by most governments or the World Health Organization(WHO). Many efforts led by WHO, national governments, networks, and academics from the 1990s to the present have tried to turn physical activity into a public health priority. Since its launch in 2015, the Global Observatory for Physical Activity-GoPA! has monitored the progress of national physical activity surveillance, policy and research. The GoPA! Policy Inventory created in 2017, contributes to physical activity policy monitoring and aims to collect data worldwide.In this symposium we will address several key questions about physical activity policy by examining different initiatives such as GAPPA and the experience of monitoring policy globally with the GoPA! policy inventory. We will examine whether it is feasible to track physical activity policy at the global and country levels, if the existence of ?good? physical activity policy is associated with less physical inactivity and how policy indicators may be used for advocacy and guidance in the coming years.Findings show that PA policy monitoring has and still varies substantially by geographic area and country income group. Effectiveness and implementation of PA policies remains challenging worldwide. PA policy indicators can enhance understanding of the links between policy and population levels of PA.GoPA! is committed to continue improving PA policy monitoring for informing and encouraging policy to address physical inactivity worldwide.Agenda and PresentersIntroduction: Michael Pratt (10-minutes)Talk 1: Developing and monitoring physical activity policy: 1990 to today \u2013 Michael Pratt (15-minutes)Talk 2: Instruments for the analysis of national-level physical activity and sedentary behaviour policies: a systematic review \u2013 \u017deljko Pedi\u0161i\u0107 (15-minutes)Talk 3: The GoPA! Policy Inventory: Progress and methods - Andrea Ramirez (15-minutes)Talk 4: The GoPA! Policy Inventory: preliminary findings and lessons learned \u2013 \u017deljko Pedi\u0161i\u0107 (15-minutes)Q&A from the audienceConclusion by discussant Adrian Bauman (20-minutes)"}
+{"text": "Group Name: Working Group on Neonatal Infectious Diseases of the Section of Neonatology of the Dutch Paediatric SocietyBackground: Central-line\u2013associated bloodstream infections (CLABSIs) are a main focus of infection prevention and control initiatives in neonatal care. Standardized surveillance of neonatal CLABSI enables intra- and interfacility comparisons, which can contribute to quality improvement. To date, there is no national registration system for CLABSI in neonatal care in the Netherlands. Across neonatal intensive care units (NICUs), several different sets of CLABSI criteria and surveillance methods are used for local monitoring of CLABSI incidence rates. To achieve standardized CLABSI surveillance, we conducted a consensus procedure with regard to nationwide neonatal CLABSI surveillance criteria. Method: A modified Delphi consensus procedure for the development of nationwide neonatal CLABSI surveillance criteria was performed between January 2016 and January 2017 in the Netherlands. An expert panel was formed by members of the Working Group on Neonatal Infectious Diseases of the Section of Neonatology of the Dutch Paediatric Society. The consensus procedure consisted of 3 expert panel rounds. Figure Result: The expert panel achieved consensus on Dutch neonatal CLABSI surveillance criteria, which are summarized in Figure 2. Neonatal CLABSI is defined as a bloodstream infection occurring >72 hours after birth, associated with an indwelling central venous or arterial line and laboratory confirmed by 1 or more blood cultures. In addition, the blood culture finding should not be related to an infection at another site and one of the following criteria can be applied: (1) a bacterial or fungal pathogen is identified from 1 or more blood cultures; (2) the patient has clinical symptoms of sepsis and (2A) a common commensal is identified in 2 separate blood cultures or (2B) a common commensal is identified by 1 blood culture and C-reactive protein (CRP) level is >10 mg/L in the first 36 hours following blood culture collection. Conclusion: The newly developed Dutch neonatal CLABSI surveillance criteria are concise, are specific to the neonatal population, and comply with a single blood-culture policy in actual neonatal clinical practice. International agreement upon neonatal CLABSI surveillance criteria is needed to identify best practices for infection prevention and control.Funding: NoDisclosures: None"}
+{"text": "The AgingME Geriatrics Workforce Enhancement Program (AgingME GWEP), a statewide collaboration led by the University of New England and the University of Maine, is guided by an annual statewide survey of community and professional stakeholders. The aim of this research is to identify training and resource gaps related to age-friendly healthcare and topics of interest. Of the 245 survey respondents, 15% indicated existing knowledge of the 4Ms framework. The top sources of 4M\u2019s framework exposure included trainings or webinars (30%) and web-based resources (19%). Of those with knowledge of the 4M\u2019s, 33% of providers and 29% of older adults/community members reported employing the 4Ms in their professional practices and personal lives, respectively. Respondents also noted the need for more training on how to use technology to locate healthcare information (33%), using technology to reduce isolation and loneliness among older adults (29%), and keeping providers connected with older patients (26%). Additional write-in responses (11%) suggest a need for general technology training and improving access to technology overall. Respondents' (N = 157) top five categories for needed aging-related training topics were community resources for older adults (15%), aging-in-place (14%), exercise and nutrition (11%), improving provider/patient communication (9%), and 4M\u2019s of age-friendly healthcare overview (8%). Responses also identified themes related to improving patient/provider communications, availability of resources, and ageism that could be addressed through upcoming GWEP activities. Results indicate a need to facilitate the translation of 4Ms knowledge into practice and increasing technology training and access."}
+{"text": "Pandemic is accompanied by \u201cinfodemic\u201d that is related to higher anxiety . We suggest that indefinite and stressful situation of pandemic provoke magical thinking leading to lower adherence with recommendations for self-isolation.The aim was to reveal the structure of beliefs about reasons, manifestation and consequences of coronavirus and their relationship with magical thinking, anxiety and COVID-19-related behaviour.In April 2020 (2-3 weeks of self-isolation regimen) 402 adults aged 18-64 years old filled checklist including beliefs about pandemic , Magical Ideation Scale Eckblad, Chapman, 1983) as well as scales measuring anxiety and protective behaviour in pandemic and monitoring of information about coronavirus .Factor analysis revealed three groups of radical beliefs about coronavirus . Belief about the particular meaning of coronavirus was associated with the magical thinking (r=.21), less anxiety about infection (r=-.19) and poorer adherence to self-isolation (r=-.26). Belief in the negligence as a cause of coronavirus was more typical for those with better adherence (r=.18) while catastrophic beliefs about the consequences of pandemic were related to frequent monitoring of the information about the pandemic (r=.24), and anxiety regarding future negative consequences of the pandemic (r=.46).Dysfunctional beliefs about coronavirus could be a factor of poorer adherence related to magical thinking and could be addressed in psychological interventions. Research is supported by the Russian Foundation for Basic Research, project No. 20-04-60072."}
+{"text": "We tested the following genotype-related mechanisms generating race-dependent disparity in Alzheimer\u2019s Disease (AD) risk: i) the frequencies of SNPs with genotypes associated with AD are higher in the Black subpopulation; ii) the effects on AD risk of genotypes associated with increased AD risk is higher in the Black subpopulation; iii) there is a small group of SNPs with a large difference in the effects on AD race-dependent risk generating disparities; alternatively, the disparities are generated by a collective effect of multiple SNPs with minor or moderate effects. We modified the GWAS algorithm to use it with the Cox regression multivariable model and the outcome accounting for race-related differences in AD risk. Using the modified GWAS we have identified loci in charge for the disparity between Whites and Blacks and used the results along with SNPs of a special interest which were identified from the literature in the Cox multivariable regression model and generalized Oaxaca-Blinder approach. The following genes had the strongest effects on racial disparities: i) NYAP1 neuronal tyrosine-phosphorylated phosphoinositide-3-kinase adaptor; ii) RPA3-UMAD1 loci RPA3 replicates protein A, interacting with gastric tumor and hepatocellular carcinoma; iii) TOMM40 associated with an increased risk of developing late-onset AD; iv) ACE - responsible for making the enzyme which converts angiotensin which regulates blood pressure; v) PSME3IP1 - proteasome activator subunit 3 interacting protein 1; vi) MARCHF1 regulator of glucose-tolerance and lipid storage and vii) LINC01146 which belongs to coagulation cascade pathway and linked to hepatocellular carcinoma."}
+{"text": "Cognitive Stimulation Therapy (CST) is an evidence-based treatment for people living with dementia that is not in widespread use in the United States. To better understand barriers and facilitators to implementation of CST, we conducted virtual focus groups of newly trained facilitators of Cognitive Stimulation Therapy (CST). Of 12 facilitators trained, representing two settings of care (The Program for All-inclusive Care of the Elderly and a Continuing Care Retirement Community), 4 facilitators, representing Social Work n = 2, Speech Therapy n = 1, and Recreation Therapy n = 1, participated. We analyzed interview transcriptions using framework analysis guided by constructs from the Consolidated Framework for Implementation Research (CFIR). Themes that emerged across constructs were 1) balancing competing personal, stakeholder, and organizational needs; 2) lack of mastery experiences and the need for opportunities for more practice, reflection, and feedback from trainers; 3) building a community of facilitators to provide peer support; 4) logistical concerns; and 5) identifying appropriate participants who would most benefit from CST. The barriers to implementation imposed by the ongoing COVID-19 pandemic were also a cross-cutting theme. Many of these barriers are readily managed, and professionals who implement CST in their sites should be aware of and take into consideration these barriers and facilitators."}
+{"text": "Pharmacists play an important role in infection control and antimicrobial stewardship teams in hospitals and the community. The need for education on antimicrobial resistance (AMR) and clinical infectious diseases (CID) is increasing. However, the status of Japanese pharmaceutical education on CID and AMR is unclear.We conducted a nationwide cross-sectional survey of pharmaceutical department in Japanese universities between February and March 2022. Data on the following were collected using questionnaires: 1) basic information; 2) number of faculty members with experience in CID; 3) lecture times for CID and AMR; 4) self-evaluation of CID and AMR education; and 5) the most important issues in CID and AMR education. Descriptive analyses were conducted.Among the 74 participating universities, 44 (59.5%) universities responded. The median number [IQR] of faculties of infectious disease education was 7 [4\u201312], and clinical faculties was 3 [1\u20136]. Twenty-seven (62.8%) of the universities had faculties with clinical experience in infectious diseases. Lectures time for CID and AMR varied among the universities.Respondents indicated that CID and AMR lectures were insufficient, compared to microbiology basic lectures. Additionally, insufficient lecture time and specialists were the most common responses as the most important issues in CID and AMR education.University background and questions regarding CID and AMR lectures (N=44)Boxplot of lectures time for clinical infectious disease and antimicrobial resistance educationSelf-evaluation of clinical infectious disease and antimicrobial resistance educationThis study revealed that educational status and resources for CID and AMR education varied widely, and that practical lectures on CID and AMR may be insufficient. We suggest that the entire core curriculum and resources, including the number of faculties, needs to be examined and improved.The most important issues in clinical infectious disease and antimicrobial resistance education.All Authors: No reported disclosures."}
+{"text": "Our previous systematic review on the health benefits of different sport disciplines included 69 studies published before 2013. We found moderately strong evidence of health benefits for running and football while the evidence for other sport disciplines was either inconclusive or tenuous. The purpose of this report is to update the evidence base on published studies through 2013-2019.A systematic literature search of observational and experimental studies on the association between the participation in sport and health outcomes was conducted through electronic databases: MEDLINE via PubMed, Scopus, and Web of Science. The inclusion criteria were: participants heathy adults; type of studies cross-sectional, cohort or intervention designs; study group participation in specific sport disciplines; non-participation comparison group; health-related outcome variables in terms of mortality, morbidity, disease risk factors and function. Studies on sport injuries were excluded.A total of 3909 titles and abstracts of studies published between 2013-2019 were identified for potential inclusion. The study selection process yielded 30 studies for further assessment. These studies included 26 different sport disciplines with 54 sport vs. no sport comparisons. The most prevalent sports were cycling (10 studies) and running (8 studies). Together with the previous systematic review the combined data includes 99 studies, 40 sport disciplines and 159 sport vs. no sport comparisons. Significant health benefits were found for a range of sport disciplinesThe updated systematic review provides new relevant data for an extended analysis of the health benefits of different sport disciplines and strengthens the existing evidence base for the promotion of health through participation in sports."}
+{"text": "Nature Communications 10.1038/s41467-022-34321-6, published online 04 November 2022Correction to: The original version of this Article contained an error in the caption of Figure 3a, which incorrectly read \u2018showing ratios of rapid intensification (RI) cases satisfying the critical environmental thresholds divided by entire samples satisfying thresholds (blue histograms) and the analogous ratios for cases where the critical thresholds are not met (red histograms)\u2019. The correct version replaces sentence with \u2018showing the probability of rapid intensification (RI) for cases satisfying the critical environmental thresholds (blue histograms) and the probability of RI for cases where the critical thresholds are not met (red histograms)\u2019. This has been corrected in both the PDF and HTML versions of the Article."}
+{"text": "ALS Forum  is an online support group for those who have motor neuron disease or amyotrophic lateral sclerosis (ALS). It provides information, advice, connection, care, and assistance to persons living with ALS and their family caregivers. This study aimed to analyze the online discussion posts by caregivers of persons with ALS and assess their perceptions, experiences, and challenges of using assistive technologies (AT). Posts were extracted from the ALS caregiver discussion forum via web scraping using Python in March 2022. The extracted posts are dated between June 2005 and January 2022. The total number of posts and replies generated during this period was 52,292 by 2,397 unique users. Additional searches were conducted using assistive technology-related keywords to create the text dataset. A total of 263 posts by 137 unique users were identified. After the initial review, 186 posts were included in the final analysis. Thematic analysis revealed six major themes: (1) Uses of AT ; 2) Barriers and Facilitators ; 3) Usability (hardware and software-related); 4) Sharing Experience on AT; 5) Giving Advice; 6) Seeking Information on AT. The findings are consistent with previous literature that online health discussion forums provide access to rich data that contains lived experiences of patients and caregivers. The findings may inform the design of future assistive technology that incorporates the patients\u2019 and caregivers\u2019 perspectives to increase the adoption and long-term sustainability of the technology for people living with ALS and their caregivers."}
+{"text": "A 54-year-old man presented with cough and 3-month history of pain in bilateral knees and fingers. Physical examination revealed digital clubbing  and b an(1). 95%-97% of the cases are caused by underlying conditions; the most common being non-small cell lung carcinoma (2). Screening for underlying conditions, particularly lung cancer, should be performed after hypertrophic osteoarthropathy diagnosis.Hypertrophic osteoarthropathy is characterized by digital clubbing accompanied by arthralgia and periostosis and typically involving the tibia and fibula NoneHK wrote the manuscript, and AO and KS critically revised the manuscript for the intellectual content. All authors have read and approved the final manuscript.Written informed consent was obtained from the patient.Ethical approval was waived by the Ethics Committee of Tokyo Metropolitan Bokutoh Hospital."}
+{"text": "Previous research has established the role of lifelong learning in promoting psychological wellbeing and active aging. Population aging necessitates an understanding of the unique opportunities and challenges around formal and informal learning in later life. This paper will share findings from a mixed methods study with the MIT AgeLab 85+ Lifestyle Leaders, a panel comprised of octogenarians and nonagenarians from across the United States. Drawing on an online survey and virtual focus groups with 29 Lifestyle Leaders from January 2021, findings suggest the Lifestyle Leaders most often learned new things from talking with others (46%) and reading print (54%) or online (54%) sources. The majority were familiar with attending in-person lectures or classes (89.7%) and were now using videoconferencing to do these (78.6%). A majority (56.7%) had or are currently participating in a lifelong learning program. Most consider themselves lifelong learners and described this around remaining curious and engaged with life, choices around what one learns, and greater enjoyment of learning. In the survey, a plurality of Lifestyle Leaders indicated the top two challenges affecting their ability to learn were sensory burdens  (35%) and their energy level (32.4%); focus group data revealed that recall also is a barrier. Focus group data further highlighted generational experiences around early life learning and career paths, specifically how gender roles, diagnoses of learning disabilities, and evolving digital technology have affected these and changed over the course of their lifetimes."}
+{"text": "People with schizophrenia have a life expectancy that is 10\u201320 years shorter than the general population. The high incidence of metabolic syndrome, cardiovascular disease and diabetes mellitus in this patient group are thought to be major \u2013 and potentially modifiable \u2013 factors contributing to this premature mortality. Therefore, annual monitoring of physical health parameters is recommended by organisations including the Scottish Intercollegiate Guidelines Network (SIGN). The SIGN guideline on schizophrenia advises that the following parameters are checked annually for patients with schizophrenia who are on anti-psychotics: ECG, blood glucose, lipid profile, prolactin, BMI/weight, smoking status and blood pressure. Traditionally, this monitoring is overseen in the community by general practitioners. This audit aimed to capture how the COVID-19 pandemic impacted on the annual physical health monitoring of patients under the care of NHS Borders Community Rehabilitation Team.A retrospective audit was performed by reviewing notes of the 100 patients on the NHS Borders Community Rehabilitation team caseload. Notes from the years of 2019, 2020 and 2021 of all 100 patients on the caseload were reviewed, for documentation of the following seven parameters as recommended by SIGN: ECG, blood glucose, lipid profile, prolactin, BMI/weight, smoking status and blood pressure. Results were then entered manually into a secure spreadsheet. Permission for this audit was granted by NHS Borders.Initial results for the parameters of: ECG, blood glucose, lipid profile and prolactin levels demonstrate that routine monitoring of all four domains has decreased since the start of the COVID-19 pandemic. In 2019 the following numbers of patients had monitoring in these domains: ECG 56 (56%); blood glucose 84 (84%); lipid profile 74 (74%) and prolactin levels 62 (62%).During 2020, the number of patients having monitoring in all four domains fell: ECG 31 (31%); blood glucose (72%); lipid profile 64 (64%) and prolactin levels 48 (48%). During 2021, monitoring levels remained low: ECG 30 (30%); blood glucose 71 (71%); lipid profile 62 (62%) and prolactin levels 43 (43%).Data collection for the parameters of blood pressure, BMI/weight and smoking status is ongoing.Initial results indicate that the COVID-19 pandemic has negatively impacted on the routine physical health monitoring of patients under the care of the community rehabilitation team in NHS Borders. These results imply opportunities to treat and prevent conditions such as diabetes mellitus and hypercholesterolemia are being missed, further perpetuating an existing health inequality for patients with severe and enduring mental illness."}
+{"text": "Inflammatory bowel disease (IBD) advanced training programs in Canada are heterogenous in their education, structure, and case exposure, resulting in differences in trainee experience. While competency based medical education (CBME) is becoming the primary educational framework in residency training, there is no CBME-based curriculum for IBD advanced training programs. Adopting a CBME framework for IBD fellowships may help standardize training to increase competence.The purpose of this study was to develop a CBME-based curriculum for IBD advanced training programs in Canada.Strategic groups consisting of 25 IBD experts were assigned to develop 15 entrustable professional activities (EPAs), which were then refined by experts in medical education and curriculum development. Acceptable EPAs were assessed using an electronically administered round-less Delphi panel. Panel members evaluated each EPA using a Likert scale, which asked participants to consider appropriateness of each EPA for an advanced IBD curriculum. A consensus strength greater than 70% was the acceptable threshold for inclusion into the final curriculum. Milestones were modelled after CanMED roles for each EPA.Of the 15 initial EPAs, nine were recommended for the roundless Delphi panel by the selection committee: (1) identification, diagnosis, and treatment of new onset IBD; (2) assessment and treatment of outpatients with IBD; (3) the endoscopic evaluation of disease activity and the effective communication of endoscopic findings for patients with IBD; (4) provide effective inpatient management and coordinate transition to outpatient care for patients with IBD; (5) recognize and institute preventive health maintenance strategies in patients with IBD; (6) management and treatment of special populations with IBD; (7) identification, diagnosis, and treatment of the various extraintestinal manifestations of IBD; (8) Engage health care systems to improve the quality of care for patients with IBD; (9) engage in scholarly activities related to IBD. Eight of the nine EPAs achieved a consensus score greater than 70%, with the EPA, \u2018engage in scholarly activities related to IBD\u2019 failing to meet this cut-off. Associated milestones were developed for the eight final EPAs.This study was the first attempt to develop a CBME-based IBD curriculum in Canada. With proper funding and guidance, we hope our model can be implemented across Canada in IBD advanced training programs. These methods may also help facilitate the development of CBME curricula for other advanced training programs.NoneNone Declared"}
+{"text": "Mediterranean ports are sources of significant economic activity and at the same time they act as recipients of considerable anthropogenic disturbance and pollution. Polluted and low-in-oxygen sediments can negatively impact benthic biodiversity and favour recruitment of opportunistic or invasive species. Macrobenthic communities are an important component of the port biota and can be used as environmental quality indicators. However, a baseline database for benthic biodiversity in Mediterranean ports has not yet been widely established.Mollusca were the most abundant group (34%) in all ports. The highest percentage of opportunistic taxa per station was found before the touristic period in the shipyard of Heraklion port (89.3%).Macrobenthic assemblages were recorded in three Mediterranean touristic ports under the framework of the ENPI CBC MED project MAPMED (MAnagement of Port Areas in the MEDiterranean Sea Basin). Samples were collected from Cagliari , Heraklion  and El Kantaoui (Tunisia) ports during February, May and September 2012. The sampling stations were selected according to the different sectors within each port . A total of 277 taxa belonging to 12 phyla were found, of which the 96 taxa were present in all three ports. El Kantaoui port hosted the highest number of macrobenthic taxa.  Mediterranean ports are sources of significant economic activity and they strongly support local, regional and national economic development. The Mediterranean Sea hosts about 480 ports and terminals and is one of the busiest maritime areas of the world . ShippinThis dataset includes macrobenthic taxa identified in three touristic ports in the Mediterranean, located at Cagliari , Heraklion  and El Kantaoui (Tunisia) . SamplinMAPMED: MAnagement of Port areas in the MEDiterranean sea basinDr Eva Chatzinikolaou , Dr Panagiotis Damianidis (taxonomic identification), Dr Christina Pavloudi (taxonomic identification), Dr Katerina Vasileiadou (taxonomic identification), Dr Sarah Faulwetter (taxonomic identification), Kleoniki Keklikoglou (taxonomic identification), Wanda Plaiti (taxonomic identification), Dimitra Mavraki (data management), Stamatina Nikolopoulou (data management) and Dr Christos Arvanitidis .Mediterranean touristic ports: Cagliari , Heraklion  and El Kantaoui (Tunisia).During this study, differences in macrobenthic assemblages were examined across three levels: a) geographical differences (three countries), b) use-sectoral differences (3-5 stations within ports) and c) temporal differences (three seasons in relation to the touristic period).This project has been financed by the European Union under the ENPI CBC Mediterranean Sea Basin Programme in the framework of the project \u201cMAnagement of Port areas in the MEDiterranean Sea Basin\u201d (MAPMED) (Grand Contract 6/2019-25/ 7/2011). This publication has been supported by the LifeWatchGreece infrastructure (MIS 384676), funded by the Greek Government under the General Secretariat of Research and Technology (GSRT), ESFRI Projects, National Strategic Reference Framework (NSRF) and from LifeWatch ERIC.Five replicates of sediment samples were collected from each station using a box corer (13.5 cm \u00d7 13.5 cm \u00d7 16 cm) manually operated from a small boat. A Garmin 60 CS portable GPS and a depth meter were available on board to record the exact position and depth of each station respectively. The sediment samples were sieved through a 0.5 mm sieve and then fixed and preserved in 5% formaldehyde buffered with seawater and stained with Rose Bengal. The benthic organisms were sorted out of the sediment under a stereoscope, counted and identified down to the lowest possible taxonomic level.http://www.marinespecies.org/aphia.php?p=match) on 10-03-2021.All scientific names were standardised against the World Register of Marine Species using the Taxon Match tool (2) located on the southern coast of Sardinia . The port of Heraklion  and it is located on the northern coast of Crete (Greece). The port of El Kantaoui  on the eastern Tunisian coast. Both the ports of Heraklion and Cagliari host a leisure marina, large passenger, cruise and cargo vessels, while El Kantaoui port offers moorings only for smaller fishing boats, luxury yachts and boats for sporting activities. Heraklion port has also a shipyard section.Three Mediterranean touristic ports were selected as study sites and they are presented in Fig. ion Fig. C is medioui Fig. D is a smSampling stations were selected in order to achieve good spatial coverage in each port and also to represent sectors with different uses according to the Water Management Units in MAPMED Action Plans MAPMED 2015). Four stations were selected in the port of Heraklion, five stations in the port of Cagliari and three stations in the port of El Kantaoui , Annelida (28.2%) and Arthropoda (24.2%) were also highly represented, while each of the remaining groups contributed less than 5% in the benthic assemblages studied  was calculated for each station as the percentage of abundances for eta taxa  in the teta taxa . The higAdditional statistical analysis has been applied to the species composition matrices of the specific dataset by Data range: 2012-2-13 \u2013 2012-9-25.Three seasonal sampling campaigns were carried out during 2012: one in winter (February), one in spring before the beginning of the touristic season (May) and one in late summer after the touristic season (September).Benthic communities and environmental parameters in three Mediterranean ports .5% formaldehyde buffered with seawater.Hellenic Centre for Marine Research (HCMR), Institute of Marine Biology, Biotechnology and Aquaculture (IMBBC), Heraklion, Crete, Greece.Open Data Commons Attribution LicenseCreative Commons Attribution (CC-BY) 4.0 License. All data in the database can be freely used provided it is fully cited even if only partially used.This work is licensed under a Benthic communities and environmental parameters in three Mediterranean ports .https://www.gbif.org/dataset/9b11f305-fb7a-4a65-826e-7fb97af06e5fhttp://ipt.medobis.eu/resource?r=mapmed_ports1Benthic communities and environmental parameters in three Mediterranean ports .Darwin Core Archive.UTF-8http://ipt.medobis.eu/resource?r=mapmed_portsMedOBIS (Mediterranean node of Ocean Biodiversity Information System),Integrated Publishing Toolkit (IPT) which has been established through the LifeWatchGreece Research Infrastructure and is hosted in the Institute of Marine Biology, Biotechnology and Aquaculture (IMBBC) of the Hellenic Centre for Marine Research (HCMR). The data are also harvested by and made available through the Ocean Biodiversity Information System (OBIS).The dataset is available as a DarwinCoreArchive and all fields are mapped to DarwinCore terms.The dataset is available via the This publication refers to the most recent version of the dataset available through the IPT server or MedOBIS. Future changes to the dataset due to quality control activities might change its content or structure.The current publication refers to the \"occurrence\" source file (txt file) that is associated with the particular dataset. Additional details about the sampling events can be found in the \"event\" source file (txt file) associated with the same dataset."}
+{"text": "The current coronavirus pandemic (Covid-19) is posing new critical challenges on mental health due to widespread social alarm as well as long lasting \u201cphysical distancing\u201d as a result of public health protection measures or voluntary conduct. In a period of uncertainty, certain rewarding behaviors, such as the use of the Internet, exercise among other coping strategies might have increased considerably. We will share the results of an international cross-sectional investigation on the impact of physical-distancing on such potentially addictive behaviours to mitigate the pandemic effects, while identifying the most risky patterns and vulnerable populations. The studied sample consists of 3161 participants from Italy (41%), Spain (16%), the UK (12%), Lithuania (12%), Portugal (11%), Japan (6%), and Hungary (4%). Results are currently being analysied.No significant relationships."}
+{"text": "Depressive symptoms affect the physical and cognitive health of approximately 20% of older adults. These symptoms have strong, bidirectional ties with physical activity levels and mobility disability. Physical activity has a positive impact on mood and depression and is highly recommended for symptom management across all ages. However, it\u2019s unclear whether elevated depressive symptoms interfere with potential benefits that physical activity has on other health outcomes like mobility loss. The Lifestyle Interventions and Independence for Elders (LIFE) Study randomized over 1,500 older adults (aged 70+) to either a physical activity (intervention) or successful aging (control) program with an average of 2.2 years of follow-up. Our analysis used Cox proportional hazards models to evaluate whether elevated depressive symptoms -11 scale with a cutoff score of 16/22 points) moderated the relationship between intervention status and the primary outcome . In a secondary analysis of 1,534 older adults , we confirmed significant main effects of both the physical activity intervention and elevated depressive symptoms on incident major mobility disability but found no evidence of moderation . Results indicate that the benefits of the intervention were comparable between those with and without significant depressive symptoms at baseline, supporting the inclusion of individuals with depression in clinical trials. In addition to potential symptom relief, promoting physical activity in older adults with depression is important for protecting against mobility loss."}
+{"text": "Persons Living with HIV (PLWH) with chronic kidney disease progress to end-stage renal disease (ESRD) at a faster rate than HIV-negative individuals. Unfortunately, there is increasing data to suggest that PLWH are less likely to be waitlisted. We reviewed the transplant care continuum among PLWH at the Medical University of South Carolina (MUSC).st, 2012 and December 31st, 2021. Cases were included if a PLWH and ESRD had not died before being referred for kidney transplant, had evidence of pursuit of kidney transplant, and sufficient data of their transplant process were available in the medical record system. Descriptive statistics were used to analyze demographic and clinical characteristics as well as the transplant care continuum of PLWH and ESRD at MUSC.This was a retrospective review of PLWH and ESRD who either received care at MUSC Health Care System or were referred for Kidney transplant at MUSC between May 157 PLWH and ESRD were included in the analysis. Of these, 45 (79%) were referred for kidney transplant (Table\u00a01). The median age at the time of referral was 52 (range 26 - 78), 33 (73%) were males and 42 (93%) were of the Black race. The most common causes of ESRD were Multifactorial (36%), HIV-Associated Nephropathy (24%) and unknown (16%). Almost all patients had hypertension (96%) and 29% of patients had diabetes. Additionally, prevalent comorbidities include psychiatric conditions (53%), history of substance use (43%) and history of tobacco use (36%). Of those referred for kidney transplantation, 32 (71%) started a transplant evaluation, 24 (53%) completed the transplant evaluation, 22 (49%) were waitlisted, and 13 (29%) were transplanted. Common reasons why patients did not complete transplant evaluation included not meeting HIV criteria for transplant (9%), having too many comorbidities (9%), and not completing testing (9%).Clinical Characteristics of the 45 HIV Patients with ESRD Who Were Referred to Kidney Transplant at MUSCClinical Data on Transplant Care Continuum, n = 45The majority of PLWH with ESRD seen at MUSC were referred for kidney transplant and started the evaluation process. More is needed, though, to assist patients in completing the transplant evaluation process and making it to the transplant waitlist, with the ultimate goal of transplantation.All Authors: No reported disclosures."}
+{"text": "Psoriazis and major depressive disorder (MDD) have a high degree of overlap, and inflammatory citokines like tumor necrosis factor alpha, interleukins 1, 2, 6 and 10, and C-reactive protein have been involved in their common pathogenesis. The prevalence of MDD in patients with psoriazis has been reported to range between 28% to 67%.To monitor the core symptoms evolution in patients diagnosed with psoriazis and MDD during antidepressant treatment.Four patients diagnosed with psoriazis and MDD (according to the DSM-5 criteria) were monitored during 6 months using Physician Static Global Assessment (PSGA), Hamilton Depression Rating Scale (HDRS)-17 items, and Global Assessment of Functioning (GAF). All patients underwent specific psoriazis and antidepressant treatment .All patients significantly improved their depressive symptoms during sertraline or escitalopram treatment , while their global functioning increased . The PSGA score decreased and reached a level of signifiance at week 24 . The duration of active periods of psoriazis was less longer during the 6 months of monitoring than in the 6 months previous to the antidepressant initiation . No treatment discontinuation due to low tolerability was reported.Antidepressant treatment with selective serotonin reuptake inhibitors is efficient and well tolerated in patients with MDD and psoriazis. The duration of active symptoms of psoriazis tends to be less longer than previous to the antidepressant initiation."}
+{"text": "Byssinosis is a disabling occupational lung disease caused by cotton dust. It is a well-known occupational respiratory disease in cotton industry workers caused by cotton dust pollution. Many studies have been documented the effects of cotton dust onpulmonary function among workers employed in cotton-spinning mills. However, little data exist on the prevalence of this disorder in female workers particularly in western part of India. The present study was conducted to analyze the effects of exposureto cotton dust on pulmonary functions among female workers. The study was designed to assess the effects of exposure to cotton dust on lung functions among female cotton industry workers. Study group comprises 50 Female workers of cotton industry andcontrol group comprises 50 age matched females who were neither worked in cotton industry nor exposed to cotton dust. Information was collected using standardized questionnaires, physical examination and spirometric measurements. Student's T test was usedto find the difference between spirometric parameters. All the respiratory parameters  were reduced in cotton industry workers as compared with control subjects (p<0.0001) and no significant differenceof SpO2 between groups. Cotton dust exposure makes huge impact on respiratory parameters of the cotton industry workers. This deterioration in respiratory health deteriorates with increasing duration of exposure. The health hazards caused by cotton dust shouldbe controlled by creating awareness among the workers & employers. Byssinosis is a crippling occupational lung disease caused by cotton dust. It is a well known occupational respiratory disease among cotton mill workers induced by cotton dust pollution. Byssinosis also called Brown Lung or Brown Lung disease is a typeof Pneumoconiosis caused by dust from cotton fibers. Inhaled dust stimulates histamine release which causes constriction of the air passages, making breathing difficult over time. Inhalation of the dust particles depends on its aerodynamic diameter, surroundingair's velocity, and breathing rate of the person. The inhaled fine cotton dust particles would get sedimented in the gas-exchange part of the lung tissue, where air flow is slow. These fine particles get lodged in the respiratory bronchioles within the centralpart of the acinus. The duration of exposure to cotton dust, type of dust, concentration of dust and the size of dust particle influence the effect on lungs . The preThe present study was conducted in department of physiology, Nootan Medical College & research Centre, Sankalchand Patel University, Visnagar, Mehsana district. This study composed of two groups which contains totally 100 subjects. Group A(Study group) comprises 50 Female workers of cotton industry. The workers were selected from different cotton textile industries of Mehsana district. Group B (control group) comprises 50 age matched females who were neither worked in cotton industrynor exposed to cotton dust. Female subjects of cotton industry, relatives of patients attending various outpatient departments in the age group of 18 - 40 years, who come forward for the study voluntarily and satisfied the inclusion criteria, wererecruited. Subjects on medication for Cardiovascular respiratory illness and Central nervous system (CNS) disorders, subjects with past and present history of CVS disorders, diabetes, psychiatric illness, subjects with history of drug abusing,smoking were excluded.A elaborate clinical history of these volunteers were taken such as relevant past history, family history, drug history, personal history like alcoholism, smoking etc. A structured questionnaire was given to all volunteers (subjects) to obtain the detailsof occupational history and history of past or present respiratory illnesses. The present study was approved by the Institutional ethics committee  and an informed consent was taken from all the subjects after explainingthe test procedures and the goal of the study in local language. The anthropometric measurements such as height, weight, Body mass index (BMI), body surface area (BSA), lean body mass (LBM), Fat % were recorded for each subject by using standard procedure[7 - check with author]. SpO2 (Oxygen saturation) was measured with a digital handheld pulse oximeter  to investigate oxygen saturation (blood oxygen level) in blood. Participants rested at least15 minutes before examination of SpO2. PFT was done with the help of spirometer (RMS Helios 401). The following variables were evaluated for spirometry: FVC (L) , PEF (L/S) (Peak expiratory flow), FEF 25-75% (Forced expiratory flow),FEV1 (L) (Forced expiratory volume in first second of FVC), MVV (Maximum voluntary ventilation), and FEVI/FVC (%). The subjects were briefed about the procedure of conduction of spirometry and demonstration was given before initiation of procedure. The subjectswere instructed to take deep inspiration from outside and then to expire as forcefully and as fast as she can inside the mouthpiece and recorded the activities. Using all aseptic techniques, the pulmonary function tests were conducted on subjects in standingposition and wearing nose clips. Each test was repeated three times and the best results among the three were considered for analysis. Experiments were done in accordance with revised Helsinki Declaration of 2000.Statistical analysis was performed with SPSS  (version 17.0). Results are expressed as mean \u00b1 standard deviation (SD) and assessed using Student's t-test. P-value < 0.05 was considered statistically significant.Table 1(see PDF) describes baseline (anthropometric) characteristics of the subjects. It can be seen that majority of the subjects were adults and all the subjects were females. There was no significant difference between the two groups (control & studygroup) in terms of anthropometric measures. Table 2(see PDF) describes the lung function parameters (Spirometry) of study and control group subjects. All the respiratory parameters  were reduced significantlyin cotton industry workers as compared with control subjects (Group B) (p<0.0001). The mean predicted values of FEV1 and FVC parameters were reported in Table 1(see PDF). Predicted value of FEV1 in study subjects were decreased significantly (p<0.0466),predicted FVC value was also decreased in study group however it was not statistically different (p<0.0802). The prevalence of various respiratory symptoms was shown in Table 2(see PDF) and the most common finding was reported is dyspnea followed by chesttightness & cough (16% & 20% respectively). No such symptoms were noted in control group (Group B). Figure 3(see PDF) shows Mean value of SpO2 (Oxygen saturation) in study and control groups. No significant difference of SpO2 between study and controlgroups (p<0.6612). Table 3(see PDF) shows duration of Cotton dust exposure among cotton industry workers. In the present study majority of the subjects had an exposure of at least 10 years or more showing an increased risk of developing lung diseases relatedto byssinosis.Women working in the cotton industry are more susceptible to various health problems much to their counter parts in other sectors. In the present study the anthropometric parameters of study and control group showed no significant difference thus makinggroup comparable. In the present study, Forced vital capacity (FVC) was significantly decreased in cotton industry workers. This is supported by a report of Fishwick and Jadhav A.J et al ,9.StudiThe Present study showed a strong coalition between cotton dust exposure in the cotton industry environment and lung function abnormalities. The pulmonary parameters are decreased significantly in the subjects working in cotton industry. This suggeststhat more aggressive measures must be taken in the workplace and enforcing the use of personal protective equipment, such as respirators and face masks. The health hazards caused by cotton dust should be controlled by creating awareness such as regular healthcheck-ups, personal protective measures and proper ventilation among the employees & employers and thereby ensuring the quality of life of the cotton textile industry workers."}
+{"text": "The links between body image disturbances and distorted relationships with parents were supposed since the early conceptualizations of AN by Hilde Bruch. The empirical studies however were concerned with perceptual aspects of body image and much less is known about how the attitudinal aspects and the body-related behaviors are affected.To study the attitudinal and behavioral aspects of body image in adolescents with AN in relation to perceived parental care and the attachments to close people.The Body Investment Scale (BSI), Parental Bonding Instrument (PBI) and Attachment Style Questionnaire (ASQ) were used. 53 girls with Anorexia Nervosa were compared to 63 controls (adjusted by age).Girls with AN scored significantly higher on BIS Body attitude (p<.001) and Protection scales (p<.01), while displayed equal results on Body Care scale. They displayed lower Confidence in relationships (p<.01), higher Need for approval, Discomfort and preoccupation in close relationships (p<.05). No differences were found on PBI, excerpt for AN group perceiving less paternal control (p<.05). The correlation analysis, while showing a number of similar correlations within groups, suggests that in AN group positive Body image was more closely linked to perceived early care, especially from father (r=.6), in contrast with controls. In current relationships negative Body image for AN is stronger related to Discomfort and Need for approval (r>0.6), while Discomfort with Touch is less linked to problems in relationships than in controls.Results suggest the importance of studying the father\u2019s mediating role in the formation of body attitudes in AN.No significant relationships."}
+{"text": "Perceived control is an important psychosocial resource for healthy aging. Using data from the National Study of Daily Experiences , we examined aging-related changes in stressor control across 10 years and compared these trajectories with measures of general control . Over 8 consecutive days in waves conducted in ~2008 and ~2017, people reported their perceived control over four types of stressors . Longitudinal analyses revealed declines in stressor control across 10 years (p<.001), driven by declines in home stressors specifically. The rate of decline did not depend on baseline age. General control trajectories showed unique patterns of age differences in aging-related change such that declines  were steeper among older adults (p<.001). Results suggest that stressor control is a distinct domain of control beliefs with aging-related declines that differ based on type of stress experienced."}
+{"text": "Growing evidence has shown that genetic factors play crucial roles in the disorder of eye development and the progression of ocular diseases . Ocular The eye consists of three main types of tissues: 1) refracting tissues that focus incoming light onto light-sensitive tissues , 2) light-sensitive tissues that convert detected light into electrical signals and transmit them to the brain (including the retina and optic nerve), and 3) support tissues that provide the architectural support for the shape of the eyeball  . These pThis topic summarizes ten original research articles that explored the genetic effects and mechanisms of genetic factors contributing to eye development and disease from diverse aspects, providing new insights into treating eye diseases . AccordiInherited eye diseases affect approximately one in 1,000 people worldwide, but the molecular mechanisms underlying most of them remain unclear . IdentifWei et al. identified mitochondrial mutations (OPA1 and LHON-mtDNA) in nearly half of patients with ethambutol-induced optic neuropathy (EON), a well-recognized ocular complication associated with ethambutol treatment in tuberculosis patients. Since some patients with EON have severe and permanent visual loss even without the known risk factors, their findings that mitochondrial genetic variations are major predisposing factors for the development of EON provided a better understanding of EON and additional support for genetic counseling.Zhang et al. found variants in BMP4 contribute to a novel phenotype of pathologic myopia rather than syndromic microphthalmia that have been reported in a previous study  , the second leading cause of pediatric lens surgery after congenital cataracts, could be caused by mutations in cbEGF-like domains of fibrillin-1 (FBN1) . HoweverLuo et al. presented work on the role of the mouse double minute 2 (MDM2) gene single nucleotide polymorphism (SNP) T309G in the development of epimacular membranes (EMMs), relatively common sight-threatening conditions characterized by fibrocellular proliferation along the surface of the internal limiting membrane (ILM) of the retina. They first reported that the MDM2 SNP309\u00a0G allele was a risk allele for EMM in a Chinese population. Their observation provides new insights into the molecular mechanism underlying these pathologies.Since the experimental studies of many inherited eye disorders in human beings are limited, the availability of genetically engineered animal models is very valuable for exploring the pathogenic mechanisms of these conditions and developing translational therapies.Zhao et al. generated a knock-in mouse model with lanosterol synthase (Lss) G589S mutation, which can recapitulate human congenital cataract resulting from G588S mutation in human LSS. Mice with homozygous Lss G589S mutation exhibited disrupted lens fiber differentiation at early-stage of lens development and down-regulated cholesterol synthesis signaling pathways. Their findings elucidate the important roles of LSS in lens development, contributing to a better understanding of LSS defects and disturbed sterol signaling in cataractogenesis and the development of therapies for cataracts.Hejtmancik et al. generated and characterized the Kcnj13 knockout mouse and RPE-specific conditional Kcnj13 knockout mice. Their work provides a potential mouse model system for elucidating the pathology of these diseases and developing gene therapy trials.Mutations in KCNJ13 are responsible for both snowflake vitreoretinal degeneration (SVD) and Leber congenital amaurosis (LCA) . ExistinASRGL1) has been reported as a causing mutation for retinitis pigmentosa (RP), an inherited retinal degenerative disease for which there is currently no cure  could be reprogramed into functional retinal ganglion cells (RGCs) in vivo by Math5 and Brn3b together, two crucial transcription factors (TFs) involved in retinal ganglion cell (RGC) generation and differentiation  and the optic nerve are the common features shared by all forms of glaucoma . In vivontiation . Their sHou et al. profiled a single-cell transcriptome atlas of human RPE (hRPE) cells and provided a map of disease-related genes in the hRPE. They found two subpopulations, the macular RPE and peripheral RPE clusters which exhibited substantial differences in gene expression patterns and functions, play crucial roles in the potential treatment of retinal diseases. Their work provides important information for understanding the cellular mechanisms and treating pathological conditions of the hRPE associated with ocular diseases.These research articles on the topic show that elucidating the genetic underpinnings of ocular disorders leads to a better understanding of these diseases, which will contribute to clinical diagnosis, genetic counseling, early intervention and targeted treatment. The application and advancement of integrated multi-omics will further improve our knowledge of complex traits and provide new insights into the pathogenesis of ocular diseases. New genetic methodologies based on automated methods are expected to be developed for accurate and routine diagnosis of eye diseases that have highly diverse genetic causes and are difficult to identify. And gene and cell therapies will open new doors for the treatment of currently incurable eye disorders."}
+{"text": "Chronic functional gastro-intestinal disorders can affect cognitive functioning of patients (1). Wong et al (2) showed attentional and executive function impairment, Aizawa et al. (3) found impairment of cognitive plasticity and activity of frontal and temporal arias of brain during performing tests in these patients.Assessing of cognitive functioning of the female patients with chronic functional constipation.42 Rome IV adult female patients with chronic functional constipation and 26 adult normative female volunteers were tested with Brief Assessment of Cognition in Schizophrenia (BACS).Both groups were comparable by age  In both groups subjects demonstrated normal level of cognitive functioning but the scores of the patients were closer to the lower level than the scores of the volunteers. The difference was significant in composite scores and in several other scores (Tab.1). Table1.The findings of the study once more indicate some link between gastrointestinal dysfunction and cognitive functioning. Even these slight decrease in some aspects of cognition from normal population could have negative impact on everyday functioning. The origin of this link is still under question.No significant relationships."}
+{"text": "Mapping positional features from one-dimensional (1D) sequences onto three-dimensional (3D) structures of biological macromolecules is a powerful tool to show geometric patterns of biochemical annotations and provide a better understanding of the mechanisms underpinning protein and nucleic acid function at the atomic level.We present a new library designed to display fully customizable interactive views between 1D positional features of protein and/or nucleic acid sequences and their 3D structures as isolated chains or components of macromolecular assemblies.https://github.com/rcsb/rcsb-saguaro-3d.Bioinformatics online. Mapping positional features from 1D sequences onto 3D structures of biological macromolecules facilitates interrogation of relationships between shape and function. Sequence to structure mapping enables identification of spatial correlations and geometric patterns among protein or nucleic acid annotations that would be obscured if they were analyzed solely using linear polymer sequences. Over the last few years, various libraries, web applications and software tools have been developed to compute alignments among structures, and protein and gene sequences, and visualize positional features over the different levels of molecular organization from genome to macromolecular assemblies. 3DBIONOTES  annotatiIn this work, we present a new TypeScript/JavaScript module designed to create custom interactive views between 1D sequence positional features and 3D structures of macromolecules over the web. The main motivation behind this development is to provide the structural bioinformatics community with a flexible and fully customizable tool that can be adapted for use in various contexts. To achieve this end, the library exposes multiple event callbacks that allow software developers to define bidirectional interactions between 1D positional features and 3D atomic coordinates of experimental structures (from PDB) or computed structure models ; the US Department of Energy [DE-SC0019749]; and the National Cancer Institute, National Institute of Allergy and Infectious Diseases and National Institute of General Medical Sciences of the National Institutes of Health [R01GM133198] .Conflict of Interest: none declared.btac317_Supplementary_DataClick here for additional data file."}
+{"text": "Oesophageal cancer survivorship is afflicted by cancer cachexia related weight loss and nutrition impact symptoms. Identifying the factors which predict cancer cachexia specifically is warranted in order to identify those at risk and render the right kind of support. We aimed to assess if preoperative and postoperative body mass index (BMI) adjusted weight loss grading system (WLGS) is predictive of cancer cachexia at one year after surgery for oesophageal cancer.p\u2009<\u20090.05 together with a clinically relevant difference of 10-points in mean scores was considered as a significant difference.Data were used from a prospective nationwide cohort study on patients operated on for oesophageal cancer in Sweden between 2013 and 2018 included at one year after surgery. The study exposure is BMI adjusted weight loss graded into one of five distinct weight loss grades (grades 0\u20134), defined in accordance with the WLGS by combining BMI and percentage weight loss, assessed at two clinical time points: preoperative and at 6 months post-surgery for oesophageal cancer. The study outcome is subjective measures of cancer cachexia one year after surgery, assessed using the cancer-cachexia specific questionnaire EORTC QLQ-CAX24. Multivariable linear regression models calculated mean score differences (MD) with 95% confidence intervals (CI) adjusted for predefined confounders. Statistical significance at Among a total of 232 patients, the highest grade of preoperative WLGS 4 was associated with significantly worse physical decline than lower grades of WLGS 1  and WLGS 2 . Those with preoperative WLGS 2, 3 and 4 reported lower scores on the adequacy of information on weight loss provided to them than those with preoperative WLGS 0. Those with the highest postoperative WLGS 4 had greater eating and weight loss worry than WLGS 2  and WLGS 3  and worse physical decline than WLGS 0 .Higher grades of both preoperative and postoperative WLGS are predictive of cancer cachexia related physical decline one year after surgery for oesophageal cancer. Additionally, preoperative and postoperative WLGS were also predictive of inadequate information concerning weight loss and more worry regarding eating and weight loss, respectively. The WLGS may be an effective risk prediction tool for postoperative cachexia related physical decline in patients undergoing treatment for oesophageal cancer emphasizing its usability in the clinical setting. Despite improving survival rates with multimodal treatments such as chemotherapy and radiotherapy, an extensive surgical procedure remains the cornerstone of curatively intended treatment for oesophageal cancer , 2. CancOesophageal Surgery in Cancer patients: Adaptation and Recovery (OSCAR) cohort, a nationwide and prospective study of patients who were operated on for oesophageal cancer in Sweden from 2013. The data collection for the OSCAR study is ongoing. The OSCAR study is explained in detail elsewhere . Th. Th14]. n) and proportions (%). Multivariable linear regression models were used to calculate the association between preoperative and postoperative WLGS and the cachexia scale scores from QLQ-CAX24. A linear model was used since a pre-established cut-off is not available for cachexia scores and mean scores difference (MD) of 10 or more points (10%) were tested for statistical significance. A 10-point difference was regarded as clinically relevant based on previous research [Descriptive statistics were presented as counts , age at operation (continuous), comorbidities (Charlson comorbidity score 0/1/\u22652), histological sub-type (adenocarcinoma and high-grade dysplasia/squamous cell carcinoma), pathological tumour stage (0-I/II/III-IV) and neoadjuvant therapy (yes/no). For the postoperative WLGS at six months after surgery in addition to the above confounders, type of operation , postoperative complications (Clavien-Dindo score (CDS); low grade (0-II)/high grade (III-IV), enteral and/or parenteral nutrition support for at least 1 week postoperatively (yes/no) was adjusted for. Statistical analysis was conducted using SAS 9.4 software .n\u2009=\u200925) or other reasons (because they did not want/had the energy to participate (n\u2009=\u2009119), were too sick (n\u2009=\u200928), other reasons (n\u2009=\u20091)). In total, 253 (58% of eligible) completed the EORTC QLQ-CAX24 questionnaire, and 232 had complete data concerning WLGS before operation and clinical data from medical charts, hence were included in the analysis.Between January 2013 and 15 May 2019, a total of 839 patients underwent surgery for cancer of the oesophagus in Sweden. Of those, 636 patients were alive at the one-year follow-up, 113 were unreachable and one patient was excluded owing to cognitive impairment, leaving a total of 522 patients eligible for inclusion in the OSCAR cohort and 438 eligible for the current study as 84 were included in the cohort before the EORTC QLQ-CAX24 questionnaire was introduced. Among those identified as eligible, 173 (39%) declined to participate for reasons namely, cancer recurrence  had a higher comorbidity score than those in the other categories of WLGS 1\u20134 (15.1% to 23.1%). More patients (43.5%) with WLGS 4 had a higher pathological tumour stage (III-IV) than those with the least WLGS 0 (31%). As many as 91.3% of patients in the WLGS 4 received enteral or parenteral nutrition support compared to 77.5% in the WLGS 1  from the five weight loss grades were reported in the eating and weight loss worry dimension MS 30 to 38) and food aversion dimension (MS 28 to 34) [Table 0 to 38 aAmong the dimensions of the QLQ-CAX24 as per the five grades of postoperative WLGS at six months after surgery, the highest MS were reported in the eating and weight loss worry dimension MS 21 to 38) and food aversion dimension (MS 21 to 33) [Table 8 and fooThis population-based prospective cohort study on patients who underwent surgery for oesophageal cancer, exploring if the WLGS is a predictor of long-term cancer cachexia indicated that higher grades of both preoperative and postoperative WLGS are associated with cancer cachexia related physical decline at one year after surgery for oesophageal cancer. Additionally, higher grades of preoperative WLGS were also associated with inadequate information on weight loss aspects of cancer cachexia. Meanwhile, higher grades of postoperative WLGS was also predictive of eating and weight loss worry among patients. The results signify that the WLGS maybe a useful predictor of specific cancer cachexia related decline in oesophageal cancer patients.Several methodological aspects in the present study add to its strength. The population-based nationwide data collection with a longitudinal design minimised selection bias and increased generalisability of the results. The OSCAR cohort is comprised mostly of male patients, which is typical for oeophageal cancer and hence considered representative of the disease demographics and generalisable. Adherence to a strict protocol for data collection further reduced the scope for bias, and another added strength is the unique home-based data collection which reduced missing values. However, selection bias through non-participation of those who were unreachable and declined participation in the study cannot be neglected and may be considered a potential limitation. The choice of the WLGS as the assessment tool for the exposure and EORTC QLQ-CAX24 for the assessment of the outcome is also a strength in the present study. The WLGS has marked a crucial step in redefining clinically important weight loss where BMI is included and has thus been included in the current international clinical practice guidelines for nutrition and cancer . MoreoveIn our study, both the higher grades of preoperative and postoperative WLGS was predictive of physical decline at one year after surgery for oesophageal cancer. In the treatment of patients with oesophageal cancer, resection surgery remains the cornerstone of curatively intended treatment . The surOur results highlight that the WLGS may be a good risk prediction model for the cancer cachexia related physical decline in patients undergoing treatment with oesophageal cancer emphasizing its usability in the clinical setting. The persisting and long-term issues concerning eating and weight status are also a major challenge for health care and the WLGS is a more clinically relevant and robust tool for cachexia related physical decline after surgery for oesophageal cancer.Table S1Table S2"}
+{"text": "Night work has been widely studied for the associations with diseases, sickness absence (SA) and disability pension (DP), but less for sustainable working life. We aimed to investigate the longitudinal changes in sustainable working life among those with or without baseline night work.Using data from Swedish national registers, sustainable working life was defined as employment during follow-up without interruptions due to SA/DP, unemployment, and old-age pension. Survey data for two cohorts  were utilized to assess night work at baseline (yes/no) in 1998-2003 and 2004-2006, respectively. The final samples for the two cohorts were 34680 and 19637, respectively. Group-based trajectory models were applied.Among those born before 1959 , a five-trajectory solution was best for those with and without night work. The trajectory groups were stable sustainable working life (38-42%), stable unsustainable working life (24-25%), early (13%) or later (13%) decreasing sustainable working life, and between sustainable and unsustainable working life (7%). Among those born after 1958 , four trajectories were detected for those with night work: stable sustainable working life (81%), stable unsustainable working life (6%) and increasing (7%) and decreasing (5%) sustainable working life. For those without nightwork, a three-trajectory solution was best: stable sustainable working life (83%), stable unsustainable working life (6%) and between sustainable and unsustainable working life (11%).Sustainable working life was similar across baseline night work statuses of older cohort but differed in younger cohort. The findings suggest that at least night work at one time point does not affect sustainable working life. However, night work at early stages of working life could be accompanied with lifestyle counselling for sleep and recovery.\u2022\u2002Trajectories of sustainable working life seem similar for those with or without night work adding to the understanding of effects of such work to health.\u2022\u2002From public health perspective, counselling employees with night work already at early stages of working life for health behaviours including sleep and recovery could support sustainable working life."}
+{"text": "This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases. The diverse small molecules are described according to the date of approval and their syntheses is discussed. This review comprises classical chemical scaffolds together with innovative drugs such as a deuterium-containing drug. The constant research for innovative therapies leads every year to molecules that are approved by the United States Food and Drug Administration (FDA), a federal agency of the U.S. Department of Health and Human Services.Novel building blocks and their connections have been explored much in recent years allowing drug hunters to explore a much bigger chemical space .Small molecule drugs are organic compounds with low molecular weight. For a long time, they have been the backbone of the pharmaceutical industry. There are several benefits that make small molecules important drugs in therapy, such as the possibility of oral administration and cell membrane permeability which allow them to reach specific tissue and targets. For this purpose, small molecule drugs can be designed in order to acquire, for example, specific affinity and selectivity  .The goal of this review is to highlight the chemical entities approved in the year 2022 for clinical use. The approved drugs (and their synthesis) are listed according to their chronological approval date . This pa11) (brand name Quviviq\u00ae) is a 1,2,3-triazole derivative with an expected global sales to 2026 of $1052 million pyrimidine 14  in the presence of diisopropylethylamine (DIPEA) to give the intermediate 15 which underwent the deprotection of carboxylbenzyl protecting group under acidic conditions (HBr) to afford 16. The free primary amino group of 16 reacted with the propane-1-sulfonyl chloride 17 to provide the sulfonamide 18. The last stage (yield: 74%) involved the removal of tosyl group by using lithium hydroxide or sodium hydroxide in ethanol to generate Abrocitinib (19).Approved in January 2022 (14 January 2022), abrocitinib  was approved for the treatment of hereditary hemolytic anemias  sta sta16] s41) was authorized for the treatment of seizures in cyclin-dependent kinase-like 5 deficiency disorders  to provide PSMA-617 (52).Its structure is composed of PSMA-617, a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium, Lu 177 (177Lu) . The syn177Lu) ,23. The 67, brand name Vivjoa\u00ae) was approved in April 2022 (26 April 2022) with the indication of reducing the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are not of reproductive potential [The antifungal oteseconazole  at \u221265 \u00b0C to afford derivative 57. The following Henry reaction provided the mixture of nitro alcohols 59  and 60 (S enantiomer of 59) in the presence of 5% mol of organocatalyst 58. The enantiomeric ratio of the couple 59:60 was 90:10. The organocatalyst 58 proved to be the most effective in stereoselectivity among the many others tested. The subsequent catalytic hydrogenation  of the mixture of nitro alcohols led to the corresponding amines 62 and 63. The conversion of 62 and 63 to the corresponding tetrazoles 64 and 65 was mediated by trimethylsilyl azide and trimethyl orthoformate in the presence of acetic acid. The last step involves a Suzuki coupling between the aryl bromide of 64 and 65 and the boronic ester 66 catalyzed by (diphenylphosphino) ferrocene] dichloropalladium (II) to generate the desired oteseconazole 67. The authors claim that an enantioenriched (95.9%) form of 67 was obtained via diastereomeric recrystallisation with (S)-Camphor sulfonic acid  ,26 25,26\u00ae) was approved in April 2022 (28 April 2022) for the treatment of certain classes of obstructive hypertrophic cardiomyopathy [Mavacamten  which upon reaction with trimethylsilyl isocyanate 70 is converted to isopropylurea 71. The reaction between 71 and dimethyl malonate in the presence of sodium methoxide as base gave 1-isopropyl barbituric acid 72. The subsequent conversion to chloride derivative 73 is mediated by POCl3 using triethylbenzylammonium chloride (TEBAC) as phase transfer catalyst. The last stage is the nucleophilic addition of (S)-methylbenzylamine (74) to 73 in order to afford mavacamten 75. Last step yield was 69% [Its synthesis  29] sta sta29] s\u00ae) was approved in May 2022 (3 May 2022) for the treatment of Helicobacter pylori infection  sta sta35] s\u00ae) was approved in September 2022 (9 September 2022) and for the treatment, as in the case of tapinarof, of plaque psoriasis [Deucravacitinib (brand name Sotyktusoriasis . It is esoriasis .It is a deuterated drug launched by Bristol Meyers Squibb  selectiv89 which is firstly methylated with methyl iodide and later converted into amide by ammonolysis to afford the intermediate 90. The treatment of 90 with DMF-DMA followed by condensation with hydrazine hydrate yielded the triazole 91 which was then methylated in presence of methyl iodide and potassium hexamethylsilazide to generate compound 92 in a good regioselectivity (8:1) over compound 93.Its synthesis  38] sta sta38] s92 was subjected to catalytic hydrogenation  to give the substituted aniline 94 which was then mixed with the pyridazine 95  and aqueous potassium triphosphate resulted in a better yield and milder conditions if compared to the triad XantPhos/Pd2(dba)3/Cs2CO3. Last step yield was 76%.Pure compound azine 95  in the pApproved in September 2022 (21 September 2022), gadopiclenol is used to detect and visualize lesions, together with Magnetic Resonance Imaging (MRI), with abnormal vascularity in the central nervous system and the body  ori ori42] o\u00ae dichloropalladium (II)] between halide 124 and alkyne 125 provided the derivative 126. The subsequent nucleophilic attack (resulting in inversion of configuration) of 126 to mesyl-protected alcohol 127 afforded the pyrrolidine derivative 128 which was subjected to BOC-removal by addition of HCl to give 129. The final step involves another nucleophilic attack (acylation) of 129 to acryloyl chloride (130) followed by neutralization with sodium bicarbonate to yield futibatinib (131).Its structure contains a pyrazolo-pyrimidine scaffold and the synthesis  53,54] ,54 53,54Sulfonamide-containing drugs (four entities) are arising among the approved molecules in 2022. Sulfonamides were among the first examples of carboxylic acid isosteres to show utility in drug design .\u00ae, In the previous year (2021), only odevixibat (brand name Bylvay19), a pyruvate kinase enzyme activator , a potassium-competitive acid blocker (P-CAB) represented by vonoprazan  and a selective prostaglandin E2 receptor agonist . None of these molecules  in the synthesis of folic acid which is essential for the further production of DNA in the bacteria [Historically, the first sulfonamide drug was prontosil rubrum . This cobacteria . Anotherbacteria .Interestingly, none of the sulfonamides approved by FDA in 2022 belong to the last two groups of inhibitors, creating novel opportunities in hitting novel and diverse targets.Moreover, a key-feature that would help in the design of novel bioactive compounds is the fact that sulfonamides possess high hydrolytic stability .In this work, all small molecule drugs that were approved by the FDA in 2022 were discussed. For each compound, the biological activity and the chemical synthesis were provided. It appears that sulfonamide-containing drugs are dominating the year 2022 with four molecules approved. Their physicochemical and pharmacodynamic properties still play an important role many years after the discovery of the first sulfonamides endowed with antibacterial activities.Deuterium-containing drug deucravacitinib represents, on the other hand, an example of novel approaches in drug discovery incorporating an unusual isotope to provide drug stability.The discovery of pyrimidinedione mavacamten for the treatment of cardiomyopathy and the huge forecasted sales  for thisThe combination of drugs, for example vonoprazan (in combination with amoxicillin and clarithromycin) and taurursodiol (in combination with sodium phenylbutyrate) is still a valid weapon for the treatment of unmet medical diseases.The 15 FDA-approved small molecules  in 2022"}
+{"text": "Sphenoid sinus mucocele (SSM) caused by obstruction of sinus ostium while sphenoid sinus retention cyst (SSRC) is due to obstruction of mucinous gland ostium which could enlarge to obstruct the sinus ostium and lead to acute sinusitis or mucocele,Incidence of isolated SSM is about 2% out of paranasal sinus (PNS) mucocele, but there is no specifically occurrence rate regarding SSRcWe herein describe one case of SSM and two cases of SSRC with sudden unilateral visual loss that recovered following endonasal endoscopic sinus surgery.A 25-year-old man with left-sided vision loss (light perception (LP), afferent pupillary defect (APD)) occurred within 24 hours, was referred after 10 days of the attack.Magnetic resonance imaging (MRI) showed a mass with rim enhancement obstructing the sphenoid sinus ostium . ComputeA 12-year-old boy with a history of gradual visual loss of left eye over 2 month-period was referred because of left sphenoid sinus mass in MRI with no Gadolinium uptake that was compatible with SSRC. There was no obvious compression of the optic nerve in the CTS or MRI .(28-year-old woman) showed up with total visual loss (LP and APD) of the right eye over 34 day period and retro-orbital pain. She had a similar attack 4 years earlier treated with 2-week administration of Dexamethasone. MRI showed an RC in the sphenoid sinus  touchingAll patients were referred by ophthalmologist with the first diagnosis of retrobulbar optic neuritis (RON) following incomplete recovery with administration of glucocorticoids. The patients underwent endoscopic endonasal approach and the cysts were removed. Total vision and visual field recovery were achieved in case 1 and 3 and partial recovery in second case.Isolated inflammatory diseases of SS are infrequent comparing to other paranasal sinuses. However neglected sphenoiditis could lead to critical complications by affecting adjacent vital structures such as cranial nerves II, III, IV, VIVisual loss and blindness often occur following circulatory disorders of the optic nerve caused by prolonged mucocele pressure that erode the bone and put the nerve in jeopardyMucocele could show four patterns of MRI signal intensity according to the protein concentration revealing its chronicityA high index of suspicion is needed for proper diagnosis of this entity especially for neurologists and ophthalmologists who are usually first physicians visiting sudden visual loss cases."}
+{"text": "Scientific Reports 10.1038/s41598-022-10708-9, published online 05 May 2022Correction to: The original PDF version of this Article contained errors in the Results section under the subheading \u2018Pulse width\u2019, where the confidence intervals of the median relative perception thresholds The confidence intervals of the median relative attention thresholds The confidence intervals of the median relative intolerance thresholds Table 2 shows the results of linear regression The original PDF version of this Article has been corrected."}
+{"text": "The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed the benefits of blood pressure (BP) lowering for secondary stroke prevention in stroke survivors for the first time after a long dispute in the last century  and trigIn the present post hoc analysis of RESPECT, Kitagawa et al. examined the effect of intensive BP lowering on recurrent stroke subtype risk in patients with a history of ischemic stroke, accounting for 84% of the overall participants in RESPECT . The majAnother major finding of the RESPECT sub-analysis was that the risk of recurrent ischemic stroke was almost identical between two treatment groups with different BP lowering targets . The uncAs the adverse events of intensive BP lowering, the authors of the RESPECT sub-analysis indicated caution regarding falls and renal dysfunction . Acute kThe current guidelines recommend systolic BP control aiming at <130\u2009mmHg or 120\u2013130\u2009mmHg for adults who experience ischemic stroke \u201312. RESP"}
+{"text": "Drawing on the life course perspective and multi-channel sequence approach, this research identifies long-term financial hardship and income security patterns among older adults and examines their relationship with depressive symptoms. Data were from the 2010 to 2018 HRS with 3,077 older workers aged 62\u201371 in 2010. Four clusters of key sequences were identified: 1) High food and low medical insecurities with private pension plans (43%); 2) Moderate food and low medical insecurities with gradually acquired private pension plans (13%); 3) High food and low medical insecurities with both private and employment-based pension plans (40%); 4) High food insecurity with employment-based pension plans(3%). Regarding the association with depressive symptoms, a group of people who experienced high food and low medical insecurities with private pension plans  and those who experienced moderate food and low medical insecurities with gradually acquired private pension plans  were more likely to have depressive symptoms compared to those high food and low medical insecurities with both private and employment-based pension plans. These findings highlight the heterogeneity of long-term patterns of financial hardships and patterns of income security, including the limited accessibility for a pension plan through their occupation and that an individual pension plan may not be sufficient to ensure mental health in later life. The results imply the importance of dual security of private and employment-based pensions on their mental health and provide important insights for future tailored income support programs for older adults."}
+{"text": "Alzheimer's disease (AD) is the most common dementia syndrome in the elderly and a devastating neurodegenerative disease without any cure available currently. AD patients usually present insidious onset and progressive cognitive impairments with unique post-mortem diagnostic brain pathology including accumulation of amyloid beta (A\u03b2) and hyper-phosphorylated tau proteins  and highlights both basic and clinical studies in the relevant field. In total, seven original research articles from investigator groups across the world using multiple state-of-art scientific approaches reported AD- or ADRD-related metabolic signaling alterations in rodent models or human subjects.The current Research Topic \u201cZhao et al.) analyzed plasma metabolites profile in the MCI patients by using a high-resolution mass spectrometry metabolomics approach. The results indicate an association between dysregulated sphingolipid metabolism and behavioral performance in the MCI patients, providing insights into development of novel blood biomarker for MCI.The Qi Guo group  examined the relationship between AD polygenic risk score (PRS) and longitudinal decline of cognition function in older adults with type 2 diabetes (T2D). Interestingly and contrary to the authors' hypothesis, the analysis revealed no significant association between the AD PRS and multiple measurements in older adults with T2D such as cognitive decline, hippocampal volume, and A\u03b2 burden. Their findings indicate a complex relationship between AD genetic susceptibility and cognitive impairments in T2D.The Lior Greenbaum group  reported that global knockout of the mRNA translation factor eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) led to improvement of cognitive function in a mouse model of AD without affecting the brain A\u03b2 pathology. The study provides further evidence to suggest that targeting eEF2K signaling dysregulation might be a feasible therapeutic approach for ADRDs.The laboratory of Tao Ma  biometric components and the gray matter volume (GMW) in different brain regions. They found that decreased GMV across all the examined brain regions in the MetS patients is correlated best with waist circumference. Surprisingly, posterior cerebellum is the brain region mostly correlated to the MetS biometric components.Weise et al. analyzed the data of the MCI participants from the AD Neuroimaging Initiative (ADNI) study and reported a correlation of higher body mass index (BMI) with greater regional cerebral metabolic rate for glucose (rCMGgl) and slower cognitive decline in MCI. Such association is not related to leptin levels. Future studies are necessary to illustrate the mechanisms underlying such correlations between brain glucose utilization and body weight.Smith et al.) reported their unexpected findings revealing novel roles of the AD risk gent Abelson interactor family member 3 (Abi3) in metabolism. They found that the Abi3 knockout mice exhibited impaired energy expenditure, increased body weight and body fat, and impaired glucose tolerance and insulin sensitivity. The study may contribute to our understanding of the metabolic factors in AD development.The laboratory of Jungsu Kim (Kurano et al. examined postmortem human brains to understand potential association of the bioactive lipid regulation with the AD pathology. The study showed distinct pattern of bioactive lipid modulation correlated to AD pathogenesis.Frontiers in Aging Neuroscience is to increase overall interest in this under- investigated area of research and bring investigators from both basic science and clinical research fields. We are encouraged and excited by the findings reported in these articles and look forward to future in-depth studies on the topic to facilitate our underlying of the mechanisms underlying aging and ADRDs.In summary, accumulating evidence indicates a link between metabolic signaling dysregulation and cognitive impairments associated with aging and Alzheimer's disease. An important goal of this Research Topic in TM wrote the manuscript. RC and SM edited the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "Many elder abuse interventions and tools designed to screen for abuse exclude older adults with cognitive impairments (CI) due to the challenges associated with screening and whether the older adult with CI can reliably report elder abuse. However, it has been shown that older adults with CI are among the most vulnerable to experiencing elder abuse. VOICES is an innovative, automated tablet-based elder abuse screening and prevention intervention that is self-administered by the older adult in the provider\u2019s waiting room or office. The VOICES Elder Abuse Intervention (EAI) provides screening, educational modules, and brief psychoeducational intervention to enhance and improve identification of elder abuse when there are no visible signs of abuse. The VOICES EAI was already proven successful in terms of feasibility and acceptability in cognitively intact older adults in a busy emergency department setting with . In this study we tested the VOICES EAI with (N=30) participants 60 and above with cognitive impairment at a geriatric center using the Montreal Cognitive Assessment (MoCA) to determine cognitive capacity. Experts in the field of geriatrics and cognitive impairment assisted in grouping participants within three cognitive categories: Mild cognitive impairment (MoCA 23-25), mild dementia (MoCA 16-22) or moderate dementia (MoCA 8-15). Of the (N=30) participants, 29 were able to successfully use the VOICES EAI independently, and most participants were satisfied with the tool. We will discuss the findings of this preliminary study and the implications for future research with older adults with CI."}
+{"text": "The advent of the SARS-CoV-2 virus necessitated behavior changes for most older adults. Changes were largely associated with voluntary or enforced compliance with social distancing policies. Whereas the value of social distancing for mitigating the spread of the dangerous SARS-CoV-2 virus is not the subject of serious debate among public health advocates, policies that encouraged or enforced social distancing have been met with skepticism in the general public. Understanding patterns in behavior changes may be helpful to public health professionals and policymakers who develop health communication and revised guidelines in the efforts to contain the spread of the SARS-CoV-2 and future public health infections. Our study examined patterns in behavior changes. This study had two aims. First, using survey responses from 661 adults living in rural areas about changes they made to 20 different behaviors, we identified four classes of behavior changes: (1) non-social distancers (10.7%), (2) social distancers (54.0%), (3) social distancers making civic exceptions (24.0%), and (4) social distancers making religious exceptions (11.3%). Second, polytomous logistic regression was used to predict the probability of membership in those latent patterns of behavior change. Predictor variables included demographic variables  and variables theoretically predicted to covary with patterns of behavior change . This study provides insight into behavior changes during the outbreak of the SARS-CoV-2 virus that may be used by practitioners to understand variations in how people responded to the outbreak."}
+{"text": "The ductus venosus (DV) carries oxygen-rich blood from the umbilical vein (UV) to the heart, bypassing the fetal liver. In 1:500 to 1:2500 pregnancies, the DV is either missing or it drains at an atypical site. The types of DV abnormalities are grouped according to the drainage site (intra- or extrahepatic) and whether they bypass the liver . The presence of a DV abnormality increases the risk of other fetal defects, especially cardiac and genetic abnormalities (3).In the image, color Doppler is used to demonstrate normal DV anatomy and five typical abnormalities:Figure Figure Figure Figure Figure Figure Figure"}
+{"text": "ESCs can be obtained from the inner cell mass of the blastocysts and give rise to all the embryonic three germ layers, however, the critical ethical predicament limits ESCs clinical applications. iPSCs possess the same differentiation capacity as ESCs but avoid ESCs usage-associated ethical dilemmas. Therefore, the generation of iPSCs Stem cells inhabit specialized microenvironments called \u201cstem cell niches\u201d that maintain a hypoxic and low level of reactive oxygen species (ROS) environment. The stem cell niche is essential for preserving stem cell stemness and self-renewal potency. ROS has been considered for a long time to be implicated in stress and various disorders and has been redefined as a vital signaling molecule with multifaceted functions in modulating stem cell biology and differentiation .2O2) and the superoxide anion radical (O2.-), are produced primarily by NADPH oxidases and controlled by growth hormones, cytokines, cytokines, mitochondrial electron transport chain. There are more than 40 enzymes involved in this process. H2O2 is implicated in a vast majority of redox-associated modulation of biological activities  reactions and form oxidative alteration on biological macromolecules, and ultimately activate key redox signaling and its related biological functions. Two key ROS signaling molecules hydrogen peroxide /protein kinase B (Akt) pathway. This finding is the main attribute in cyclic mechanical stress-mediated PDLSCs\u2019 osteogenic differentiation.The cyclic mechanical stress was found to boost the ROS level and induce the expression of nuclear factor erythroid-2-related factor-2 (Nrf2) and its downstream molecules including heme oxygenase 1 (HO1) and NADPH dehydrogenase quinone 1 (NQO1), which ultimately promoted the osteogenic differentiation in human periodontal ligament stem cells (PDLSCs) . In thisSinenko et al. covers the recent advances in the physiological functions of the intracellular ROS as a signaling molecule and a secondary messenger of a wide range of cellular signaling in modulating the potency and differentiation of stem cells as well as the development of invertebrate Drosophila.A well-written review paper from Sheng et al. showed that a novel natural antioxidant compound, Caffeic acid (CA) efficiently delayed the aging events in the Drosophila gut, which is associated with the aberrant function of intestinal stem cells (ISCs) and the subsequent dysplasia. This beneficial antioxidant effect is attributed to the potency of CA to suppress oxidative stress-induced JNK signaling.A study by Drosophila as a proper genetic model for studying the mitochondrial electron transport chain and mitochondrial ROS-associated biological functions and the necessity of translating various pathophysiological aspects in Drosophila that are enigmatic in humans. While editing this Research Topicr, we hoped that the contributed research work would serve as an inspiration for scientists in the field to investigate further mechanisms and applications of ROS signaling in flies that could be translational for promoting ROS-mediated enhanced stem cell function and clinical applications.These studies underscored the importance of Wang et al. demonstrated the beneficial effects of the bone marrow mesenchymal stem cell-derived exosomes on the pathogenesis of osteoarthritis through targeting the competitive endogenous RNA (ceRNA) networks represented in LYRM4-AS1/GRPR/miR-6515-5p signaling pathway.Moreover,"}
+{"text": "Delusions are a key feature of schizophrenia psychopathology. From a phenomenological approach, Jaspers (1913) differentiates between \u201cprimary\u201d or true schizophrenic delusions, defined as an unmediated phenomenon that cannot be understood in terms of prior psychological origin or motivation, and \u201csecondary\u201d delusions, understandable from the patient\u2019s mood state or personality. Primary delusions have been considered the hallmark of reality distorsion dimension in schizophrenia, disregarding a possible affective patwhay to delusional belief.The present study was aimed at elucidating the psychopathological trajectories to delusion in schizophrenia through the investigation of both affective and schizotypal trait dispositions.Seventy-eight participants affected by schizophrenia were administered the Peters Delusional Inventory (PDI), the Positive and Negative Affective Scale (PANAS), the Experience of Shame Scale (ESS), the Referential Thinking Scale (REF), the Magical Ideation Scale (MIS) and the Perceptual Aberration Scale (PAS).The severity of delusional ideation (PDI) was positively related to both affective  and schizotypal traits . Moreover, referential thinking (REF) mediated the relationship between \u201cmagical ideation\u201d (MIS) and delusions severity , whereas experience of shame (ESS) was a moderating factor in the between referential thinking and delusion severity .The study findings suggest that in schizophrenia patients, severity of delusions is underpinned by an intertwining of both affective and schizotypal pathways.No significant relationships."}
+{"text": "The link between social connectedness and dementia risk and resilience has been examined using a diverse set of measures. Though different measures of connectedness reflect distinct social processes and underlying mechanisms , few studies have compared them. Using data from two social network studies of older adults (N=283), we compare associations between 29 measures of social connectedness and general cognitive function (MoCA), and non-verbal (Rey) and episodic memory (Craft). Measures of social participation  and social support were unassociated with cognitive outcomes, net of controls. Quality of friendships (p<.05), family relationships (p<.01), and marriage (p<.05) were sporadically associated. Measures indicating large, diverse, and expansive networks were strongly and consistently related to all cognitive outcomes . We discuss implications for theories of cognitive reserve."}
+{"text": "Spouses often assume the role of informal caregivers for older adults living with mild cognitive impairment (MCI). These couples represent a population with low levels of physical activity, however, there is limited research regarding promotion of physical activity among these dyads. The purpose of this study was to evaluate the feasibility of a dyadic intervention, hypothesized to enhance physical activity via mutual support. We recruited three dyads (mean age: 66 [MCI] and 67 [spouse] years) from a local memory clinic. The dyads were asked to engage in physical activity together for 16 weeks. The weekly intervention consisted of 150 minutes of moderate-to-vigorous physical activity (MVPA) on their own and two lower body strength training sessions per week, one videoconferencing-supervised and one on their own. The adherence rate to the weekly MVPA and strength training was 88% and 83%, respectively. However, the percentage meeting the goal of 150 minutes/week of MVPA as measured using a Fitbit was 31% and 73% among those with MCI and spouses, respectively. There were no issues with the retention rate (100%) or safety; satisfaction scores were high . Exit interviews revealed three key themes: (1) value of the program , (2) difficulties , and (3) suggestions to improve the program (incorporating various types of strength training). Our dyadic intervention was feasible to support regular physical activity for older adults living with MCI and their spouses. Future work will incorporate participants\u2019 feedback to optimize the intervention."}
+{"text": "ASD with epileptic seizures (ES) and/or specific epileptic activity on EEG (EEG SEA) and repetitive movements and vocalizations (RMV) can be determined by different variants of genetic polymorphism or by different variants of gene expression, determined by different influences.To study the features of the clinical phenotype of ASD in preschool and school-age children with ES, EEG SEA and RMV.: The study group was divided 116 children aged 2-10 years with ASD into three subgroups: subgroup A - 23 children with a history of ES, subgroup B - 35 children with EEG SEA without ES, subgroup C - 19 children with ASD having EEG SEA, RMV . The control group consisted of 39 children with ASD non a history of ES and EEG SEA.: Children with ASD, complicated by severe and frequent ES are charactered by impaired social reciprocity and communication against the background of regression / stagnation of speech and motor skills development . Disoders of communication and repetitive behavior in ASD in children of different ages are represented by different monoqualitative syndrome (phenotypes). Movement stereotypes predominated in children with ASD without ES and without EEG SEA . In children with ASD and EEG SEA, motor stereotypes and repetitive behavior were equally common .: Disorders of social reciprocity, communication, repetitive behavior are diagnostically significant for ASD complicated by ES, ASD with EEG SEA.No significant relationships."}
+{"text": "Emotion globalizing is an individual difference variable referring to the extent to which daily variations in an individual\u2019s current emotions spillover into their evaluations of life satisfaction. The present research sought to: 1) extend the conception of emotion globalizing to stressor-related emotions, 2) examine age differences in these processes, and 3) differentiate associations with evaluations of life satisfaction and day satisfaction. To do so, we used daily diary data from two adult lifespan community samples . Multilevel models revealed older (compared to younger) adults exhibited less negative (but not positive) emotion globalizing and stressor-related emotion globalizing. No age differences were revealed in the association between stressor-related emotions and day satisfaction. These findings support and extend assumptions underlying the mechanisms of emotion globalizing and inform theories of emotional aging."}
+{"text": "The International Health Regulations (IHR) 2005 are an international legal instrument adopted by World Health Organization General Assembly to strengthen global health security and empower the countries to prevent and respond to public health threats.This study was done within the Joint Action on Strengthened International Health Regulations and Preparedness in the EU (SHARP JA) with the aim to assess the strengths and weaknesses in preparedness and IHR implementation in order to develop and improve countries\u2019 IHR capacities. Desk-based review and analysis of available data from the States Parties Annual Report tool (SPAR) from 2019 were done. Data (for 13 IHR capacities with 24 indicators) were analyzed for 15 countries participating in SHARP JA with gross national income (GNI) less than 90% of the EU average.The overall capacity for IHR implementation in low GNI countries is 69%, ranging from 33% in Bosnia and Herzegovina to 84% in Spain. The highest capacities are recognized in the area of Legislation and financing - 78%, IHR Coordination & NFP Functions - 77%, Food Safety - 76%, and Health service provision - 76%. The weak areas with the need for further improvement are recorded in the Points of entry (PoE) - 51%, Risk Communication - 52%, Chemical events - 60%, National health emergency framework - 65%, Surveillance - 66%, and Human Resources - 67%. The overall IHR capacity of low GNI countries is lower compared to the SHARP JA countries and the European average (76% and 73% respectively).The results have shown the strongest and the weakest points of the IHR implementation in low GNI countries. This indicates the need for capacity building and further development in identified areas .\u2022\u2002The assessment of the strengths and weaknesses in preparedness and IHR implementation is the key prerequisite for identifying countries\u2019 needs for their capacity enhancement.\u2022\u2002Special attention should be given to the strengthening low GNI countries\u2019 capacities."}
+{"text": "There is emerging literature about older adults\u2019 experience of loneliness during the COVID-19 pandemic in long term care (LTC) facilities due to isolation protocols. Additionally, staff challenges while providing care for older adults in LTC has also been highlighted. While the literature emphasizes negative pandemic experiences, a gap exists with understanding resilience during the pandemic in LTC settings. The aim of this qualitative descriptive study was to explore the experience of resilience in a Continuing Care Retirement Community (CCRC) among residents, their family members, and staff. We conducted 19 in-person interviews and 1 via Zoom in fall 2021 with 5 residents (65 and older), 5 family members, and 10 staff . A conventional content analysis was employed. While we did hear how the pandemic had a negative impact on everyone, the main themes of resilience identified were: 1) overcoming the pandemic together (sense of community); 2) experience and adaptation (over time being able to adapt to the disruption in their life); 3) staying safe (engaging in precautions and self-care strategies); and 4) positivity . Study findings can inform CCRC administrators on how to support residents, their family, and staff during future pandemics and other challenging times that may disrupt normal routines."}
+{"text": "This study examines the psychosocial impact of COVID-19 on cognitive aging Middle Eastern/Arab Americans immigrants and refugees in Michigan. Sociopolitical experiences as an immigrant and/or refugee may have unique effects on late-life cognitive health. Given that social engagement reduces the risk of ADRD, this study sought to examine the consequences of COVID-19 socialization restrictions on familial and communal support systems for aging Middle Eastern/Arab immigrants and refugees. Three focus groups discussions with 8-10 participants each (N=31) conducted at local Arab organizations and religious institutions were conducted followed by inductive analysis. Preliminary results indicate two prominent themes: 1) Social and Familial Hardships; and 2) Isolation. Narratives illustrate the prevalence of psychosocial ADRD risk from COVID-19. Findings are discussed within a stress framework to advance universal and unique elements of Arab immigrant and refugee cognitive aging."}
+{"text": "In Alberta, Canada, we quantified the rate of potentially inappropriate oral antibiotic prescribing in emergency departments for viral infections or conditions not likely requiring antibiotics from 2010-2020 and assessed the impact of two Choosing Wisely Canada (CWC) campaigns (2015/2016 and 2018) discouraging inappropriate antibiotic prescribing in emergency medicine.We linked emergency department adult and pediatric records from the National Ambulatory Care Reporting System and medication dispensations from community-based pharmacies in the Pharmaceutical Information Network. From January 2010 to February 2020, we identified emergency department visits for 5 conditions that were potentially inappropriately treated using antibiotics per CWC recommendations . We used an interrupted time series design to detect changes in antibiotic prescribing by fitting Autoregressive Integrated Moving Average (ARIMA) models to account for secular trends and seasonality, allowing for change in slopes to measure the effect of each CWC intervention.Antibiotics were commonly prescribed in emergency departments for bronchitis (proportion of visits with antibiotics: 57%) and asthma (22%) in adults; bronchiolitis in children (43%); pharyngitis (39%) and acute otitis media (54%) in adults and children. Based on visual inspection, the proportion of emergency department visits for each condition where antibiotics were dispensed remained relatively consistent. The ARIMA models demonstrated mixed impacts on potentially inappropriate antibiotic prescribing associated with two interruptions: the 2015/2016 CWC recommendations and subsequent 2018 CWC Using Antibiotics Wisely campaign. Following each interruption, antibiotic prescribing was slightly reduced for bronchitis  and bronchiolitis (not significant) , but unchanged for asthma  and pharyngitis , and slightly increased for acute otitis media (not significant) .Rates of potentially inappropriate antibiotic prescribing remained constant over the past 10 years in Alberta. Campaigns to rethink antibiotic use in emergency medicine may have resulted in small decreases in antibiotic use; however, further initiatives building upon existing campaigns are required to substantially reduce rates of inappropriate antibiotic prescribing."}
+{"text": "Children with acute brain damage make up a large group of patients who require multi-stage rehabilitation. Rehabilitation requires the creation of special conditions for psychiatric care and psychological and pedagogical correction of the consequences of severe damage to the nervous system.To identify the options for mental activity during the restoration of the level of consciousness in children after acute severe brain damage.210 children under the age of 18 with severe brain damage . Clinical-psychopathological, pedagogical methods were used; additionally diagnostic scales, questionnaires.4 groups were formed: 1st 37 (18%) patients had manifestations of mental activity with physical, cognitive and social capabilities in the minimal consciousness \u201c+\u201d ; 2nd 67 (32%) - manifestations of physical and cognitive abilities with minimal consciousness \u201c-\u201d (a- / hyperkinetic mutism without reactions); 3rd 95 (40%) - only the manifestation of physical capabilities at the exit from the vegetative status. 4th 11 (10%) - a low manifestation of mental activity in the form of physical capabilities with a vegetative status.4 variants of mental activity in children after acute severe brain damage have been identified: from minimal involuntary reactions or their absence in vegetative status to voluntary actions according to the instructions of an adult in minimal consciousness \u201c+\u201d. Taking into account the variability of mental activity helps to differentiate the methods of psychiatric and psychological-pedagogical assistance in the recovery of children already in the early stages of rehabilitation."}
+{"text": "A key facet of innate immunity in plants entails the recognition of pathogen \u201ceffector\u201d virulence proteins by host Nucleotide-Binding Leucine-Rich Repeat Receptors (NLRs). Among characterized NLRs, the broadly conserved ZAR1 NLR is particularly remarkable due to its capacity to recognize at least six distinct families of effectors from at least two bacterial genera. This expanded recognition spectrum is conferred through interactions between ZAR1 and a dynamic network of two families of Receptor-Like Cytoplasmic Kinases (RLCKs): ZED1-Related Kinases (ZRKs) and PBS1-Like Kinases (PBLs). In this review, we survey the history of functional studies on ZAR1, with an emphasis on how the ZAR1-RLCK network functions to trap diverse effectors. We discuss 1) the dynamics of the ZAR1-associated RLCK network; 2) the specificity between ZRKs and PBLs; and 3) the specificity between effectors and the RLCK network. We posit that the shared protein fold of kinases and the switch-like properties of their interactions make them ideal effector sensors, enabling ZAR1 to act as a broad spectrum guardian of host kinases. Arabidopsis thaliana, the extracellular domains of leucine-rich repeat receptor kinases form a complex and multi-layered network through physical interactions to regulate their roles in a wide range of biological functions  also form extensive networks, both with other NLRs and distinct receptor classes, to mediate immunity against a broad range of pathogens  was first characterized for its genetic requirement in the recognition of the Pseudomonas syringae acetyltransferase effector HopZ1a (zed1 (hopZ-ETI-deficient1) mutant as also being deficient in HopZ1a ETI  Kinase7) to suppress immunity   in thaliana . Membersthaliana . Severalthaliana , all of or AvrAC . ZRK3 is HopF2a)  and ZED1 HopF2a) . OverallX. campestris effector AvrAC provided crucial mechanistic insights into ZAR1 activation, culminating in the first structure of a plant resistosome  . HoweverA. thaliana has no apparent effect on PTI or plant development  also share a similar distribution pattern to AtZAR1 orthologs and have been identified across several angiosperm lineages (Solanum lycopersicum (tomato), the Magnoliid Liriodendron chinense (Chinese tulip tree), and the monocot Colocasia escuelenta (taro), among others are able to interact with their corresponding ZRKs , a member of the RLCK XII family of proteins and a paralog of ZED1, to mount an immune response against the Xanthomonas perforans YopJ family effector XopJ4 , sesame (Sesamum indicum), rice (Oryza sativa), false flax (Camelina sativa), canola (Brassica napus), and N. benthamiana , Natural Sciences and Engineering Research Council of Canada Postgraduate Awards (CB-M and BL), an Ontario Graduate Scholarship (CB-M), and the Centre for the Analysis of Genome Evolution and Function (DSG and DD).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-13850-6, published online 14 June 2022Correction to: The original version of this Article contained an error.As a result of an administrative mistake the incorrect number of the IRB approval was included in this manuscript. The study was performed under two protocols approved by the Institutional Review Board of Seoul National University Dental Hospital: CRI14037 and CRI20004. As a result, in Methods, under the subheading \u2018Subjects\u2019,\u201cThe study was approved by the Institutional Review Board of Seoul National University Dental Hospital and informed consent was obtained from all individual participants included in the study (CRI 08027).\u201dnow reads:\u201cThe study was approved by the Institutional Review Board of Seoul National University Dental Hospital and informed consent was obtained from all individual participants included in the study (CRI14037 and CRI20004).\u201dThe original Article has been corrected."}
+{"text": "Depressive symptoms in schizophrenia have a high prevalence \u2013 up to 20-60 %, at the different illness stages. Non-pharmacological treatment, namely rTMS, seems like a promising approach that lacks side-effects typical for antidepressants. RTMS is widely applied in the treatment of depression, however the studies within schizophrenia domain are still rather fewThe aim was to examine a potential of neurophysiological data for prediction of the effects of rTMS in the treatment of patients with schizophrenia with depressive symptoms20 male patients with schizophrenia  were examined at the stage of incomplete remission with predominance of prolonged (more than 6 months) treatment resistant depressive symptoms. An examination  fragments)) was repeated twice - before and after a course of 10 Hz rTMS .Poor outcome was associated with initially higher coherence in alpha and lower - in beta1 EEG bands. The amplitudes of non-target N100 and mismatch negativity didn\u2019t differ the groups of responders and nonrespondersThe disturbances within brain networks of beta1 and alpha generators merit attention as potential neurophysiological markers with predictive value in rTMS treatment of patients with schizophrenia with depressive symptoms.No significant relationships."}
+{"text": "As the restaging [18F]FDG PET showed intense [18F]FDG uptake in the urinary bladder at the resection site concerning for recurrence, the lesion was subsequently resected and histopathology showed extensive granulation tissue with foreign body-type giant cell reaction with no suspected foreign bodies or neoplasia.Foreign body-type giant cell reaction is typically a biological and immunological reaction to the presence of foreign bodies such as catheters, parasites or biomaterials with a collection of fused macrophages (giant cell). We reported an unusual case of [ The main limitation of Lugano criteria with a high false-positive rate of FDG avid lesions is well recognized  post-initial resection and chemotherapy, with histopathologic findings of foreign body-type giant cell reaction.We present a case of intense FDG PET/CT in May 2021, an intensely hypermetabolic bladder wall lesion at the prior resection site was identified with a maximum standard uptake value (SUVmax) of 67.9 (SUVmax of radiourine was 32.3), with a ratio of 30.9 and 25.1 when scaled to uptake of blood pool and liver . In the present case, the markedly intense uptake (SUVmax of 68) is rarely observed, likely indicative of rapid tumor response to chemotherapy with extensive tumor necrosis and active inflammatory process.The inflammatory process with foreign body-type giant cell reaction is known to be associated with increased [18F]FDG avid lesion with foreign body-type giant cell reaction could occur without the presence of a foreign body and may be indicative of rapidly dying tumor cells in initial response to chemotherapy. We concluded that the intensity of [18F]FDG uptake in the suspected lesion in diffuse large B cell lymphoma following chemotherapy may be nonspecific and should not be used as the diagnostic criterion for malignancy.In conclusion, highly ["}
+{"text": "The 2019 coronavirus epidemic (CoViD-19) in Italy originated in Lombardy, on February 21, 2020. Crowding has been defined as a worldwide problem and causes reduced quality of care. It is due and identified by three orders of factors: those at the access (input); those related to the patient\u2019s process (throughput); and those at the exit from the ED (output).We evaluated all the population who went to ED for mental disorder. Due to the high level of care needed and the simultaneous exposure to risk factors, an excessive duration of ED process can be counterproductive.We evaluated all patients accessing our ED for mental disorder from February 22 to May 1, 2020 and during the same period of the previous year.We enrolled 345 patients. The Crowding input factors are lower in the pandemic period: reduced attenders (142 vs 203) and reduced average waiting times (40 min vs 54 min). The Crowding throughput factors have instead worsened: LOS (length of stay) for both visit rooms (383 vs 271 min) and holding area (1735 min vs 797 min). The Crowding output factors also worsened: the percentage of access block is higher during the pandemic (100% vs 20%). The Total Access Block Time is significantly higher in the CoViD period for both the visit rooms (3.239 vs 649 min) and the holding area (590 vs 185 min).The pandemic period presented a worsened crowding for these patients due to the Access Block."}
+{"text": "Composite child feeding indices (CCFIs) developed from various relevant measures of dietary intake by infants and young children have several potential applications in nutritional epidemiological studies for the development and deployment of precise public health nutrition interventions against child undernutrition. The predictive utility of some CCFIs (computed from varying formulation components) for child nutritional status  were compared. The purpose of the study was to identify the most suitable among them for possible standardization, validation, and adoption by nutritional health researchers. Using cluster sampling, data from 581 mother\u2013child pairs were collected. Multivariable regression analyses were applied to the data obtained through a community-based analytical cross-sectional survey design. Three of the CCFIs were found to be significantly associated with only wasting (WHZ) from the linear regression models after adjusting for potential confounders and/or correlates. None of the CCFIs  was consistently predictive of all three measures of child nutritional status, after controlling for potential confounders and/or correlates, irrespective of the choice of regression method. CCFI 5 was constructed using a dimension reduction technique\u2014namely principal component analysis (PCA)\u2014as the most optimal summary index in terms of predictiveness for child wasting status, validity, and reliability (Cronbach\u2019s \u03b1 = 0.80) that captured relevant dimensions of optimal child food intake. The dimension reduction approach that was used in constructing CCFI 5 is recommended for standardization, validation, and possible adoption for wider applicability across heterogeneous population settings as an optimum CCFI usable for nutritional epidemiological studies among children under five years. Child food intake and/or nutrition-related factors are estimated to be associated with about 45% of global mortality amongst pediatric populations under five years . The seeIYCF indicators are widely utilized within the nutritional epidemiological research (NER) community. They constitute some of the key indicators reported by nutritional epidemiologists, pediatricians, public health nutritionists, and researchers in global, national, regional, and community nutrition study reports. However, NER literature is replete, with study findings of inconsistencies in the predictive utility of the individual IYCF indicators for child nutritional status, contrary to the association theoretically postulated and espoused by the developers and users alike within the NER community ,12,13. FThe purpose of this study was to compare the predictive utility of some CCFIs (computed from varying formulation components) for child nutritional status  using a cross-sectional study data set obtained from a resource-constrained study setting in northern Ghana, a West African country in Sub-Saharan Africa (SSA).The northern region of Ghana has the country\u2019s highest prevalence rate of stunting  according to the Ghana Demographic and Health Survey 2014 report  and the A community-based analytical cross-sectional design was used for this study conducted in June 2018. Together with their children (6\u201323 months), 634 mothers of reproductive age (15\u201349 years) were selected using a two-stage cluster sampling technique from stunting-endemic districts of the northern region of Ghana. There are several languages and dialects spoken in northern Ghana. However, the major languages spoken in the selected study districts are Dagbani (Dagombas), Gonja, and Nanumba. The study participants were drawn from 25 communities across five of the districts in the northern region with a relatively high prevalence of stunting (\u226530%) amongst children under five years of age .n = 284. The required minimum sample size was estimated to be n = 568 based on the assumption of a correction factor of 2.0 due to the design effect for cluster sampling [The final sample size used for the statistical analyses of the study data was 581 and was determined from the standard formula for one-point sample estimation ,44. The sampling . The calsampling .A local field research team , recruited mostly from the northern region and provided with training prior to the pilot and definitive surveys, was led by the principal investigator to conduct an interviewer-administered survey of 634 mother\u2013child pairs. The training exercise was to ensure high intra- and inter-rater reliability ,46. The Self-reported dietary intake indicators of child breastfeeding and complementary feeding status and/or practices were used to construct five CCFIs with varying components and scoring guides as summarized in Measures of child nutritional status were the outcome variables in this study. The heights/lengths and weights (anthropometric measurements) of the children and mothers were measured to determine nutritional status. The following measurements were used to calculate the anthropometric (bodily) indicators of underweight, stunting and wasting status, respectively: WAZ (weight-for-age), LAZ (length-for-age), and WLZ (weight-for-length: SD < \u22122) for the children and BMI (body mass index) for the mothers using the WHO Anthro Software Version 3. Computed Z-scores were based on the 2006 WHO growth standards, expressed as standard deviation units from the median value for the WHO growth reference groups . ImprobaThe independent variables of interest in this study were the CCFIs in the continuous and categorical forms, constructed from various indicators of infant and young child feeding practices. The determinants (independent variables) of undernutrition in the northern region of Ghana in this study were classified into proximal or immediate, intermediate, or underlying and distal or basic factors based on an adapted version of the UNICEF hierarchical conceptual framework  as descrThe child feeding practice indicators of this study were estimated from self-reported 24 h food recall (24HFR) ,7. Each Minimum acceptable diet (MAD) was defined as the proportion of children who received both the MMF and MDD for their age category, as classified by the WHO. Intake of micronutrient-rich foods (MRF) was also estimated for vitamin A and iron (Fe), using the 17 food groups as classified by the FAO . ChildreAppropriate complementary feeding (ACF) was a composite child feeding index (CCFI) constructed from TICF, MMF, and MDD as previously described ,30. ACF,n = 634) were coded, entered, and screened using IBM SPSS Software (Version 27). Cases with missing values and/or implausible Z-scores were deleted from the dataset. The cleaned data set (n = 581) were evaluated for compliance with the key assumptions underlying multivariable regression analyses. These diagnostics included sample size adequacy, missing values, univariate outliers, multivariate outliers (Cook\u2019s distance), normal distribution of residuals (P-P plot), linearity (scatter plots), homoscedasticity , multicollinearity (variance inflation factor (VIF)), and independence of observations or residuals (Durbin\u2013Watson statistic) [Responses from the interviewer-administered questionnaires n = 4 were coatistic) .t-test  and Pearson\u2019s chi-square ((\u03c72) tests . The means and standard deviations (SD) and relative frequencies were reported for the continuous and categorical forms of the CCFI component variables, respectively. Bivariate analyses were conducted also to determine associations  between each categorical independent variable (IV) and the categorical form of the dependent variables (less than \u22122 SD for stunting and wasting) using Pearson\u2019s chi-square ((\u03c72) tests at p < 0.05. Pearson correlation coefficient (r) and simple linear regression were used to measure the strength, direction, and significance of the relationships between the covariates  and the continuous form of the DVs at p < 0.05 [Descriptive analyses were performed to summarize the characteristics of the study participants, all the other covariates or factors (independent variables (IVs)), and prevalence of the dependent variables  using mean and standard deviation for the continuous variables, counts, and relative frequencies (percentages) for the categorical variables. Bivariate analyses were also performed to examine the distribution of each CCFI using ANOVA and p < 0.05 ,66.p < 0.05. However, explanatory variables that were considered to have clinical relevance from literature search and were also statistically significant at p < 0.10 were included in the multivariable regression models [A predictive statistical modelling approach was used to analyze the association between each CCFI and the measures of child nutritional status , accounting for the effects of potential confounders (relevant factors and/or covariates) in the model specifications ,68. Multn models ,69. The 2 for the logistic regression models. The coefficient of determination (R2) was used as a measure of goodness of fit and parsimony for the multiple linear regression models [The overall model performance  were assessed using the Hosmer\u2013Lemeshow goodness of fit test and the Nagelkerke Rn models ,71. Two-Content and construct validity of the five CCFIs were assessed qualitatively by the authors based on consensus, cognizant of inferences from the previous studies . InternaSensitivity (what-if) analyses of the study results were conducted to assess the robustness of the final parsimonious models based on the form of the CFFI used  and the exclusion of breastfeeding status from CCFI 1 formulation ,76,77.In accordance with the requirements of the Helsinki Declaration, ethical clearance was obtained from the Ghana Health Service Ethics Review Committee (GHS-ERC: 011/11/17) in Accra, Ghana, and the Ethics Committee of Bielefeld University (EUB 2018-083) in Bielefeld, Germany. Community and household entry protocols for the study area were followed accordingly to gain access to the study participants. Written informed consent prior to enrolment was obtained from each mother by endorsement with a thumb print and/or signature on the consent forms provided after explaining the purpose and scope of the study to the participants in their native languages. Verbal consent was also obtained from the household heads in accordance with their cultural values and community normsCharacteristics of study participants and prevalence of child nutritional status are as follows:The majority of participating mothers (55.2%) were aged 25\u201334 years, farmers (55.6%), married (97.2%), and currently breastfeeding (96.4%). The majority of children (89.9%) weighed less than 2.5 kg at birth, with 32.2% being stunted .p < 0.05). Of the five CCFIs, the child age group of 9\u201311 months had the highest median score (50th percentile) for CCFI 1, all the three age groups had the same median score for CCFI 2, child age group of 12\u201323 months had the highest median score for CCFI 3, child age group of 9\u201311 months had the highest median score for CCFI 4, and child age group of 12\u201323 months had the highest median score for CCFI 5 , maternal age and height, child age group, usage of insect-treated nets (ITN), and the number of occupants per the child\u2019s household, which were significantly associated with child stunting status in the bivariate analysis. Religion, tribe (ethnicity), marital status, maternal body mass index (BMI), child age group, child gender (sex), child health status (morbidity in the last two weeks and frequency of diarrhea in the last six months), child immunization status, frequency of prenatal care (PNC) services attended, and the source of power (energy) for household utility were significantly associated with child wasting status in the bivariate analysis. The district of residence, community, tribe, type of community , maternal BMI and height, child age group and gender, child health status (morbidity in the last two weeks), the source of power (energy) for household utility, and the number of people per room in the household were significantly associated with child underweight status in the bivariate analysis. Child gender, child\u2019s recent morbidity status, and maternal BMI were consistently associated significantly with wasting status in the multivariable regression models, alongside with CCFI 1, 4, and 5.None of the CCFIs in the continuous form was consistently predictive of all three measures of child nutritional status  after controlling for potential confounders and/or correlates. The continuous forms of CCFI 1, 4, and 5 were significantly predictive of only wasting (WHZ) from the linear regression models after adjusting for potential confounders and/or correlates .The continuous form of the CCFIs were all not significantly predictive of child stunting (HAZ), wasting (WHZ), and underweight (WAZ) status in the bivariate regression models except CCFI 2 for stunting (logistic regression) and underweight status (linear regression); CCFI 3 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression), CCFI 4 for wasting (linear regression) and underweight status (linear regression), and CCFI 5 for stunting (linear and logistic regression), wasting, and underweight status (linear regression). Only CCFI 3 and CCFI 5 were consistently associated with child nutritional status in the bivariate analyses irrespective of the type of regression method used except for the simple logistic regression analyses between CCFI 3 and wasting or underweight status and that between CCFI 5 and wasting status .There was consistency in the predictive outcomes of the continuous forms of the CCFIs irrespective of the choice of regression methods (linear or logistic) used except CCFI 1 for wasting (multivariable), CCFI 2 for stunting (bivariate) and underweight status (bivariate), CCFI 3 for wasting (bivariate) and underweight status (bivariate), CCFI 4 for wasting (multivariable and bivariate) and underweight status (bivariate), and CCFI 5 for wasting status (multivariable and bivariate) .There was consistency in the predictive outcomes of the continuous forms of the CCFIs for child nutritional status compared with the adjusted (multivariable) and unadjusted (bivariate) models except CCFI 1 for wasting (linear regression); CCFI 2 for stunting (logistic regression) and wasting status (linear regression); CCFI 3 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression); CCFI 4 for underweight status (linear regression); and CCFI 5 for stunting (linear and logistic regression) and underweight status (linear and logistic regression). Only the continuous form of CCFI 1 exhibited Simpson\u2019s paradox, that is, a spurious reversal of statistical significance, strength, and/or direction of association for the prediction of wasting (WHZ) in the linear regression model. The bivariate association between CCFI 1 and wasting was not statistically significant, but after controlling for the potential confounders and/or correlates, CCFI 1 became significantly associated with wasting .None of the CCFIs in the categorical form was consistently predictive of all three measures of child nutritional status , irrespective of the regression method (linear or logistic), after controlling for potential confounders and/or correlates .The categorical form of each CCFI was not significantly predictive of child stunting (HAZ), wasting (WHZ), and underweight (WAZ) status in the bivariate regression models except CCFI 1 for stunting (linear and logistic regression) and underweight status (linear and logistic regression); CCFI 2 for underweight status (linear regression); CCFI 3 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression); CCFI 4 for stunting (linear and logistic regression) and underweight status (logistic regression); and CCFI 5 for stunting (linear and logistic regression), wasting, and underweight status (linear regression). None of the categorical forms of the CCFIs was consistently associated with all the three measures of child nutritional status in the bivariate analyses for both linear and logistic regression model specifications .There was consistency in the predictive outcomes of the categorical forms of the CCFIs irrespective of the choice of regression methods (linear or logistic) used except CCFI 2 for underweight status (bivariate), CCFI 3 for wasting (bivariate) and underweight status (bivariate), CCFI 4 for underweight status (bivariate), and CCFI 5 for wasting (bivariate) and underweight status (bivariate) .There was consistency in the predictive outcomes of the categorical form of the CCFIs for child nutritional status compared with the adjusted (multivariable) and unadjusted (bivariate) models except CCFI 1 for stunting (linear and logistic regression) and underweight status (linear and logistic regression); CCFI 2 for underweight status (linear regression); CCFI 3 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression); CCFI 4 for stunting status (linear and logistic regression); and CCFI 5 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression). None of the categorical forms of the CCFIs exhibited Simpson\u2019s paradox .CCFI 1 and CCFI 5 had the lowest and highest Cronbach \u03b1 values, respectively, in correspondence with the number and relevance of the test item components used in their construction . Breastf2) used to assess the trade-off between the goodness of fit and parsimony for the multiple linear regression models explained 6.7% of the variance in child wasting status for CCFI 1, 7.5% for CCFI 4, and 7.5% for CCFI 5  used in the modeling. The adjusted coefficient of determination (adjRr CCFI 5 .The purpose of this study was to compare the predictive utility of CCFIs (computed from varying formulation components) for child nutritional status . After controlling for potential confounders and/or correlates in the regression models, CCFI 5, which was constructed using a dimension reduction statistical technique, namely PCA, was found to have a relatively higher predictive utility for child wasting status compared to CCFI 1, which was constructed following the seminal formula of Ruel and Menon . It was In most of the studies that adopted the Ruel and Menon  approachTo the best of our knowledge, no study has adopted the PCA approach to construct CCFI. However, similar epidemiological and public health studies that used dimension reduction as a statistical technique to generate a summary index for predictive modeling purposes found it to be robust and clinically useful ,80,81.Acute undernutrition also referred to as wasting status (WHZ/WLZ) is one of the key nutritional health indicators used in the construction of the Global Food Security Index (GFSI) and Global Hunger Index (GHI) for the classification of populations prone to food insecurity, hunger, and/or malnutrition. The consistency and suitability of the CCFIs especially CCFI 5 for predicting wasting status can also therefore be useful as a public health tool to rapidly identify undernourished children under five years under acute food shortage or emergency situations.The measurement validity  of the CCFIs as constructed in this study were generally rated subjectively  as ranging between low and very good even though the test items of the sub-domains covered the relevant aspects of optimal child food intake, namely breastfeeding and complementary feeding ,74. CCFIThe Cronbach alpha values of CCFI 1, 4, and 5  were indicative of low to very good internal consistency as a measure of reliability (or homogeneity of the test items) of the construct representing optimal young child food intake ,82,83. TThe findings from the sensitivity analyses and model performance evaluations agree with studies that suggest that the choice of statistical method, form of the predictors in the regression models, and the selection criteria for inclusion or exclusion of one or more IVs in regression models could influence the inferences obtainable ,85. ThisThis study is the first attempt to compare the predictive utility of variously formulated composite child feeding indices (CCFIs) that reflect the multidimensionality of optimal child dietary intake for identifying infants and young children at risk of undernutrition . Even though the cross-sectional design used for this study precludes it from establishing causality, the reliability, validity, model performance, and sensitivity analyses conducted provides additional confidence in the study results. It also highlights some important conditions that potentially debunk or otherwise accentuate the robustness of the postulated association between CCFIs and child nutritional status measures.Some possibly unmeasured confounders and residual confounding coupled with potential reporting bias (under- or overestimation from 24 HDR) and probable covariate selection bias may have suppressed or otherwise potentiated the effects of the CCFIs on child nutritional status ,87. The No internal and external model validation analyses were conducted; thus, the practical utility and generalizability of the CCFIs identified to be predictive of wasting status (WHZ) of children under five years cannot be proffered from this study. No clinical utility or practical epidemiological significance evaluation of the predictive models were conducted because none of the CCFIs was consistently predictive of all the three measures of child nutritional status (undernutrition) in this study after adjusting for potential confounders. No interaction analyses were conducted to assess the moderation effects of covariates such as child age and gender on the association between CCFI and wasting.The predictive utility of CCFIs for child nutritional status is sensitive to the components and/or various measures of child feeding practices used in their formulation and construction. After adjusting for the potential confounders measured, CCFI 1, CCFI 4, and CCFI 5 were significant predictors of wasting status of children under five years.The dimension reduction approach (PCA), which was used in formulating and constructing CCFI 5, is recommended for internal and external validation and possible adoption for wider applicability across heterogeneous study settings as the potentially optimum composite child feeding index usable for nutritional epidemiological studies among children under five years. Just as the hunger index (HI) and global food security index (GFSI) are used for ranking the vulnerability to malnutrition across communities, countries, and geographical regions, CCFI 5 could be used for a similar purpose.More robust study designs  and validation methods should be considered for exploration to address some of the limitations widely known to be inherent in cross-sectional design studies and self-reported dietary intake measurement instruments during the validation of these study findings. A comparative study of the effects of the choice of various regression methods  on the predictive utility of CCFIs for undernutrition, with or without the dichotomization (or categorization) of continuous data, is also recommended as explored by Sauzet et al.  in an ob"}
+{"text": "This talk will explore: 1) the conceptual importance of select interpersonal factors inherent to Black culture and bereavement, and 2) the impact of these factors on grief in a Black bereaved sample. 103 Black adults aged 45+ were administered items assessing cultural  and bereavement-specific  factors. Using linear regressions, closeness (p<.001), suddenness (p=.020), anger (p<.001), and communalism (p<.001) predicted reported levels of grief. This study identifies factors which substantially dictate the experienced levels of grief of bereaved Black adults in the latter half of life. With cultural factors notably impacting the Black bereavement experience, individuals seeking to work with this population must adopt strategies to keep bereaved Black adults connected to their communities throughout their loss. Resources to support Black adults in maintaining healthy continuing bonds with the deceased through abrupt or unsettling losses also appear paramount."}
+{"text": "Reminiscence therapy (RT) is a multi-sensory treatment that uses a combination of sight, touch, taste, smell and sound to help persons with dementia (PWD) remember events, people and places from their past lives. Currently, digital technologies such as mobile applications and immersive solutions including virtual and augmented reality, are gaining momentum as supplementary tools for RT. This paper presents a usability study of a web-based and virtual reality application to understand the limitations and opportunities of digital platforms for facilitating engaging experiences for PWD towards recalling memories, while easing the therapy process for the caregivers. A total of ten healthcare caregivers were recruited from the Geriatric Dementia Unit and Geriatric Transitional Unit in Ontario Shores Center for Mental Health Sciences, Ontario Canada. Usability feedback from the caregivers were collected from the interviews after the completion of the System Usability Scale (SUS) questionnaire. Institutional caregivers found both web-based and virtual reality (VRRT) usable with SUS score above average (68/100), but required improvements related to the onboarding training of caregivers. The interview revealed four overarching themes related to the VRRT: (1) Ease of use; (2) Positive impact on caregiving; (3) Potential of reduction in responsive behaviors; (4) Feasibility for promoting social connection during COVID-19 pandemic. Next steps will focus on improving the user experience and expanding the application for immersive VR supporting head-mounted displays, hand tracking, and physiological measures, as well as conducting an usability study with PWD to expand our understanding of using RT digital tools with various levels of immersion."}
+{"text": "This case series describes the kinetics of humoral deficiency in patients with relapsed refractory multiple myeloma treated with bispecific antibodies, the infectious complications, and response to COVID-19 immunization. We report on the kinetics of humoral deficiency among patients with RRMM treated with bsAb, the infectious complications, and response to COVID-19 immunization.Bispecific antibodies (bsAb) targeting novel antigens are a promising class of therapeutics for relapsed refractory multiple myeloma (RRMM).6 and antibiotic prophylaxis was prescribed per current institutional guidelines. Statistical analysis details are provided in the eMethods in the In this case series, we included patients with RRMM treated in early phase 1 and 2 clinical trials of bsAb at our institution between January 1, 2019, and December 31, 2021. Patients self-reported their sex and race and ethnicity; the latter data were collected due to the high incidence of multiple myeloma among racial and ethnic minority groups. Serial immunoglobulin levels and infections confirmed by clinical, imaging, microbiologic, or histopathologic evidence were captured retrospectively from the start of therapy until last follow-up or 3 months after study exit. Cytokine release syndrome and immune effector cell\u2013associated neurotoxicity syndrome were graded per American Society for Transplantation and Cellular Therapy criteria,reporting guideline for case series.The Medical College of Wisconsin Institutional Review Board approved this study and waived the need for informed consent owing to its retrospective design. This study followed the Forty-two patients contributing 49 treatment periods (7 patients were counted twice) were included in our analysis . The The overall cumulative risk of infections increased with increasing duration of therapy with risk at 3 months of 41%; at 6 months, 57%; at 9 months, 64%; at 12 months, 67%; and at 15 months, 70%. The most common infections were bacterial (44 of 81 [54%]), followed by viral (33 of 81 [41%]) and fungal (4 of 81 [5%]) infections. Respiratory tract infections accounted for 41 of 81 infections (51%). Four deaths were attributed to infections, including 2 patients who died within 90 days of treatment . On multThe findings of this case series highlight the prolonged hypogammaglobulinemia and increased risk of infectious complications with a 70% cumulative infection risk in patients with RRMM treated with bsAb therapy. The risk of infection was associated with the degree of hypogammaglobulinemia and increased with treatment. We also noted an increasing rate of seroconversion with COVID-19 booster vaccination series. Our study is limited by the small sample size and heterogenous patient population treated with differing dose escalations and combinations with other myeloma therapies; nevertheless, our findings underscore the changing continuum of humoral immunodeficiency and infection risk with this growing class of therapeutics in RRMM."}
+{"text": "HIV rapid testing services is one among key interventions in the controlling of HIV/AIDS. Despite availability of quality standards, the quality of HIV rapid testing services remains questionable since non-laboratory testers are allowed to conduct testing while they are not specialized in providing testing services.To evaluate the compliance to the quality standards of HIV rapid testing services provided by non-laboratory testers in Makete District, TanzaniaAn explanatory descriptive study employing quantitative approach of data collection was used. An observation of 23 non-laboratory testers performing HIV rapid tests, observation of HIV testing points and documents review was done in 23 testing points to collect data. Data were analyzed using a programmed excel sheet and a three-point scale was used to determine the level of compliance to quality standards.Analysis shows that out of 23 testing points visited, the level of compliance to quality standards was lower for 22 (95.6%) testing points and moderate in 1 (4.4%) testing point. None of the testing point was highly complied to quality standards for HIV rapid testing services.The quality of HIV rapid testing services provided by non-laboratory testers is below the established quality standards for HIV rapid testing services. HIV rapid testing services is among key interventions in the controlling of HIV/AIDS since it provides chances to access HIV care, treatment, prevention, and support services.5Several studies have been conducted to evaluate the quality of HIV rapid testing services. An auditing study conducted in Caribbean and African countries, which involved 968 HIV testing points demonstrated that 20% of the testing points scored level 0; 46% of the testing points scored level 1; 31% of the testing points scored level 2; while 3% of the testing points scored level 3 and none of the testing point that had high level of compliance to quality standards such that none of the testing points scored level 4.6Furthermore a study conducted in 102 private health facilities in Kampala Uganda to evaluate the quality of HIV rapid testing services demonstrated that the quality of HIV rapid testing services is below the recommended quality standards.7Tanzania has also adopted the WHO quality standards for the implementation of HIV rapid testing services.The study was conducted at Makete District Council in Njombe Region, Southern Tanzania. HIV Records for 2016/2017 show that Njombe Region has the highest HIV prevalence (11.4%) in Tanzania.Purposive sampling technique was used to select both public and private health facilities where by all HIV rapid testing points were studied and non-laboratory testers who provided services on the day of the study were observed when performing actual HIV rapid tests.An on-site checklist for document review and observation adopted from WHO by the Tanzania Ministry of Health was used to collect quantitative data. The main areas of observations included: personnel training and certification; physical facility; safety; pretesting phase; testing phase; documentation and records as well as external quality assessment.Ethical clearance to conduct this study was obtained from Research and Ethics Committee (REC) of Muhimbili University of Health and Allied Sciences (MUHAS). Permission to conduct the study was requested from the District Medical Officer of Makete District and officer in charges of the respective health facilities. Study participants were informed about the purpose of the study, procedures, risk and benefits for them to participate in the study. Informed written consent was obtained from each study participant after agreeing to participate in the study.Data were collected manually and entered into excel sheets and they were cleaned and validated. All descriptive data were analyzed using programmed excel sheets and data were presented in frequency tables of numbers, percentages  and level of compliance to quality standards for HIV rapid testing service. Summation of each response of the open ended question in each quality standard was used to determine the average compliance for each quality standard. A three-point scae  was used to determine the level of compliance to all quality standards for HIV rapid testing services for each testing points whereas testing points scored level 4 (score of 90% or higher) were defined as highly complied to quality standards; level 3 (score of 80% \u2013 89%) were defined as moderately complied to quality standards; level 2 (60% \u2013 79%), level 1 (40% \u2013 59%) and level 0 (less than 40%) were defined as lower complied to quality standards.Most of the HIV testers (34.8%) worked on wards, Reproductive and Child Health section (21.7%) and Care and Treatment Centre (13%). The majority of the testers (52%) were from the district level health facilities while about 22% of them were from dispensaries. Majority of the testers (78%) worked in the government health facilities and the remaining 22% worked in private health facilities. Most of testers were women (78.3%) while 21.7% were men. All testers (100%) had ordinary level of secondary education whereas among them 69.6% testers had certificate level of education and 30.4% had diploma level of education. Only one study participant (4.4%) was clinical officer, 30.4% were enrolled nurses and 34.8% were Medical attendants while 30.4% were assistant nursing officers.Evaluation results show that out of 23 testing points visited, the level of compliance to the quality standard was lower for 22 (95.6%) testing points. Two (2) testing points (8.7%) scored level zero, 13 (56.5%) testing points scored level one and 7 (30.4%) scored level two. The level of compliance to HIV rapid testing quality standards was moderate in 1 (4.4%) testing point. None of the testing point had high level of compliance to the HIV rapid testing quality standards, meaning that no testing point attained level four. Average compliance for each quality standard was also determined by observing how non-laboratory testers and testing points operations comply with such standards. These standards include: personnel training and certification; physical facility, safety, pretesting phase, testing phase, documentation and records as well as external quality assessment. The average compliance to personnel training and certification quality standards was 15% whereas: only 9 (39%) out of 23 non laboratory testers that provided HIV rapid testing services on the day of the study received comprehensive training on HIV rapid testing using the nationally approved curriculum; only 2 (9%) non-laboratory testers were trained on external quality assessment (EQA)/proficiency testing (PT) process; only 5 (22%) non-laboratory testers were trained on safety and waste management procedures and practices. No any non - laboratory tester has been certified or licensed through a national certification program to perform HIV rapid testing services.Average compliance to physical facility quality standards was 65% whereas: 16 (66%) testing points have designated area for providing HIV rapid testing services; 11 (48%) testing points were clean and organized for testing; 22 (96%) of testing points had sufficient lighting; none of the testing points store test kits in temperature-controlled environment and there was no device to monitor temperature in all visited testing points and 18 (78%) testing points had sufficient and secure storage space for test kits and other testing consumables.Average compliance to safety standards was 56% whereas: only 2 (9%) testing points had SOPs to manage spills of blood and other body fluids; only 4 (17%) testing points had SOPs to address accidental exposure to potentially infectious body fluids through a needle stick injury, splash or other sharps injury; all 23 (100%) testing points had personal protective equipment (PPE) and testers properly used PPEs through the testing process; 13 (57%) testing points had hand-washing facilities such as water and liquid soap. Only 6 (26%) testing points handled properly waste materials such as sharps, infectious and non-infectious waste and only 13 (56%) testing points disinfect working area with the appropriate disinfectant such as chlorine.The average compliance to pre testing phase standards was 63% whereas: only 9 (39%) testing points had national guidelines for HIV testing services; all 23 (100%) testing points use national algorithm and approved HIV rapid kits; expired HIV rapid test kits such as uni-gold were available in 9 (39.1%) testing points; only 4 (17%) testing points had a standard process for stock management; only 4 (17%) testing points had posted job aides on client sample collection; 19 (82%) testing points had sufficient supplies for client sample collection and in only 9 (39%) testing points, client's identifiers were recorded in the HIV testing register and on test devices as per national guidelinesThe average compliance for testing phase standards was 53% whereas: only 5 (54%) testing points had SOPs on HIV testing procedures and posted at the testing area; timers were available and used routinely in only 1 (4.3%) testing point; sample collection devices such as capillary tube, loop, disposable and pipettes were used accurately in 22 (95%); testing procedures such as correct use of buffer and reading of results on time were adequately followed in 16 (70%) testing points and positive and negative quality control specimens were routinely used in 13 (57%) testing points. Retest for verification was done in 4 (67%) health facilities out of 6 health facilities visited.Average compliance to documentation and records standards was 92% whereas: 20 (87%) testing points had standardized register for documentation, which contain key elements in the registers such as client demographics, kit names, lot numbers, expiration dates and tester name. The final HIV results were recorded correctly in 16 (70%) testing points; client documents and records were securely kept throughout all phases of the testing process in 22 (95%) testing points.Average compliance to External Quality Assessment was 40% whereas: 11 (48%) testing points were enrolled in Proficiency Testing (PT) program; out of 11 testing points enrolled into PT program, only 4 (36%) testing points implement corrective action in case of unsatisfactory PT results; 21 (91%) testing points received periodic supervisory visit and written supervision report was available in only 1 (5%) testing point.This study has shown that the level of compliance to the quality standards for HIV rapid testing is below the recommended standards. Majority of observed HIV testing points scored level one and none of the testing point was highly complied to quality standards, meaning that no testing points scored level four. The results of this study are similar with the study conducted in Kampala Uganda to assess the quality of HIV counseling and testing services, which demonstrated that the quality of HIV testing services is below the recommended standards.13In this study, the highest average compliance score was seen on documentation and records followed by physical facility that included availability of conducive designated areas for provision of HIV rapid testing services and the lowest average compliance score was seen on personnel training and certification, followed by External Quality Assessment, testing phase, safety and pre testing phase. In addition, this study revealed that availability of new National HIV register that require all key elements to be documented in one register has contributed to improved documentation and record keeping for different data hence results into higher score for documentation and records quality standards. Furthermore, this study shows that most of the non-laboratory testers did not receive comprehensive training to perform HIV rapid testing services and none of them were certified/licensed to perform HIV rapid test through the National Certification Program. This situation has resulted into the lower score for the personnel training and certification quality standards, which was below the recommended quality standards for HIV rapid testing services, which requires that services should be provided by testers who received comprehensive training as well as evaluated for their competence and certified to provide testing services.7In this study we observed low compliance to the quality standards for External Quality Assessment (EQA) and about half of the testing points were enrolled into proficiency testing program and most of the testers were not trained to perform samples for proficiency testing. A study conducted in South Africa to evaluate the quality management system for HIV rapid testing services reported similar findings indicating that the compliance to EQA standards was low and only two clinics out of eleven clinics were enrolled into proficiency testing program. 6In this study, non-adherence to testing procedures including the use of small volume of buffer and non-adherence on time to read result whereby timers were not used during testing were observed. Similar findings were reported in a study conducted in Zambia National Reference Hospital in which the use of inadequate volume of specimen and use of incorrect volume of buffer leading into poor quality of test results was reported.11Our study has shown that a few testing points had guidelines for HIV testing services and Standard Operating Procedures (SOPs). These guidelines and SOPs are important documents for providing guidance and procedures needed to be followed during testing hence lack of guidelines and SOPs compromises the quality of HIV rapid testing services.19Some of the testing points were temporarily closed during data collection period due to lack of trained testers to provide service, and probably such testing points could have useful information regarding the practice of implementation of HIV rapid testing services in studied facilities. Furthermore, due to resource constrains only six facilities were studied, which might have limited the data collected. However, we believe that this study provides valuable insights regarding the quality of HIV rapid testing services provided by non-laboratory testers in the rural setting district in Tanzania.The quality of HIV rapid testing services provided by non-laboratory testers in Makete District is below the established quality standards set for provision of HIV rapid testing services. Most of the non-laboratory testers were not trained, evaluated for their competencies and were not certified or licensed to provide HIV rapid testing services. Some of HIV rapid testing points do not have Guidelines and SOPs that guide provision of HIV rapid testing services, which compromises the quality of HIV testing services. The Ministry of Health and Management of the health facilities should invest more efforts in training and strengthening of certification of non-laboratory testers, increasing enrolment of testing points into proficiency testing and strengthening supervision of testing points in order to improve compliance to quality standards."}
+{"text": "Self-isolation regime is an effective measure to contain the pandemic , but the psychological factors predicting compliance with stay-at-home recommendations (CSHR) are understudied. We hypothesized that 1) defensive optimism and constructive optimism will have opposite effects on CSHR, 2) the effect of defensive optimism will be mediated through a decrease of anxiety (fear of infection).. The purpose of this study was to assess the direct and indirect (through the fear of infection) effects of defensive optimism (belief that coronavirus problem is exaggerated) and constructive optimism (belief that people\u2019s efforts help to prevent infection and spread of the virus) on CSHR, controlling for dispositional optimism.. A longitudinal study (from 10/4/2020 till 2/6/2020) was conducted on a sample of 306 university students  using a single-item measure of CSHR, LOT-R , the scales of defensive and constructive optimism , and anxiety in a pandemic situation questionnaire .. During seven-week interval CSHR has decreased dramatically  while the other variables remained stable. Using SEM we have showed that CSHR at the end of study (T2) is predicted by the CSHR (T1) and through it by the defensive optimism  and constructive optimism . Negative effect of defensive optimism on CSHR is also mediated by the fear of infection (T2), reducing it. Dispositional optimism is associated only with constructive optimism.. Defensive and constructive optimism/ pessimism are essential in explaining health-related behavior.No significant relationships."}
+{"text": "Age-friendly community initiatives (AFCIs) have become key policy efforts aimed at improving quality of life for older residents, but there is limited evidence about the process. This mixed methods study draws on survey and demographic data from 350 municipalities in Massachusetts to characterize communities by these categories: 1) not interested in AFCIs (n=109); 2) interested in learning more about AFCIs (n=84); 3) planning for age-friendly action (n=71); and 4) maintaining an AFCI (n=86). Interview data from key-informants contextualize the process of developing an AFCI. Thematic analyses suggest that progression through AFCIs is self-defined by the accumulation of momentum. Communities committed to AFCIs have higher proportions of vulnerable residents . Municipal resources  correlate with more advanced stages of AFCIs. Implications of the variability across AFCIs, including the effort required for moving from concept to execution of AFCIs, will be discussed."}
+{"text": "Vaccination is one of the main mitigation strategies to protect people from COVID19 mortality. People incarcerated in jails experienced disparate rates of COVID19 infection compared to people in the community, thus operationalization of COVID19 vaccine delivery in jails was prioritized in several states, including Massachusetts (MA). The goal of this project was to track COVID19 vaccine ordering in MA jails and compare numbers and types of COVID19 vaccines ordered by MA jails to those in the MA community, with specific attention to the Centers for Disease Control and Prevention\u2019s (CDC) guidelines for COVID19 vaccines.MA jails received COVID19 vaccines free of charge through the MA Department of Public Health. We requested de-identified, facility-level data from the MA DPH including: number of vaccines ordered by each jail, type of vaccine, and date of the vaccine order from December 2020 - January 2022. We obtained COVID19 vaccines distribution data for the MA general population from the CDC.Vaccine orders were available for 13/14 MA jails. A total of 23,060 vaccines were ordered from the MA DPH between December 2020 - January 2022. January 2021 marked the highest number of vaccine orders by the jails, and all other months were orders < 33% of the January 2021 order. Moderna COVID vaccines were most frequently ordered by the MA jails (88%), followed by Janssen (11%) then Pfizer (1%). In the general population, Pfizer was the most frequently distributed vaccine type (59%), followed by Moderna (37%), then Janssen (4%).Prioritization of jails in MA led to a strong initial push for vaccine distribution which then waned. Potential reasons for the drop in orders include: the initial vaccine orders in January 2021 may have lasted several months, people entering jail after spring 2021 may have received vaccines in the community, and clinical and administrative fatigue may have limited continued robust vaccine protocols. Tracking COVID-19 vaccine orders by jails is a way to assess equitable vaccine operationalization. As recommendations for vaccination evolve, public health and carceral leaders should collaborate to ensure consistent low-barrier COVID19 vaccine access in jailsAll Authors: No reported disclosures."}
+{"text": "Since the Global Polio Eradication Initiative (GPEI) was established in 1988, the number of reported poliomyelitis cases worldwide has declined by approximately 99.99%. By the end of 2021, wild poliovirus (WPV) remained endemic in only two countries (Pakistan and Afghanistan). However, a WPV type 1 (WPV1) case with paralysis onset in 2021, was reported by Malawi a year after the World Health Organization (WHO) African Region (AFR) was certified as WPV-free and circulating vaccine-derived poliovirus (cVDPV) cases were reported from 31 countries during 2020\u20132021  the nonpolio AFP (NPAFP) rate,African Region. Among 28 priority countries in AFR, 50% met both national surveillance indicator targets in 2020 and 79% met the targets in 2021 . Subnational surveillance performance also improved in AFR; both surveillance indicator targets were met in 52% of first subnational administrative level areas in 2020 and 75% in 2021 , eight met both national surveillance indicator targets in 2020 and all but one (Djibouti with stool adequacy of 75%) met both targets in 2021. Most EMR countries performed well at the subnational level, but gaps were apparent in Djibouti. In 2020, a total of 140 WPV1 cases were detected in EMR countries (56 in Afghanistan and 84 in Pakistan), compared with five in 2021 (four in Afghanistan and one in Pakistan). Cases of cVDPV2 in EMR countries declined from 516 in 2020 to 68 in 2021, and cVDPV1 cases declined from 31 in 2020 to three in 2021 .European Region. In the WHO European Region (EUR), surveillance performance was assessed in Tajikistan and Ukraine. In 2020 and 2021, Tajikistan met both national indicators, whereas Ukraine met only the stool adequacy target. In Tajikistan, the proportion of the population living in areas that met both indicators increased significantly from 2020 to 2021.South-East Asia Region. Surveillance performance was assessed in the WHO South-East Asia Region (SEAR), country of Burma (Myanmar),Western Pacific Region. In the WHO Western Pacific Region (WPR), surveillance performance was assessed in Papua New Guinea and the Philippines. In 2020 and 2021, the Philippines met the NPAFP rate indicator, and Papua New Guinea did not meet either of the surveillance indicators. None of the subnational areas in Papua New Guinea met the indicator targets in either year; in the Philippines, 20.5% of the population lived in subnational areas in which both surveillance indicators were met in 2021  in 22 countries in 2021.Poliovirus environmental surveillance is the systematic collection and testing of sewage specimens to identify poliovirus circulation. Because paralysis occurs in <1% of poliovirus infections, environmental surveillance can detect poliovirus circulation even in the absence of confirmed paralytic polio cases  to 75 across 30 sites in 2021 (53% from Afghanistan). During 2020\u20132021, 27 cVDPV emergence groups (24 cVDPV2 and three cVDPV1) were detected in sewage samples collected in 32 countries, including 22 (69%) from AFR, seven (22%) from EMR, two (6%) from WPR, and one (3%) from EUR.In Afghanistan, WPV1 was isolated from only one environmental surveillance sample in 2021 compared with 35 samples from 15 sites in 2020  comprises 145 quality-assured poliovirus laboratories in the six WHO regions. GPLN laboratories implement standardized protocols to 1) isolate polioviruses ; 2) conduct intratypic differentiation (ITD) to distinguish between WPV, Sabin  virus, and VDPV (134 laboratories); and 3) conduct genomic sequencing (28 laboratories). Poliovirus transmission pathways are monitored through sequence analysis of the viral protein 1 (VP1) capsid protein from virus isolates. The accuracy and quality of testing at GPLN laboratories are monitored through a comprehensive standardized quality assurance program of onsite reviews and proficiency testing  accounted for 18 of 140 (13%) WPV1 isolates from AFP patients in 2020 and two of six (33%) in 2021.All priority countries faced setbacks in surveillance performance in 2020 because of the COVID-19 pandemic and associated risk mitigation measures  surveillance, the primary means of tracking poliovirus transmission, is supplemented by environmental surveillance of sewage samples. The COVID-19 pandemic negatively affected polio surveillance.Analysis of 2020\u20132021 AFP surveillance data from 43 priority countries experiencing or at high risk for poliovirus transmission found that national AFP surveillance performance improved from 2020 to 2021 in many priority countries, particularly in the World Health Organization\u2019s African Region; however, substantial national and subnational gaps persist.Surveillance gaps need to be identified and addressed to ensure timely detection of poliovirus circulation and achieve eventual eradication."}
+{"text": "This study assesses the extent to which changes in mental health among older adults from pre- to during the pandemic varied by cognitive functioning and the role that decreases in social resources played in this association. We use data from the National Social Life, Health, and Aging Project (NSHAP)\u2014a population-based panel study of older U.S. adults that has surveyed respondents every 5 years since 2005\u2014and the NSHAP COVID-19 supplement, conducted between September 2020 and January 2021 . Results from linear regression models suggest that (1) higher cognitive functioning in 2015 was associated with greater loneliness  during the pandemic; (2) this association is explained in part by a decrease in emotional support during COVID-19 ; and (3) cognitive status did not moderate links between social resources with happiness nor loneliness. Results emphasize the importance of social resources for older adults\u2019 mental health, regardless of cognitive ability."}
+{"text": "The nursing home population is vulnerable and medically complex, yet little is known about models of medical service provision and associated quality outcomes. The goal of this study is to examine the association between physician (MD) and nurse practitioner (NP) accessibility and practice sensitive outcomes. This project used data from the Translating Research in Elder Care (TREC) longitudinal study and the routinely collected Resident Assessment Instrument \u2013 Minimum Data Set version 2.0 (RAI-MDS 2.0) to test the association between the availability of MDs and NPs in nursing homes (NH) and clinically-relevant resident outcomes of antipsychotic medication (APM) use without indication of psychosis, physical restraint use, hospitalization and emergency department (ED) transfers, and polypharmacy. Eight models were created using logistic regression to test the association between the access measures of daily presence of MD or NP on unit and MDs being involved in care planning and each of the four resident outcomes. The sample consisted of 10,888 residents across 320 units in 92 facilities. Staff from 277 (86%) units reported an MD or NP visited daily and 318 (99%) units reported that the MD or NP could be reached when needed. Following adjustment for multiple confounding variables, there were no associations between either measure of access and any of the resident outcomes. Although we did not find any associations between our measures of access and resident outcomes, additional research which more directly measures physician and NP activities in the NH is required."}
+{"text": "Improving the quality and timely access of home health care is a new quality measure and particularly crucial in high-risk ADRD adults following hospitalization. However, a significant portion of older patients waits longer than 2 days to receive home healthcare. In this study, we examine how the quality of home health agency and race are associated with the delay in care among ADRD patients receiving home healthcare and how this delay mitigates the risk of rehospitalization. We find that Black patients in low rated home health agencies have 28% higher odds of delay in care compared to White patients in high rated home health agencies (Odds ratio (95% CI) =1.28 (1.21 - 1.36)). Timely initiation of home health care also reduces the risk of rehospitalization in minority older adults with ADRD."}
+{"text": "There is evidence that maternal perinatal depression is associated with adverse neurodevelopmental and mental health outcomes in children. No study has yet examined the association between maternal depressive symptoms during pregnancy and the postpartum period and the risk of oppositional-defiant disorder (ODD) in children and adolescents.This study aimed to investigate whether there is an association between perinatal depressive symptoms and the risk of ODD in offspring from age 7 to 15 years.We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based prospective birth cohort study in the UK. Offspring ODD at the age of 7, 10, 13 and 15 years were assessed by using parental reports the Development and Well-Being Assessment (DAWBA). We applied Generalized Estimating Equation (GEE) modelling to examine associations across the four time points.adjusted\u00a0OR = 3.59 (1.98-6.52).Maternal postnatal depressive symptoms were associated with more a two-fold increased risk of ODD overall. Third trimester depressive symptoms (measured at 32 weeks of gestation) increased risk of ODD by 72%. Offspring of mothers who had depressive symptoms both during pregnancy and in the first year of postpartum period have a four-fold increased risk of ODD over time (Offspring of mothers with perinatal depressive symptoms are at an increased risk of developing behavioural disorders."}
+{"text": "Long-acting injectable antipsychotics (LAIs) can reduce relapse and hospitalization risk but they are not widely used in first psychotic episode (FEP) patientes.To examine the effcacy of two of the most used second generation LAI antipsychotics  to reduce hospitalization rates.We evaluated in a naturalistic study a sample of patients (n=277) with a FEP. We carried out a mirror-design study to compare the number of hospitalizations and days in hospital before and after the introduction of LAI paliperidone (3 monthly) or LAI aripiprazol. In our Early Intervention Services (Lehenak) antipsychotic treatment is not protocolized and is established for each patient according to the psychiatrist criteria.We review the oucome of 277 FEP treated in our Early Intervention Service \u201cLehenak\u201d with LAI paliperidone 3 monthly (n=156) or LAI Aripiprazol (n=121)Both LAI paliperidone 3 monthly and LAI aripiprazol had a postive impact on hospitalIzation rate, decreasing them significantly after their introduction. These data also support a more extensive use of LAI paliperidone 3 monthly in FEP.Presenting author has received honouraria for lectures or advisory boards from Janssen, Otsuka, Lundbeck and Angelini in the last five years"}
+{"text": "Obsessive-compulsive disorder (OCD) is associated to a wide range of symptomatic expression and treatment response variability [1]. Sensory perception has been identified as an emerging factor in this process [2]. Sensory vulnerability and atypical sensory experience were identified as risk factors for the development of OCD [3] and a sensory subtype of the disease was proposed in which there is a positive correlation with early onset sensory symptoms, male gender and family background [4]. Adding to the atypical sensory profile, obsessions are frequently experienced as partially perceptual.Our main goals are to characterize the sensory perception in OCD patients; assess the prevalence and intensity of the sensory properties of the obsessive thoughts and explore the how sensory perception, obsessive thoughts and obsessive dimensions/clusters are interrelated.Patients with OCD diagnosis, aged 18 to 65 years and no comorbid mental disorder (except depression) will be recruited. The study battery will include participant form with demographical and clinical features, assessment of depressive and anxiety symptoms (HAM-A and HAM-D) evaluation of clinical outcome measures and obsessive dimensions/clusters  and Obsessive Beliefs Questionnaire-44 (OBQ-44)), assessment of sensory perception and sensory properties of obsessive thoughts (Sensory Perception Quotient (SPQ 21) and Sensory Properties of Obsessive Thoughts Questionnaire (SPOQ)).The results will help us understand the interaction between perceptual and cognitive processes in OCD.Better definition of OCD psychopathology and the establishment of a sensory subtype may indicate the need of specific therapeutic indications or a different escalation of treatment measures.No significant relationships."}
+{"text": "Tobacco use intersects with the COVID-19 pandemic not only in terms of health consequences, but also on public health systems, economies, and the environment.The global tobacco supply contributes significantly to environmental pollution of the natural ecosystems. The damage is compounded by tobacco consumption and its resultant waste, which leaves a significant carbon footprint on the environment, undermining the planet\u2019s ecological stability and intensifying climate change. Furthermore, tobacco use exacerbates inequalities and adds burdens to COVID-19-related mortality, which are major challenges to recovery from the COVID-19 pandemic.he pandemic has provided a chance to combat tobacco use and accelerate efforts to alleviate these challenges and accelerate progress toward Sustainable Development Goals (SDGs). The MPOWER measures from the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) can play an integral part to boost sustainable and equitable COVID-19 recovery \u2014 Monitor tobacco use (article 20); Protection from tobacco smoke (article 8); Offer help for tobacco cessation (article 14); Warn about the dangers of tobacco (article 11); Enforcing bans on tobacco advertising, promotion, and sponsorship (TAPS) (article13); and Raise tobacco taxes (article 6).To accelerate recovery, it is critical to call for actions for governments and policy-makers to strengthen synergies and policy actions to emphasise tobacco control across equity, public health, climate actions, and counteract against the tobacco industry during and beyond COVID-19 as global authorities pledge to achieve the SDGs.\u2022\u2002Global authorities must create better synergies on policies with a prime focus on reinforcing tobacco control to recover from the pandemic.\u2022\u2002The WHO FCTC MPOWER measures can play an integral part in COVID-19 recovery to fight tobacco use and accelerate progress toward SDGs."}
+{"text": "Eradication is an all-or-nothing affair. The aspirational goal set by the World Health Assembly in 1988 of eradicating poliomyelitis by 2000 was not achieved.It is thus tempting to consider eradication of poliomyelitis two-thirds complete, with wild poliovirus type 1 in Pakistan and Afghanistan being the final hurdle to finishing the \u2018polio end-game\u2019. But this is sadly not the case. The protracted eradication efforts and perpetually underperforming vaccination programmes using oral live attenuated Sabin poliovirus vaccine (OPV) have birthed calamitous outbreaks of types 1, 2 and 3 circulating vaccine-derived poliovirus (cVDPV) in countries in every World Health Organization region since the first recorded cVDPV outbreak in Haiti in 2020.6 The unprecedented surge in reported confirmed human infections and increasing number of countries with cVDPV detections, either human infections or through environmental surveillance, is cause for great concern  to bivalent oral polio vaccine , while introducing at least one dose of inactivated poliovirus vaccine (IPV) for every child, was necessary to reduce the ongoing risk of cVDPV2 outbreaks. Unfortunately the tardy rollout of IPV and outbreak response campaigns using monovalent OPV type 2 have increased the risk of cVDPV outbreaks.We must not bury our heads in the sand. Novel, genetically more stable oral polio vaccines used under emergency authorisation for cVDPV2 outbreak response provide a glimmer of hope, but this alone is not enough."}
+{"text": "The aim of the present study was to investigate emotional regulation and attachment in adolescents with anorexia nervosa (AN).Anorexia Nervosa (AN) is an eating disorder (ED) characterized by self-starvation driving by weight, shape, and eating concerns and extreme dread of food, eating, and normal body weight. Dysfunctional emotional processing and regulation play an important role in the development and maintenance of eating disorders (EDs). Difficulties with emotional awareness and regulation in EDs are hypothesized to have their origins in childhood attachment.The study population (N=20) consists of two research groups of patients with AN (group A) and general population controls (group B), matched for gender and age. The age of patients was 12-18 years. All adolescents were female. This study examined the attachment states of mind, assessed by the Adult Attachment Interview (AAI), and emotion regulation difficulties, measured by the Difficulties in Emotion Regulation Scale (DERS).Group A reported significantly higher attachment insecurity (82% vs 50%) than group B. Group A show higher DERS total  than group B.Study results show a crucial role of attachment insecurity and emotional dysregulation in the development and maintenance of AN. Developing interventions to improve emotional management skills in the treatment of patients with AN can be an important component in improving treatment outcomes."}
+{"text": "When the Global Polio Eradication Initiative (GPEI) was established in 1988, an estimated 350,000 poliomyelitis cases were reported worldwide. In 2020, 140 wild poliovirus (WPV) cases were confirmed, representing a 99.99% reduction since 1988. WPV type 1 transmission remains endemic in only two countries (Pakistan and Afghanistan), but outbreaks of circulating vaccine-derived poliovirus (cVDPV) occurred in 33 countries during 2019\u20132020  rateSurveillance performance in 42 priority countries that had recent WPV or cVDPV transmission or that were deemed at high risk for poliovirus transmission were reviewed. In the World Health Organization (WHO) African Region (AFR), the percentage of priority countries that met targets for both national NPAFP rate and stool adequacy indicators was 67% in 2019 and 48% in 2020 . Both suAll 10 of the assessed priority WHO Eastern Mediterranean Region (EMR) countries met targets for both indicators in 2019, and all but one  did so in 2020. Subnational surveillance performance remained high in most EMR countries, but gaps were apparent in Yemen and Libya, where 44% and 53% of the population, respectively, lived in areas that met both surveillance indicator targets in 2020 . From 20In the WHO European Region (EUR), surveillance performance was assessed in the two priority countries of Tajikistan and Uzbekistan. In 2019 and 2020, only Tajikistan met both surveillance indicator targets at the national level. In both years, Uzbekistan met only the stool adequacy indicator target. Subnational surveillance performance was poor in both countries in 2020 ; in UzbeSurveillance performance was assessed in Burma (Myanmar),In the WHO Western Pacific Region (WPR), surveillance performance was assessed in Malaysia and Philippines. Both countries met the NPAFP indicator target in 2019 and 2020, and neither met the stool adequacy indicator in 2019; however, Malaysia did meet the stool adequacy indicator in 2020. During 2019\u20132020, approximately one quarter of Malaysia\u2019s population and <3% of Philippines\u2019 population lived in areas that met both indicator targets ; cVDPV1 Genomic sequence analysis identified 41 cVDPV emergences from AFP cases (39 type 2 cVDPV emergences) in 18 countries in 2019 and 34 cVDPV emergences (32 type 2 cVDPV emergences) in 25 countries in 2020. More than one half (22 of 41) of cVDPV emergences detected in 2019 continued to be detected during 2020.Environmental surveillance is the systematic testing of sewage samples to identify populations shedding polioviruses; environmental surveillance in some locations, might be more sensitive to detection of poliovirus transmission than AFP surveillance, given that paralysis occurs in <1% of poliovirus infections  to 599 isolates (57% in Afghanistan) resulting from two 2019 cVDPV2 emergences and seven additional new cVDPV2 emergences in 2020.In 2019, 10 WPV1 genetic clusters (isolates with \u226595% genetic relatedness) were detected in environmental sites from four provinces in Afghanistan and four provinces in Pakistan  is an essential component of poliovirus surveillance. It comprises 145 quality-assured poliovirus laboratories in the six WHO regions. GPLN laboratories implement standardized protocols to 1) isolate polioviruses ; 2) conduct intratypic differentiation to identify WPV, Sabin  polioviruses, and VDPV (134 laboratories); and 3) conduct genomic sequencing (28 laboratories). Poliovirus transmission pathways are monitored through sequence analysis of the capsid protein (VP1) coding region from isolates. The accuracy and quality of testing at GPLN laboratories are monitored through an annual accreditation program of on-site reviews and proficiency testing  was detected in Afghanistan and Pakistan in 2019 (176 cases) and 2020 (140 cases). Orphan isolates  indicate possible gaps in AFP surveillance; in 2019, orphan isolates accounted for five of 176 (3%) WPV1 isolates from AFP patients (two in Afghanistan and three in Pakistan) and in 2020 for 18 of 140 (13%) (11 in Afghanistan and seven in Pakistan).From 2019 to 2020, national NPAFP rates and stool adequacy declined overall in priority countries; subnational surveillance performance declined overall except for WPR countries. Although the total number of WPV1 cases decreased globally from 2019 to 2020, the increase in orphan WPV1 isolates between 2019 and 2020 in both countries suggests gaps in AFP surveillance. The COVID-19 pandemic substantially affected polio eradication activities in 2020  surveillance supplemented by environmental surveillance of sewage samples.Analysis of 2019\u20132020 AFP surveillance data from 42 countries at high risk for poliovirus transmission indicated that national and subnational nonpolio AFP rates and stool specimen adequacy declined in many priority countries.The findings provided in this report can help guide improvement efforts to restore timely and sensitive field surveillance activities, which were adversely affected by the COVID-19 pandemic."}
+{"text": "Medications with anticholinergic properties are commonly used by older adults despite being associated with dementia.The anticholinergic total standardized daily dose (TSDD) is a continuous measure of exposure that has been associated with an increased risk of dementia at values >1095 over ten years in epidemiologic studies. We sought to determine a cumulative (cTSDD) and annualized (aTSDD) in a sample of community-dwelling older adults enrolled in the ongoing Reducing Risk of Dementia Through Deprescribing (R2D2) trial (NCT04270474). Participants were 65 years or older without dementia, attended at least one primary care visit within 12 months prior to enrollment, and were current users of strong anticholinergics according to the 2012 Anticholinergic Cognitive Burden Scale. Prescribed and over-the-counter medication details were collected during the baseline visit through self-report and included strength, frequency, units/dose and duration. The aTSDD was calculated for each participant assuming continuous use patterns throughout the year. The cTSDD was calculated by summing the aTSDD across the number of years since initiation. Of 66 participants, the median cTSDD was 2425 (IQR 5131), and 48 (72%) exceeded the threshold of dementia risk (>1095). Additionally, the aTSDD had a median of 730 (IQR 547), with 60 (90%) exceeding the threshold of dementia risk  while 11 (17%) exceeded dementia risk threshold of 1095 considering 1 year of exposure. Both measures identified the majority of anticholinergic users exceeding dementia risk thresholds despite some disagreement between the two approaches. However, both methods have potential for research and clinical applications."}
+{"text": "In 2020, the Los Angeles County Department of Public Health launched Healthy Brain LA (HBLA). HBLA is a multi-pronged project designed to promote cognitive health, reduce the risk of dementia, and help develop a dementia-focused strategic plan for Los Angeles County (LAC) that prioritizes the needs of those impacted by dementia and cognitive impairment and their caregivers. To support this effort, the HBLA team analyzed weighted data from the 2019 and 2020 California Health Interview Survey (CHIS) to better understand the profile of adult caregivers of individuals with dementia and cognitive impairment. CHIS is a publicly available, population-based, web and telephone survey that asks California residents about a wide range of health topics, yielding representative data on all 58 counties in the state. In 2019-2020, an estimated 1.6 million adults provided care to individuals aged 18 years or older in LAC. About 322,880 of those caregivers provided care for individuals with dementia and cognitive impairment, representing 2% of LAC\u2019s adult population. Many of these caregivers were female (59%), Latino/Hispanic (44%), and between 50-64 years of age (32%). Most of them experienced challenges, such as financial stress (61%), physical/mental health problems (18%), or a change in job status (27%), due to caregiving. These data provide the first local estimate of dementia and cognitive impairment caregiving in nearly 15 years. Results offer critical information about this population that will be used by the HBLA team and its partners to guide efforts to effectively meet the needs of caregivers in LAC."}
+{"text": "Developing a level 1 accredited geriatric emergency department during the pandemic was challenging. The greater challenge has been to support rural critical access hospitals on their journey of becoming level 2 accredited geriatric emergency departments. This has been accomplished through a novel collaborative approach between the level 1 accredited emergency department, a newly established Geriatric Center of Excellence at Dartmouth-Hitchcock Health and a HRSA funded Geriatric Workforce Enhancement Program. This talk will focus on bringing together system partners and funders who have a history of success through: (a) development, testing and dissemination of tool kits and implementation guides; (b) boot camp training that includes interprofessional team training, QI and specific geriatric content training; (c) implementation support and coaching using data and QI methodology through learning collaboratives; (d) scaling successful models of evidence based geriatric care; (e) expertise in implementation science; (f) expertise in evaluation and (g) disseminating findings to achieve our goals."}
+{"text": "Background: Due to the increasing amount of published data suggesting that endometrial carcinoma is a heterogenic entity with possible different treatment sequences and post-treatment follow-up, the Polish Society of Gynecological Oncology (PSGO) has developed new guidelines. Aim: to summarize the current evidence for diagnosis, treatment, and follow-up of endometrial carcinoma and to provide evidence-based recommendations for clinical practice. Methods: The guidelines have been developed according to standards set by the guideline evaluation tool AGREE II . The strength of scientific evidence has been defined in agreement with The Agency for Health Technology Assessment and Tariff System (AOTMiT) guidelines for scientific evidence classification. The grades of recommendation have been based on the strength of evidence and the level of consensus of the PSGO development group. Conclusion: Based on current evidence, both the implementation of the molecular classification of endometrial cancer patients at the beginning of the treatment sequence and the extension of the final postoperative pathological report of additional biomarkers are needed to optimize and improve treatment results as well as to pave the route for future clinical trials on targeted therapies. The Polish Society of Gynecological Oncology (PSGO) has developed the following recommendations for diagnosis, preoperative assessment for surgical treatment, radiotherapy, systemic treatment, treatment of recurrent disease and post-treatment surveillance of patients with endometrial carcinoma according to standards set by a guideline evaluation tool Appraisal of Guidelines for Research and Evaluation (AGREE) II .Recommendations apply to women over the age of 18 who suffer from endometrial carcinoma .The recommendations are intended for gynaecologists, gynaecological oncologists, surgeons, pathologists, geneticists, radiotherapists, clinical oncologists, general practitioners, palliative care specialists and allied health care professionals.Nomination of a multidisciplinary development group .Identification of scientific evidence.Formulation of guidelines.Assessment of coherence with ESGO/NCCN guidelines.Evaluation of guidelines by external reviewers.Integration of external reviewers\u2019 comments with the original content of the guidelines.The PSGO guidelines were developed using a six-step process:The strength of scientific evidence was defined in agreement with The Agency for Health Technology Assessment and Tariff System (AOTMiT) guidelines for scientific evidence classification  Table 1Table 1.The grades of recommendation were based on the strength of evidence and level of consensus of the PTGO development group as described in Any clinician intending to apply PSGO guidelines is expected to perform a careful medical evaluation of individual clinical circumstances to determine the best course of patient care and/or treatment.For the first time, recommendations were developed according to standards set by the guideline tool Appraisal of Guidelines for Research and Evaluation (AGREE) II in gynaecologic oncology.The strengths of the guidelines are they are comprehensive and up-to-date.The limitation is the uncertainty of how many of the authors using guideline AGREE II were methodological experts.Recommendations indicate an urgent need for changes in the system of financing health services in Poland.The 2005 WHO classification (5th edition) identifies 10 histological subtypes of endometrial cancer  3,4,5,66,7,8 (sttype I\u2014endometrioid carcinoma (adenocarcinoma) .type II\u2014non-endometrioid carcinoma, which includes serous carcinoma, clear cell adenocarcinoma, undifferentiated and dedifferentiated carcinoma, mixed carcinoma of the endometrium and carcinosarcoma   is recommended for(1)Women with postmenopausal bleeding whose endometrial thickness is > 3 mm  (strengt(2)Women with adult granulosa cell tumour undergoing fertility-sparing treatment (with preservation of the uterus)  (strengt(3)Women with bleeding during tamoxifen treatment lasting up to 5 years    .The endometrial thickness cut-off at which biopsy in asymptomatic women in the general population  and in those with increased risk of endometrial cancer  *, which would have acceptable sensitivity and specificity, has not been established. Thus, an individual approach is recommended (expert opinion) (strength of evidence V) (grade of recommendation 2B). * Note: The management of endometrial hyperplasia (a precancerous condition) is a separate subject not covered by this recommendation.The sensitivity of endometrial biopsy  is 89% and the false-negative rate is 10%  .The report should specify the histological type, and for endometroid carcinoma, its differentiation grade assessed in two categories: low-grade (G1/G2) and high-grade G3) [ 3,4,5,6,65,6,7,8The existing scientific evidence indicates(1)The advantage of the new molecular classification over the former based solely on the type of endometrial cancer and grading in making therapeutic decisions at the beginning of treatment ,21,22 (s(2)A significantly higher concordance between pre- and postoperative results for the new molecular classification based on the ProMisE classifier and/or sequencing compared to previously considered features (type and grading) ,26,27,28(3)High sensitivity and specificity of the ProMisE classifier ,30 . A similar requirement applies to high-risk patients with comorbidities who do not qualify for surgical treatment (grade of recommendation 2A).A detailed description of the ProMisE classifier and comprehensive endometrial carcinoma diagnosis algorithm NGS+IHC is included in The centres where the diagnostic minimum (ProMisE molecular classification) cannot be performed may, in the transitional period, use existing criteria: type and grading (does not apply to the decision on fertility-sparing treatment and management of nonoperable cases) (grade of recommendation 3).The report should include a verified histological type, and for endometroid carcinoma, verified grading assessed in two categories: low-grade (G1/G2) and high-grade G3) [ 3,4,5,6,65,6,7,8If molecular classification was not performed at the time of the biopsy, it must be performed for the final report (at least a basic variant of ProMisE) (grade of recommendation 2B).LVSI invasion is a very important predictive factor indicating individual risk of recurrence and a decisive factor in the choice of adjuvant therapy   and does not include LVSI within the tumour and in the immediate vicinity of the tumour margin   is magnetic resonance imaging (MRI) with contrast ,36 .In justified cases, expert ultrasound can replace magnetic resonance imaging in the assessment of changes in the pelvis (grade of recommendation 2B).FIGO staging for endometrial carcinoma is shown in Standard surgery is a simple total hysterectomy with bilateral salpingo-oophorectomy (BSO) **; peritoneal fluid sampling for cytological examination is not recommended ,38  and total robotic hysterectomy (TRH)) does not compromise the prognosis and has a significant advantage in perioperative and postoperative outcomes over open surgery ,40  increases the number of complications and does not improve results  (strengt(1)Sparing treatment in women who want to preserve fertility and who have met the criteria * and achieved complete clinicopathological remission after hormone therapy  (strengt(2)No oophorectomy in women < 45 years old who have met the criteria ** ,43,44  and exclusion of metastatic disease (CT of the abdomen and chest); bioptate G1 TP53wt or every G when POLE  strengt.HNPCC) (Lynch syndrome).** Criteria: age < 45; FIGO I/II\u2014necessary exclusion of FIGO IIIC by systematic lymphadenectomy or sentinel lymph node procedure in the group at high risk of metastases in radiologically negative lymph nodes (see indications for lymphadenectomy); and high risk of ovarian cancer excluded such as for BRCA1/2 mutation carriers or hereditary nonpolyposis colorectal cancer , does not affect overall survival and the time-to-recurrence; it is, however, associated with a significant number of complications   risk of metastases in radiologically negative lymph nodes (grade of recommendation 1).The goal of lymphadenectomy is to rule out the highly probable FIGO IIIC in this group of patients. The potential up-stage change is of prognostic significance  ;Non-endometroid carcinoma (high risk);TP53abn, every histological type (high risk);High-grade endometroid carcinoma excluding POLEmut (high risk) ,21,22  are as follows:Furthermore, in the group of patients at high risk of metastasis, lymphadenectomy should include the removal of radiologically negative pelvic and para-aortic lymph nodes up to the left renal vein because it increases overall survival  (strengtThe sentinel lymph node procedure can be considered to assess the status of the nodes (pN) ,55  is recommended ,62  and external beam radiation therapy (EBRT) are recommended (strength of evidence V) (grade of recommendation 1).There is a lack of randomised studies comparing different methods of radiotherapy (EBRT/BT) in the radical treatment of inoperable FIGO stage I/II endometrial cancer.Retrospective cohort studies have shown that the use of BT HDR in the radical treatment of inoperable endometrial cancer improves overall survival (OS) and progression-free survival (PFS) time  .Low-grade endometroid carcinoma with myometrial invasion > 50% excluding POLEmut (high-intermediate risk).Non-endometroid carcinoma (high risk).TP53abn, every histological type (high risk).High-grade endometroid carcinoma excluding POLEmut (high risk) ,21,22  with significant risk factors for metastasis to the lymph nodes, the following are recommended:In other cases, only BT should be used (expert opinion) (strength of evidence V) (grade of recommendation 2B).It is recommended that the intensity-modulated radiation therapy (IMRT)/VMAT technique or conformal radiotherapy be used in the area of the reproductive organs and lymph nodes. HDR brachytherapy should be planned based on CT or MRI performed after the insertion of the applicator (expert opinion) (strength of evidence V) (grade of recommendation 2B).Simple TLH/TRH/TAH with BSO is recommended; peritoneal fluid sampling for cytological examination and systematic lymphadenectomy is not recommended   is allowed only when the patient\u2019s general condition is good  and when the operator can perform complete cytoreduction   , the recommended method of surgical treatment is en-block cancer resection with reconstruction of the gastrointestinal tract or * radical hysterectomy (expert opinion) (strength of evidence V) (grade of recommendation 2B).Systematic lymphadenectomy, in these cases, is not recommended ,50  (strength of evidence V) (grade of recommendation 2B).CAUTION: This applies to preoperative apparent FIGO I/II cases in which FIGO IIIA or IIIC was diagnosed postoperatively as a result of surgical staging and successfully resected cases of operable FIGO IIIB.Radiochemotherapy is a method of choice  ,69  (grade of recommendation 2B). In POLE and MMRd endometrial cancer subtypes, EBRT alone is recommended because the addition of chemotherapy (CHT) before and during irradiation is of no benefit in this group of patients   who are not eligible for surgery , the method of choice is EBRT including uterus and lesions in the pelvis depending on their location  and/or metastatic para-aortic lymph nodes combined with BT (uterus) (expert opinion) (strength of evidence V) (grade of recommendation 2B).It is recommended that the IMRT/VMAT technique or conformal radiotherapy be used in the area of reproductive organs and pelvic lymph nodes. HDR BT should be planned based on CT or MRI performed after the insertion of the applicator. In cases where radical treatment is not feasible, the method of choice is systemic treatment with or without palliative radiotherapy (expert opinion) (strength of evidence V) (grade of recommendation 2B).In patients with incomplete resection  or disseminated cancer, i.e., cases with unresectable metastases to the lungs or liver with a multifocal spread in the abdominal cavity (FIGO IVB) or with unresectable recurrence, the method of choice is systemic treatment (+/\u2212 radiotherapy) ,74,75,76The type of therapy should be selected individually considering the histological type, receptor status and/or molecular profile.For patients with low-grade endometroid carcinoma, it is recommended to determine the expression of E/P receptors (receptor status) because hormone therapy is a preferred option in this group (the percentage of objective responses (ORR) is 21.6%: ER + 26.5% and PR + 35.5%) (does not apply to cases with rapid progression of the disease)   after the use of aromatase inhibitors is low (7%), but due to the high (44%) clinical benefit (stabilisation and response)  , a carboplatin and paclitaxel regimen is recommended   [p = 0.046) [In the arm of patients receiving trastuzumab, a significantly longer median PFS was achieved, reaching 12.6 vs. 8.0 months   (strengt= 0.046)  (strengtp = 0.013) [p = 0.041) [A particular benefit of trastuzumab was observed in the first line of treatment with PFS of 17.9 vs. 9.3 months   (strengt= 0.041)   is the most favourable (recommended) therapeutic option in the group of HER2-positive patients (grade of recommendation 1).The standards for determining the status of the HER2 receptor are included in Based on the results of a randomised phase III trial   may only take place in clinically justified situations or when there are limitations in the availability of immunotherapy (grade of recommendation 3).When choosing chemotherapy, the patient should be informed of a significantly worse prognosis (expert opinion) (grade of recommendation 2B).In the entire population of patients with recurrent or advanced endometrial cancer, regardless of MMR/MSI status, the use of a combination of a PD-1 inhibitor (pembrolizumab) with a multiply tyrosine kinase inhibitor against VEGFR1, VEGFR2 and VEGFR3 (lenvatinib) was superior to chemotherapy (reduction in the risk of recurrence by 46% (HR of 0.54) and the risk of death by 38% (HR of 0.62)). The objective response rate (ORR) was 32%. The rate of serious adverse events was 89%, and 33% of patients discontinued therapy  (strengtIn a single-arm study  (strengtThe objective response rate (ORR) was 44% for dostarlimab     or disseminated cancer (FIGO IVB) or with unresectable recurrence who progressed after platinum-based chemotherapy (at least one cycle), the treatment of choice is immunotherapy ,74,75 (sMMRd)/MSI-H cancers may be treated with PD-1 inhibitors (dostarlimab or pebrolizumab) or with a combination of PD-1 inhibitor (pembrolizumab) and lenvatinib (grade of recommendation 1). Due to the high percentage of treatment discontinuation observed in the combo therapy of pembrolizumab and lenvatinib, monotherapy with PD-1 inhibitors is the preferred option in this group of patients (expert opinion\u2014strength of evidence V) (grade of recommendation 2B).In the group of patients with a mismatch repair proficiency (MMRp), the treatment of choice is a combination of a PD-1 inhibitor (pembrolizumab) with lenvatinib (strength of evidence IIA) (grade of recommendation 1).There is no evidence that any post-treatment surveillance regimen for endometrial cancer improves patient survival time.The randomised TOTEM study assessed the role of intensive (INT) vs. minimalist (MIN) surveillance after the treatment of patients with endometroid carcinoma of the endometrium   (strength of evidence V) (grade of recommendation 2B).Extrapolating the results of the TOTEM study  and expeHNPCC) (Lynch syndrome).Hereditary nonpolyposis colorectal cancer    proteins [EPCAM deletions (EPCAM-MSH2) and thus has Lynch syndrome [In this group, every 8th woman  has a germinal mutation in the proteins   are detected in 3% of Lynch syndrome cases [me cases   and MSH2 (33%) and the lowest for mutations in MSH6 (26%) and PMS2 (10\u201312%) [The lifetime risk of developing colorectal cancer in the female population is 4.7%  (strengt(10\u201312%) ,87 (streMSH2 (51%) and MSH6 (49%) and the lowest for the mutations in MLH1 (34%) and PMS2 (12\u201324%) [The lifetime risk of developing endometrial cancer in the general population is 2.9%  (strengt(12\u201324%) ,86,87,88MSH2 mutation are affected the earliest (mean age 47) and MSH6 mutation carriers the latest (mean age 53) [Hereditary endometrial cancer is diagnosed in the fourth and fifth decades of life. Carriers of the  age 53)     verified pathologically;One is a first-degree relative of the other two;At least two successive generations affected;At least one relative is diagnosed before the age of 50;Familial adenomatous polyposis has been ruled out;Tumours should be verified by pathologic examination   are as follows:Other rare hereditary syndromes predisposing to endometrial cancer are described below.PTEN germline mutations (<1%) increase the risk of developing endometrial cancer by 25%   and susceptibility to treatment with platinum compounds and PARP inhibitors. In contrast, biallelic inactivation of  is rare   (Lynch syndrome) in BRCA1/2 (HBss/HBOC/HOC) and in PTEN (Cowden\u2019s syndrome) should result in genetic testing among relatives to identify carriers of the germline mutation.Confirmation of mutations in In the case of Lynch syndrome, each family member with a confirmed mutation (regardless of gender) should undergo colonoscopy screening according to the Polish Society of Oncological Surgery (PSOS) recommendations (expert opinion) (strength of evidence V) (grade of recommendation 2B).Women (Lynch syndrome and Cowden syndrome) should be encouraged to have children early and be offered prophylactic hysterectomy after the completion of reproductive plans ,87,92  (strength of evidence V) (grade of recommendation 2B).BRCA1/2 (HOC/HBOC/HOC) [Prophylactic oophorectomy and salpingectomy are recommended in Lynch syndrome ,87 (streBOC/HOC)  (strengtPTEN (Cowden syndrome) germinal mutation, a prophylactic oophorectomy and salpingectomy are not recommended [In the case of ommended  (strengtBRCA1/2 germline mutation (HOC/HBOC/HOC), prophylactic hysterectomy is not recommended [In the case of the ommended  (strengt"}
+{"text": "Cognitive training has the potential to help older adults maintain or improve their cognitive abilities, but there has been debate regarding how susceptible cognitive outcomes in these studies are to placebo effects. Some previous research has found that expectations can shape performance on study outcomes, although this is not always a consistent finding. The degree to which perceived intervention efficacy can lead to changes in the performance of objective outcome measures typically assessed in these studies is unclear. The aim of the current study is to explore the effects of perceived effectiveness of cognitive training on actual improvements in a large sample of older adults. The current study utilized data from the Intervention Comparative Effectiveness for Adult Cognitive Training  Trial. Two hundred and thirty older adults (Mean age = 72) were randomized into one of four training conditions: (1) a web-based brain game suite, Brain HQ, (2) a strategy video game, Rise of Nations, (3) Instrumental Activities of Daily Living (IADL) training, or (4) an active control condition of puzzle solving. Reasoning, memory, processing speed, and IADL performance were measured before and after the intervention. Perceived efficacy of training in those outcome domains were also measured. Bayesian ANOVA analysis showed strong evidence of group differences in perceived efficacy within all outcome domains across the training conditions whereas Bayesian regression showed moderate to strong evidence against influences of perceived efficacy on changes in performance. Discussion will focus on implications of those results on behavioral and cognitive intervention designs."}
+{"text": "A mental health promotion programme called \u2018Healthy Me\u2019, was a collaboration between Action Mental Health (AMH) MensSana, Child and Adolescent Mental Health Services (CAMHS) in the Southern Health and Social Care Trust and the Royal College of Psychiatry (RCPsych) in Northern Ireland in 2014. Adapting \u2018Healthy Me\u2019 for delivery in special schools was recommended in evaluation of this pilot programme. A co-produced pilot adapted \u2018healthy me\u2019 programme, for young people with ID was taken forward by Action Mental Health (AMH) MensSana and Intellectual Disability Child and Adolescent Mental Health Service (ID CAMHS) in the Southern Health and Social Care Trust (SHSCT). To determine the feasibility of adaptation and delivery of the programme for the needs of the ID population. To inform changes to be made before wider roll-out. To promote children's social and emotional well-being and emotional literacy through the teaching of problem-solving, coping skills, conflict management and managing feelings. To evaluate the effectiveness of this intervention with children being able to retain learning, information and ideas.Pre programme quiz July 2021 (young people)Post session 1\u20135 quizzes (young people)Post programme quiz October 2021 (young people)Simple visual blob tree (young people)Outcome MeasuresPre programme initial outcome measure (parent) The Mood, Interest and Pleasure Questionnaire-short form (MIPQ-S) July 2021Pre programme initial outcome measure (parent) non standardised, based on the strength and difficulties questionnaire (SDQ) and the Child and Youth Resilience Measure-Revised Person Most Knowledgeable version (PMK-CYRM-R) July 2021Post programme repeated outcome measure (parent) MIPQ-S October 2021Post programme repeated outcome measure (parent) Based on SDQ & PMK-CYRM-R October 2021EvaluationSix participants identified at outset and four attended and engaged consistently, young people aged between 14 and 17 years. Participants were supported 1:1 to fill in a simple evaluation forms after sessions rating their enjoyment and what they had learnt. Repeating the MIPQ-S with parents highlighted some improved scores indicating positive affect and elevated interest and pleasure.The programme will be offered to in the next stage of the pilot to Special Schools in NI. It is hoped to show that similar positive gains can be made in the school settings for children and young people with intellectual disability in terms of promoting positive mental health and social and emotional well-being."}
+{"text": "Dear Editor et al. \"The Prevalence of HPV Genotypes in Iranian Population: An Update\", which pathologically mostly lead to Squamous intraepithelial lesions (9). Our findings suggested which Pap smear report is most associated with each serotype of HPV; however, the \"No Inflammation\" state is the most common among all serotypes (39.4%). Detailed HPV PCR test and Pap smear cross-tabulation results are shown in . We recommend cytologists report the presence of Anucleated squamous or Keratinized cells and exudates in the positive smears in order to prevent HPV-related Cancers in the population.Thus Type 16 is the most serotype involving in HPV infections among the average Iranian population , 6, 7, 8"}
+{"text": "ABSTRACT IMPACT: This project will use human neuron models and bioinformatics techniques to elucidate mechanisms of cocaine neurotoxicity, which will allow treatments to be developed for minimizing or preventing neurological damage caused by cocaine abuse and overdose. OBJECTIVES/GOALS: The goals of this project are to identify genes and gene networks altered by cocaine exposure in neurons (short term), and to use these pathways to understand mechanisms of cocaine neurotoxicity for the establishment of therapeutic targets (long term). METHODS/STUDY POPULATION: To study the molecular effects of cocaine, we generated preliminary proteomics and next-generation RNA sequencing (RNAseq) data from human postmortem prefrontal cortex (Broadmann area 9 or BA9) of 12 cocaine overdose subjects and 17 controls. Future directions for this project include RNAseq analysis of neuronal nuclei sorted from human postmortem BA9 and a human induced pluripotent stem cell-derived neuron (hiPSN) model of cocaine exposure from the same postmortem subjects from whom we have brain samples. RESULTS/ANTICIPATED RESULTS: We found alterations in neuronal synaptic protein levels and gene expression, including the serotonin transporter SLC6A4, and synaptic proteins SNAP25, SYN2, SYNGR3. Pathway analysis of our results revealed alterations in specific pathways involved with neuronal function including voltage-gated calcium channels, and GABA receptor signaling. In the future, we expect to see an enhancement in neuron-specific gene expression signatures in our sorted neuronal nuclei and our hiPSN model of cocaine exposure. The hiPSN model will help elucidate which effects are due to acute versus chronic exposure of cocaine. DISCUSSION/SIGNIFICANCE OF FINDINGS: Transcriptomic signatures found with this analysis can help us understand mechanisms of cocaine neurotoxicity in human neurons. With this work and future proposed studies, we can discover targetable molecular pathways to develop drugs that can reduce or reverse cocaine-related impairment."}
+{"text": "Whereas previous studies have investigated life regrets, little attention has been paid to the important accomplishments older adults include in their autobiographic life narratives. Phenomenon such as the memory positivity effect suggest that accomplishments should be observed. We used a Health and Retirement Study 2017 Life History Mail Survey  to examine the characteristics of participants over age 65 who reported accomplishments (max = 3), what was reported, and whether early-life decisions about balancing family and work are associated with the reports. Women, whites, and people with at least high school education and normal cognitive status were more likely to report accomplishments (67%). We categorized reports as family-related (39%), personal (19%), combined family/personal (25%) or other (16%). Multinominal logistic regression models revealed that participants who themselves favored family over work in early life or whose spouse decided for family, were more likely to report family-related accomplishments."}
+{"text": "Solanum (9), Ribes (8), Berberis (7), Hypochaeris (7) and Oxalis (6). Perennial herbs are the predominant life form (40%), followed by shrubs (35%), trees (14%), and annual and biannual herbs (11%). Fruits (35.8%), roots (21.5%) and leaves (20.0%) are the parts of plants consumed the most. Nine different food preparation categories were identified, with \u2018raw\u2019 forming the largest group (43%), followed by \u2018beverages\u2019 (27%), \u2018savoury preparations\u2019 (27%), and \u2018sweet\u2019 (13%). Almost all native Chilean WEPs have reported traditional food uses, while only a few of them have contemporary uses, with food products mainly sold in local and specialised markets. Species\u2019 richness, taxonomic diversity and family representation have similar patterns to those observed for the world flora and other countries where surveys have been carried out. Some Chilean native WEPs have the potential to become new crops and important sources of nutritious and healthy products in the food industry. However, there are still many gaps in knowledge about their nutritional, anti-nutritional and biochemical characteristics; future research is recommended to unveil their properties and potential uses in agriculture and the food industry.Wild Edible Plants (WEPs) still play a vital role in the subsistence of many traditional communities, while they are receiving increasing recognition in tackling food security and nutrition at the international level. This paper reviews the use patterns of native WEPs in Chile and discusses their role as future crops and sources of food products. We conducted an extensive literature review by assessing their taxonomic diversity, life forms, consumption and preparation methods, types of use , and nutritional properties. We found that 330 native species were documented as food plants, which represent 7.8% of the total flora of Chile. These species belong to 196 genera and 84 families. The most diverse families are Asteraceae (34), Cactaceae (21), Fabaceae (21), Solanaceae (20) and Apiaceae (19), and the richest genera in terms of number of species are  The benefits derived from biodiversity are also at the heart of the Convention on Biological Diversity , with 109 WEPs (33.5%), followed by Rosids (Fabids (49 spp.) + Malvids (37) + Vitales (0)), with 86 WEPs (26.5%). Monocots contain 48 WEPs (14.8%), while gymnosperms and Monilophytes  have only 3 WEP species each . The perAccording to our revision, the main consumed parts of Chilean native WEPs are fruits and infructescences (35.8%), roots (21.5%), leaves (20.0%), seeds (9.1%), and stems (7.0%) . InfloreThe most frequent form of consumption was raw (43% of species) among the nine different categories , followeThe relation between the organs consumed and the preparation forms  showed tJubaea chilensis (Molina) Baill., an endemic Chilean palm tree; fruits and seeds are eaten fresh and used in sweet dishes; the sap is boiled to produce syrup , [binomial name + edible], [binomial name + beverages] and so on. All queries were made both in Spanish and English.Initial data were obtained from the database on the uses of Chilean native flora ) by Rodr\u00edguez et al., (2018) [http://www.plantsoftheworldonline.org/ (accessed on 12 February 2022)). The nomenclature follows the International Plant Name Index [The taxonomy of the species was updated based on the catalogue of the flora of Chile   and by rme Index  and the me Index , with whme Index , rgdal vme Index , dplyr vme Index  and doByme Index .Life forms and origins of Chilean native plants were obtained from the catalogue of the flora of Chile . To infeWe considered all species naturally occurring in Chilean territory and used as food and beverages as native wild edible plants (WEPs). According to the Economic Botany Data Collection standard (EBDCS) , plant uThe flora of Chile has a high number of native WEPs, some of which were domesticated by the original peoples of south-western South America before the Spanish conquest . In contrast, others were transformed or are the progenitors of important main crops that are part of the world food base, such as potatoes, quinoa, and Chilean strawberries. However, many more WEPs have the potential to become new crops and sources of new industrial food products in the future.Innovation based on Chilean WEPs requires strengthening both the biochemical studies to characterise the nutritional content of species in detail and agriculture research for the domestication of species and the development of breeding programmes enabling the creation of new crops.However, in the face of future social, cultural, economic, environmental and climatic change scenarios, the food development of native Chilean WEPs must be responsibly supported by sustainable consumption and food innovation, which require access to plant genetic material and the cultivation of these plants in line with international access and benefit-sharing agreements and the creation of sustainable value chains."}
+{"text": "During October 2019, the West Virginia Bureau for Public Health (WVBPH) noted that an increasing number of persons who inject drugs (PWID) in Kanawha County received a diagnosis of HIV. The number of HIV diagnoses among PWID increased from less than five annually during 2016\u20132018 to 11 during January\u2013October 2019 . KanawhaAfter suspension of the KCHD syringe services program (SSP) in March 2018 and a community-based SSP in April 2021 (because of concerns about program administration), a state lawAn HIV outbreak case was defined as a confirmed HIV diagnosis on or after January 1, 2019 in a PWID living in Kanawha County at the time of diagnosis. Investigators conducted qualitative interviews with 26 PWID and 45 community partners (including service providers),***As of October 27, 2021, 85 persons met the HIV outbreak case definition; 54 (52%) patients were male, 67 (79%) were aged 20\u201339 years at diagnosis, and 77 (91%) were non-Hispanic White. Forty patients (47%) had experienced unstable housing during the past year, and 73 (86%) had previous or current hepatitis C infection. Among 80 living persons, 20 (25%) had an HIV care visit during the preceding 90 days,Interview and medical record data indicated that methamphetamines and heroin were the most frequently injected drugs, and polysubstance use was common (57 [88%] of 65 patients). PWID reported reusing or sharing syringes, mainly because of limited access to sterile syringes after SSP closures. PWID expressed medical mistrust because of experiences of stigma and discrimination in health care settings. Medical record abstraction revealed that HIV screening tests were performed at fewer than one third of health care encounters before diagnosis, and none of the patients had been prescribed preexposure prophylaxis (PrEP). Prescriptions of naloxone for overdose prevention and medications for opioid use disorder were documented at fewer than a quarter of opioid-related health care encounters.Recommendations based on investigation findings and HIV surveillance data are guiding response activities."}
+{"text": "Scientific Reports 10.1038/s41598-021-82092-9, published online 19 February 2021Correction to: The original version of this Article contained errors. Legends for Table 1 and Table 2 were reversed.Table 1 legend \"List of all strains examined in this study with their GenBank accession numbers (BOLD ID). Geographic position and description of sample sites indicated.\"Hantzschia from studied material with similar taxa.\"now reads: \u201cComparison of species and strains of Hantzschia from studied material with similar taxa.\"Table 2 legend \"Comparison of species and strains of now reads: \"List of all strains examined in this study with their GenBank accession numbers (BOLD ID). Geographic position and description of sample sites indicated.\"These errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "This systematic review assesses variation in international and national guidelines on respiratory protection for health care professionals during the COVID-19 pandemic. We assessed variation in international and national guidelines on respiratory protection for HCPs in hospital settings during the first year of the COVID-19 pandemic.Conflicting evidence surrounding SARS-CoV-2 transmission, particularly airborne transmission, may have contributed to heterogeneous recommendations for respiratory protection across countries and organizations.PRISMA) reporting guideline. Infection prevention and control guidelines on respiratory protection for HCPs published from January 1 to December 31, 2020, by leading organizations in 4 countries and 2 international organizations were collected through a monthly consultation of their official websites  were excluded  and 59 guidelines (51.8%) were included. In January 2020, all initial guidelines recommended respirators  for HCPs in direct contact with patients with suspected or confirmed COVID-19 infection . After F3 The most recent assessment of the clinical evidence for the risk of transmission of acute respiratory infections to HCPs caring for patients undergoing AGPs dates back to a 2012 systematic review of a limited volume of studies .4 More evidence is still needed to clearly define what AGPs are and the level of risk associated with different procedures.5In this systematic review, we observed 4 strategies regarding the use of respirators: (1) systematic: recommended for care of COVID-19 patients, as in German guidelines; (2) flexible: recommended with use of MFs in the absence of available respirators, as in US and ECDC guidelines; (3) unit based, as in UK guidelines; and (4) recommended exclusively during AGPs, as in French and WHO guidelines. These discrepancies may reflect controversies related to SARS-CoV-2 transmission routes.6 Some guideline updates may have been dated incorrectly, representing the main study limitation.Initial uncertainties surrounding asymptomatic transmission of SARS-CoV-2 and the initial global shortage of MFs may explain some of the early delays in universal face-masking recommendations. The growing recognition of the role played by asymptomatic HCPs and the publication of a major positioning paper may have triggered the extension of face masking.Over the course of the COVID-19 pandemic, contextual factors  may have generated variability in recommendations owing to a lack of scientific evidence. Inconsistencies in respiratory protection guidelines between neighboring countries created confusion over optimal measures. Strong collaborations between national and international organizations are critical in such circumstances."}
+{"text": "Ebolavirus cause severe and often lethal disease in humans: Sudan ebolavirus (SUDV), Bundibugyo ebolavirus (BDBV), Ta\u00ef Forest ebolavirus (TAFV), and Zaire ebolavirus (EBOV) .,25.24,25While substantial progress has been made in the development of EBOV vaccines, multiple questions remain unanswered including the following: (1) what is the durability and the immediacy of immune responses generated by different vaccines; (2) what are the specific correlates and thresholds of protection; (3) do any interactions or interferences exist between vaccines and potential therapeutics; (4) what is the safety of these vaccines in special populations, particularly pregnant women and the immunocompromised; and (5) can vaccines be formulated to be stable for long-term storage at 2 to 8\u00b0C, which would be useful in endemic areas [Another major hurdle is mitigating the economic risks for manufacturers and distributors of EBOV vaccines since the demand may not be high enough to warrant stockpiling. Outbreaks also tend to occur in resource-poor countries leaving little financial incentive for commercial development. In January 2021, the International Coordinating Group (ICG) comprised of public and private benefactors established an Ebola vaccine stockpile in Sweden with the goal of manufacturing 500,000 doses. Stockpiling is an important step toward controlling EBOV outbreaks as it is critical for ensuring timely access to vaccines for at-risk populations .Ebolavirus: EBOV. Although multivalent vaccines  have and are being developed, no studies have specifically evaluated immune responses or efficacy against other Ebolavirus species . Future work should focus on the development of vaccines that confer protection across all medically relevant species of the genus Ebolavirus, bearing in mind that intraspecies mutations may also arise that impact vaccine effectiveness.Lastly, the most advanced vaccines are solely indicated for protection against one species of"}
+{"text": "ABSTRACT IMPACT: The pathophysiologic features of a metabolomic endotype that predicts patient outcomes due to sepsis have the potential to direct new therapies that target immune dysregulation and bioenergetic insufficiency. OBJECTIVES/GOALS: Acute respiratory failure (ARF) requiring mechanical ventilation is a frequent complication of sepsis and other disorders. It is associated with high morbidity and mortality. Despite its severity and prevalence, little is known about metabolic and bioenergetic changes that accompanying ARF. METHODS/STUDY POPULATION: In this study, semiquantitative and quantitative ultrahigh performance liquid chromatography mass spectrometry (UHPLC MS) analysis was performed on patient serum collected from the Trial with Acute Respiratory failure patients: evaluation of Global Exercise Therapies (TARGET). Serum from survivors (n=15) and nonsurvivors (n=15) was collected at day 1 and day 3 after admission to the medical intensive care unit as well as at discharge in survivors. Pathway analysis of the biochemical changes was performed to determine whether the disruption in specific metabolic pathways can identify the bioenergetic and metabolomic profile of these patients. RESULTS/ANTICIPATED RESULTS: Significant metabolomic differences were related to biosynthetic intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, and decreased acyl-glycerophosphocholines in nonsurvivors compared to survivors. The metabolites associated with poor outcomes are substrates of enzymatic processes dependent on NAD(P), while the abundance of NAD cofactors rely on the bioavailability of dietary vitamins B1, B2 and B6. Changes in the efficiency of the nicotinamide-derived cofactors\u2019 biosynthetic pathways also associate with an alteration of the glutathione-dependent drug metabolism as characterized by the substantial differences observed in the acetaminophen metabolome. DISCUSSION/SIGNIFICANCE OF FINDINGS: This metabolomic endotype represents a previously unappreciated association between severity of outcomes and micronutrient deficiency, thus pointing to new pharmacologic targets and highlighting the need for nutritional remediation upon hospitalization to improve patient outcomes due to ARF."}
+{"text": "Senior adults\u2019 reliance on the visual frame of reference for spatial orientation is a manifestation of an age-related shift in cognitive style from field independence to field dependence. We implemented a virtual reality rod and frame test (VR-RFT) to assess visual field dependence (VFD) in n=39 young adults (20-30 years old) and n=43 seniors (60 years old and above). The subjects were asked to determine subjective visual vertical (SVV) for 19 angles of frame tilt (running from -45 degrees to 45 degrees in steps of 5 degrees). The strong VFD of seniors was manifested not only by the increased error in the determination of SVV (SVVE) but also in its distribution. For small and large frame tilt angles, seniors\u2019 SVVE skewness and kurtosis were greater than those of young adults. The SVVE median dependence on frame tilt may be accounted for with a phenomenological model whose two parameters describe the strengths of primary (P) and secondary (S) visual attractors which subjects use to infer SVV: the edges of the frame and its imaginary diagonals. For young adults, these parameters were: PY=14.91 and SY=12.51. For seniors, we observed an over 50% increase in the strength of the primary attractor PS=26.31 while the strength of the secondary one was only weakly affected by aging: SS=13.74. We demonstrate that the asymmetry between the strength of attractors significantly contributes to SVVE made by seniors at large frame tilts. We hypothesize that a variant VR-RFT may be used in rehabilitation to reduce excessive VFD."}
+{"text": "Given the growing prevalence of Alzheimer\u2019s Disease and related dementias, and the intensity of this population\u2019s care needs, it is imperative that health plans (HPs) increase their dementia-capability. The Dementia Cal MediConnect (Dementia CMC) project proposes an innovative model of health care advocacy that can create dementia-capable systems change. The Dementia CMC project was a partnership (2013 \u2013 2018) between local Alzheimer\u2019s organizations and ten managed care HPs in California. It used the following model of health care advocacy: 1) Identify dementia-capable best practices to set as systems change indicators; 2) Identify and leverage public policies in support of systems change indicators; 3) Identify and engage champions; 4) Develop and advocate for a value and business case to improve dementia care; 5) Identify gaps in dementia-capable practices; 6) Provide technical assistance, tools, and staff training to address the gaps in dementia-capable practices; and 7) Track systems change. Systems change data was collected through participant observation with HPs and interviews with key informants. HPs reported making systems changes toward more dementia-capable practices such as: better pathways for identification and diagnosis; better identification, assessment, support, and engagement of caregivers; and improved systems of referral to Alzheimer\u2019s organizations. Some indicators of systems change were inconclusive as a result of variability in HP practices and the lack of common record systems between HPs and providers. The application of this advocacy model has led to systems changes that can be replicated to improve care for people living with dementia and their caregivers."}
+{"text": "Adequate sleep in hospitalised children is important for a variety of physiological and psychological processes associated with growth, development, and recovery from illness and injury. Hospitalisation often prioritises clinical care activities at the expense of age-appropriate sleep. Nurses and the wider healthcare team contribute to this paradox. However, through conscious practice and partnering with mothers, nurses are able to enact change and promote sleep.To adopt, adapt or contextualise existing guidelines to develop an evidence-based practice guideline to promote sleep-friendly ward environments and routines facilitated by nurses, and in partnership with mothers.A six-step methodology for guideline adaptation was followed, as recommended by the South African Guidelines Excellence project: (1) existing guidelines and protocols were identified and (2) appraised using the AGREE II instrument; (3) an evidence base was developed; (4) recommendations were modified, (5) assigned levels of evidence and grades of recommendation; and (6) end user guidance was developed. Expert consultation was sought throughout.Existing relevant guidance comprised 61 adult-centric recommendations. Modification of the evidence base led to six composited recommendations that facilitate sleep in hospitalised children: (1) prioritising patient safety; (2) collaborating with the mother or caregiver to promote sleep; (3) coordinating ward routine and (4) environment to improve sleep; (5) work with clinical and non-clinical staff; and (6) performing basic sleep assessments. Practice recommendations were aligned to the South African regulatory framework for nursing.Hospitalisation is a time of physiological and psychological dysregulation for children, which is amplified by poor sleep in a hospital. Nurses have the opportunity to promote sleep during hospitalisation by implementing this African-centric guideline in partnership with mothers. Sleep is crucial to the developmental processes of children Beebe , and is In critically ill adults, length of stay is adversely affected by in-hospital sleep disruption  was created. A guideline is a rigorously developed document that informs healthcare decisions through actionable recommendations  existing guidelines and protocols were identified and (2) appraised using the AGREE II instrument; (3) an evidence base was developed; (4) recommendations were modified and (5) assigned levels of evidence and grades of recommendation after which (6) end user guidance was developed. Expert consultation was sought throughout the process, particularly during the fourth and sixth stages of development. This methodology for guideline modification follows the recommendations made by the South African Guidelines Excellence (SAGE) project  approach  and staff. Involving mothers was crucial to the continuity of sleep for the child as sleep practices are known to vary by culture  and the website of the National Institute for Clinical Excellence (NICE United Kingdom [UK]), were performed to identify relevant guidance or policy documents. Keywords and MeSH terms included sleep, controlled environment, care, quiet (time), hospital, sleep and guideline or protocol. The search strategy was constructed using the P-C-C approach to aid definition of search terms and inclusion and exclusion criteria as summarised in Step 2: Appraisal of the existing guidelines: Identified sources were then screened for scope and purpose, and rigour of development using Domains one and three from the AGREE II instrument , contextualisation  and finally adaptation   resulted in the identification of 88 sources, whilst other methods identified 2345 sources (mostly grey literature). After de-duplication, a total of 2433 sources were screened by title and abstract or executive summary using the criteria described in The authors of the above sources were contacted and provided additional information that led to the identification of Elliott  and the AGREE II  safety and other special considerations, (2) collaboration with the bedside carer to promote individualised sleep, (3) coordination of the ward routine and (4) ward environment to improve sleep, (5) collaborating and communicating with staff and other persons to protect sleep and finally (6) performing a basic sleep assessment.The majority of modifications to the recommendations involved contextualisation, mainly for differences in resources and target population. As an example, original recommendations about a visitor policy were contextualised to accommodate the expected presence of a mother or other bedside carer. A sleep assessment tool for children was identified .A flowchart summary of recommendations is presented in The flowchart was incorporated into a poster summary together with an aide memoir: (1) safety first, (2) then a mother\u2019s love; (3) next comes time; (4) low noise, dim light and calm. Pack the phone away, (5) collaborate with us; (6) then make sure sleep was enough.Sleep is disrupted during paediatric hospitalisation  Safety, (2) collaboration with the bedside carer to promote individualised sleep, coordination of the (3) ward routine and (4) ward environment to improve sleep, (5) involvement of the wider ward team and (6) sleep assessment. These recommendations and the supporting evidence-base are well-described in The second recommendation, concerning collaboration with the bedside carer, was adapted from original recommendations that encouraged family members and visitors to rest at home , we noted that children\u2019s sleep needs differ in quantity by age, generally decreasing from infancy towards puberty  sleep during hospitalisation. However, nurses are ideally positioned to capitalise on time spent in hospital to aid children\u2019s sleep through engagement and partnering with families, to promote health and enact their role as patient advocates. The guideline described throughout this article seeks to guide nurses to actively engage in sleep promotion for the hospitalised child. This evidence-based African-centric approach of partnering with families during hospitalisation exemplifies collaborative healthcare and holds the promise of benefits that extend beyond discharge home in resource-constrained contexts."}
+{"text": "The dynamic interplay between dementia and psychological trauma can exert powerful effects on nursing home residents\u2019 behavioral symptoms and quality of life. Our objectives in this exploratory study were to assess care aides\u2019 perceptions of how often they worked with residents with past psychological trauma, the types of trauma encountered, and reasons for these beliefs. We conducted semi-structured cognitive interviews (n = 10) with care aides in June 2019 to inform the development of a trauma needs assessment (4 questions) that we included in a large survey of nursing staff (2019 - 2020). Care aides (n = 3761) were sampled from 91 randomly selected urban nursing homes stratified by health region, owner operator model, and size. We completed basic statistics and content analyses. Care aides identified residents they believed to have psychological trauma histories and provided reasons for their beliefs. Approximately 12% of the reported traumatic events were disclosed to staff. The most common, broad categories of trauma to emerge during analysis were abuse (40%) and war exposure (30%). Each had sub-categories. The most common categories of signs of trauma were re-experiencing symptoms such as flashbacks and nightmares (28%), and avoidance of specific triggers, such as water or intimate care (24%). The majority of the reported signs of trauma were persistent and distressing for staff and residents. Some behaviours assumed to be responsive behaviours of dementia may relate to traumatic stress symptomatology. Implementing trauma-informed supports for residents and care aides is essential to person-centred care and optimal quality of life."}
+{"text": "The authors wish to make the following correction to their paper . In the All ingredients were assessed by Weender analysis. Dry matter (DM), crude ash (CA), crude protein (CP) and ether extract (EE) were analyzed in all feedstuff. Crude fiber (CF), neutral detergent fiber (NDF) and acid detergent fiber (ADF) were analyzed in the solid feed. In concentrate feed and TMR starch was analyzed and in concentrate feed additionally sugar was analyzed."}
+{"text": "Although mindfulness therapies have demonstrated benefits for reducing stress and improving psychological symptoms in family dementia caregivers, the mechanisms underlying these salutary effects are unknown. We report a causal mediation pathway to improvement of stress symptoms in family dementia caregivers with Mentalizing Imagery Therapy (MIT), which employs mindfulness and guided imagery tools to reduce stress and improve understanding of self and others. In a randomized controlled trial of short-term 4-week MIT (N=24) versus a psychosocial support group (N=22), MIT demonstrated superior benefit for reducing perceived stress (p=.006). Increased trait mindfulness was a causal mediator of this effect (p=.02). Neuroimaging pre and post intervention found that increased mindfulness was associated with strengthened connectivity of the dorsolateral prefrontal cortex with an emotion regulation network (p<.001). The results are discussed in light of theories of cognitive control and may inform the design of future studies aimed at reducing family caregiver stress."}
+{"text": "Structural isolation such as living alone poses a mental health risk in diverse groups of older adults, including older immigrants. Given that those living with others might also be disengaged, the present investigation included eating alone as another source of isolation and examined the impact of the combination of living and eating alone. The proposes of the study were to examine (1) how living and/or eating alone would impact mental distress, (2) whether the impact would be mediated by feelings of loneliness, and (3) if there would be gender differences in the mediation effect. The data were drawn from the Study of Older Korean Americans (SOKA), which surveyed older Korean immigrants in five states during 2017\u22122018. The living/eating arrangement was classified into four-groups: living/eating with others (57%), living with others/eating alone (12.4%), living alone/eating with others (7.3%), and living/eating alone (23.1%). Using the PROCESS macro, we tested the mediation effect of loneliness and the moderation effect of gender in the relationship between the typology and mental distress controlling for background/health characteristics and social capital related variables. Two groups  had sociodemographic, health, and social capital disadvantages. Analyses demonstrated that mental distress was linked with living with others/eating alone and living/eating alone, of which relationships were mediated by loneliness only among women. Findings suggest that not only structural isolation  but also disengagement with others  need to be considered to understand emotional well-being in older immigrant population and gender difference."}
+{"text": "QuickDASH for use in assessment of limb function in patients with upper extremity lymphedema using modern psychometric techniques.This study aimed to evaluate and improve the accuracy and efficiency of the QuickDASH, and then fit the data to Samejima\u2019s graded response model (GRM) and assessed the assumption of local independence of items and calibrated the item responses for CAT simulation.We conducted confirmative factor analysis (CFA) and Mokken analysis to examine the assumption of unidimensionality for IRT model on data from 285 patients who completed the QuickDash (r\u2009=\u20090.98). Items 2 (doing heavy chores) and 8 (limiting work or daily activities) were the most frequently used. The correlation among factor scores derived from the QuickDASH version with 11 items and the Ultra-QuickDASH version with items 2 and 8 was as high as 0.91.Initial CFA and Mokken analyses demonstrated good scalability of items and unidimensionality. However, the local independence of items assumption was violated between items 9 (severity of pain) and 11 (sleeping difficulty due to pain) (Yen\u2019s Q3\u2009=\u20090.46) and disordered thresholds were evident for item 5 (cutting food). After addressing these breaches of assumptions, the re-analyzed GRM with the remaining 10 items achieved an improved fit. Simulation of CAT administration demonstrated a high correlation between scores on the CAT and the QuickDash items we can obtain estimates that are very similar to those obtained from the full-length QuickDash without the need for CAT technology.By administering just these two best performing The online version contains supplementary material available at 10.1007/s11136-021-02979-y. The disabilities of the arm, shoulder, and hand (DASH) outcome measure is a widely used patient-reported outcome measure (PROM) assessing different disorders of the upper limb as well as the extent of impairments .QuickDASH (Online Appendix A), was developed in 2005 and comprises 11 items from the original 30-item DASH while still maintaining a strong correlation with the original DASH scores , whQuickDASH substantially, we found that a more efficient and precise estimation of disability level and symptom severity for American lymphedema patients can be achieved. In the meanwhile, the Concerto, as an emerging open-source CAT delivery platform, makes this CAT QuickDASH application in a real clinic setting possible [Ultra-QuickDASH mainly consisting of two best performing items and maintaining efficient and accurate estimations could be used as a CAT technology-free version of QuickDASH. Its application and promotion can break the obstacles of complex technology on health care professionals and providers on the use of\u00a0CAT QuickDASH, making this super shortened instrument more convenient to apply into routine clinic practices.By utilizing CAT simulation based on the IRT framework to shorten the possible . All theQuickDASH Questionnaire (PDF 676 kb)Supplementary file1 Supplementary file2 (PDF 690 kb)QuickDASH Questionnaire (PDF 213 kb)Supplementary file3 Revised Below is the link to the electronic supplementary material."}
+{"text": "The International Federation of Gynecology and Obstetrics (FIGO) stage remains the standard staging system for the assessment of endometrial cancer (EC) prognosis. Thus, we aim to identify the significant genes or biomarkers associated with the stage of endometrial cancer, which may also help reveal the mechanism of EC progression and assess the prognosis of patients with EC.We compared the mRNA expression levels of EC patients with stages I and II as well as stages III and IV in the Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) of EC patients at different stages were selected by volcano plot and Venn analysis. Gene Ontology (GO) and Pathways were applied to analyze the identified genes. Protein protein interaction (PPI) network was employed to identify the correlation. The survival analyses based on TCGA database were conducted for further screening. The Human Protein Atlas, quantitative PCR and immunohistochemistry were utilized to confirm the differences in expression of DEGs in endometrial cancer samples at different FIGO stages.CKMT1A was identified as a candidate gene. Through survival analyses, we found that CKMT1A may be a poor prognostic factor in the overall survival of endometrial cancer patients. GO and Pathways revealed that CKMT1A is closely associated with the metabolic process. More importantly, Human Protein Atlas and quantitative PCR confirmed the differences in expression of CKMT1A in endometrial cancer samples at different FIGO stages.CKMT1A is a newly identified essential tumor progression regulator of endometrial cancer, which may give rise to novel therapeutic strategies in the management of endometrial cancer patients to prolong its prognosis and prevent tumor progression.In summary, this study shows that  Endometrial cancer (EC) is one of the most common malignant tumors in the female reproductive tract . AccordiSOX11) hypomethylation is an independent poor prognostic marker in EC  and poor histological differentiation . In a multivariate analysis, histological differentiation  and FIGO stage  were found to be the independent predictors of tumor progression among the patients with endometrial cancer  and the difference of stage  were independent prognostic factors for the OS of patients with endometrial cancer Click here for additional data file.S2 TableLogFC: FoldChange.(DOC)Click here for additional data file.S3 TableLogFC: FoldChange.(DOC)Click here for additional data file.S4 TableBP: Biological Process; MF: Molecular Function; CC: Cellular Component; FDR: false discovery rate.(DOC)Click here for additional data file.S5 TableFDR: false discovery rate.(DOC)Click here for additional data file.S6 Table(DOC)Click here for additional data file.S7 Table(DOC)Click here for additional data file."}
+{"text": "However, very few studies addressed its role in amyotrophic lateral sclerosis (ALS). Dominguez et al.3 recently brought some negative findings on this topic: (i) the genetic inactivation of receptor-interacting protein kinase (RIPK)1 did not protect against motor neuron degeneration in the superoxide dismutase (SOD)1 model of ALS and (ii) phosphorylated (p)-RIPK1 did not accumulate in the spinal cords of ALS compared to non-ALS patients. These findings raise doubts about the implication of necroptosis in the pathophysiology of ALS. In contrast, other studies detected robust activation of RIPK1, RIPK3, and mixed lineage kinases domain-like (MLKL) proteins in preclinical as well as clinical studies of ALS7. The discrepancies between these studies5 and others8 might be explained by (i) the use of western blotting in whole-tissue extracts8 versus in situ immunolabelling targeting motor neurons7, (ii) the removal of circulating blood cells\u2014a rich source of necroptotic markers9\u2014in some studies but not in others, (iii) the various time frame of tissue sampling, which matches or not the transient expression of necroptotic markers10, or (iv) technical limitations in the availability and specificity of in vivo tools of detection of necroptotic markers8.Interest in potential implications of necroptosis Fig. \u2014i.e., a 7, including in situ experiments focusing selectively on the cells of upmost interest, i.e. motor neurons of the anterior horn of the spinal cord7. In contrast, the studies showing the absence of activation of necroptosis assessed only one molecular step of the cascade (p-RIPK1 or unphosphorylated RIPK1)5 were often untargeted on specific neural cells, and not always targeting the phosphorylation of key necroptotic markers, which are fundamental to demonstrate the execution process of necroptosis -\u03b114.Altogether, the final conclusion about the role of necroptosis in ALS and the interplay between the various molecular mediators and cell subtypes involved would deserve further descriptive clinical findings on larger cohorts of ALS patients, as well as preclinical studies. Such research should combine pharmacological or genetic modulations of necroptotic signaling in ALS models to uncover the pathophysiological mechanisms potentially at play in the occurrence of ALS and define the key check points of putative intervention"}
+{"text": "In recent years several new drugs have been approved for treatment of heart failure and type 2 diabetes. Despite their life-prolonging benefits, uptake of new drugs is often slow among older patients with frailty due to under-representation of frail older adults in pivotal clinical trials and concerns for adverse events. To optimize pharmacotherapy, timely evaluation of the drug benefits and risks is urgently needed. We propose a novel drug monitoring framework that prospectively evaluates the effectiveness and safety of newly marketed drugs for frail and non-frail patients in real-world databases. This framework utilizes a validated claims-based frailty index (CFI)  to find early signals for effectiveness and safety of new drugs by updating the analysis at regular intervals as new data become available. In this symposium, we present early results of this prospective monitoring framework for 2 new drug classes using Medicare claims data from the approval date until the end of 2017: 1) angiotensin receptor-neprilysin inhibitor (ARNI) (approved in July 2015) for heart failure with reduced ejection fraction (HFrEF) and 2) sodium-glucose cotransporter-2 inhibitors (SGLT2i) (approved in March 2013) for type 2 diabetes. We first show the uptake of ARNI and SGLT2i over time among the eligible Medicare beneficiaries by clinical characteristics, including frailty. Subsequently we present the results of sequential cohort analysis for the effectiveness and safety results of ARNI and SGLT2i. After these presentations, the panel will discuss the strengths, limitations, and challenges of implementing our monitoring framework in real-world databases."}
+{"text": "GamePlan4Care (GP4C) is a web-based adaptation of the Resources for Enhancing Alzheimer\u2019s Caregiver Health II (REACH II) caregiver intervention, redesigned and reformatted for online delivery. The goal of GP4C is to create an online family caregiver support platform that facilitates self-directed exposure to evidence-based skills-training and support for dementia caregivers. This approach of utilizing technology enhanced with live support has the potential for scalability and sustainability. In preparation for an ongoing randomized clinical trial, the GP4C platform underwent industry standard user interface/user experience (UI/UX) testing with dementia caregivers as part of an iterative design process. Testing of caregiver\u2019s reaction to technical and content-related aspects of the system was conducted with 31 caregivers. The thematic analysis revealed three themes for technical aspects  and two themes for content aspects (satisfaction and engagement). We will discuss technical and content modifications resulting from UI/UX."}
+{"text": "Maine has a growing number of age-friendly community initiatives (AFCIs); 116 communities are actively working to adapt the social, service, and built environments for aging and 71 have formally joined the AARP Network of Age-Friendly States and Communities. During COVID, rural municipalities were faced with dynamic changes that limited older resident\u2019s access to services and social engagement. To overcome these limitations, it is critical for emergent AFCIs to have tools and strategies to maintain and further enhance healthy environments and resilient communities. This study uses group interviews with 6 leaders of established AFCIs and 6 leaders of emergent AFCIs to explore how the Lifelong Fellows Program, a peer mentoring model that matches experienced leaders with newly formed initiatives, was able to spur development of new strategies to build community resilience. Prominent themes were (1) engaging new local and regional partners; (2) intergenerational volunteerism; (3) fun and flexibility; and (4) relationship-building."}
+{"text": "A 14-year-old male adolescent, with no notable medical history presented to a medical consultation with pain and swelling in the left testicle of 5 months duration. Physical examination revealed scrotal varicosities, with small testicular volume. Doppler ultrasound (US) of the left pampiniform plexus and the renal vessels confirmed varicocele grade 3,  and revealed an associated nutcracker phenomenon . Computed tomography (CT) scan with contrast showed also the compression of the left renal vein (RV) between the superior mesenteric artery (SMA), and the abdominal aorta (AO) confirming the nutcracker phenomenon (NCS) (1) . Our patient was treated by inguinal varicocelectomy and had a partial resolution of symptoms after. He was then referred to a nutritionist to increase BMI in order to treat the NCS, before proceeding to invasive methods. Doppler ultrasound of the renal vessels must be performed in case of left varicocele to assess for an associated NCS (2)."}
+{"text": "We report 4 cases of COVID-19 in kidney transplant recipients (KTRs) 2 of them after 2 doses of Covishield vaccine and another 2 after a single dose. The study is approved by the Institutional Ethics committee. We also abided by the Declaration of Helsinki and Declaration of Istanbul principles. None of them reported any minor or major side effects postvaccination. The probable exposure was community acquired in all the 4 cases. Three patients were on triple immunosuppression. Three cases required critical care admission and received steroids, remdesivir, anticoagulation, and investigational therapies  as anti-COVID-19 therapy during the stay. Patient 1 died and patients 2 and 3 are on mechanical ventilation with a poor prognosis  has been reporting global peaks in India in April 2021. The enormous task of vaccinating such a bulk population has become more difficult in the state where health resources for managing coronavirus disease 2019 (COVID-19) are rapidly emptying amid the COVID-19 surge. Indian advisories have approved 2 vaccines: Oxford\u2013AstraZeneca COVID-19 (Covishield) and BBV152 (Covaxin) as of April 2021. The efficacy of these vaccines has been reported lesser compared with the mRNA vaccines in general population.The authors express our sincere gratitude to all the resident doctors and healthcare staffs who are tirelessly doing a mammoth job of managing the COVID-19 cases in India, despite facing resource crisis."}
+{"text": "In this study, the gamma radiation properties of four types of surgical-grade stainless steel  were investigated. The effective atomic number Z Technological development in various fields has increased the quality of life of patients by improving health services. In some circumstances, medical interventions require the use of metal materials with biocompatible compositions and properties, such as stainless steel. Stainless-steel materials are used as biocompatible mineral components for rebuilding teeth, manufacturing medical devices used in surgeries and other applications ,2. StainFour different samples of stainless steel were studied in this work. The chemical compositions and densities of the stainless steel used in this study are shown in The main parameter of photon penetration in samples is the mass attenuation coefficient Equation  23]:(1):(1)\u03bcm, wi relative to the total number of atoms of all elements in the alloy, and ith element in the alloy.Equation  shows thEquation  23]: (3: (3\u0394(\u03bcm)Equation  [23]:(4)The effective atomic number Equation .(5)ZeffThe half-value layer  24,25],25Zeff),I and The linear and mass attenuation coefficients were evaluated by using an X-ray fluorescent (XRF) system. The XRF energies produced from pure metal plates were irradiated to the annular source of radioactive The mass attenuation coefficients of surgical stainless-steel samples obtained in the photon energy range of 17.50\u201325.29 keV using XRF beams from Mo, Pd, Ag and Sn are listed in HVL is an important parameter in the design of radiation protection and refers to the thickness of the sample required to absorb half the value of the radiation falling on it. The results of theoretically and experimentally calculated HVL values are presented in An experimental XRF system and the WinXCOM program were used to evaluate the mass attenuation coefficient ("}
+{"text": "A large number of common cold outbreaks in Hong Kong schools and childcare centers during October\u2013November 2020 led to territorywide school dismissals. Increased susceptibility to rhinoviruses during prolonged school closures and dismissals for coronavirus disease and varying effectiveness of nonpharmaceutical interventions may have heightened transmission of cold-causing viruses after school attendance resumed.  Many countries implemented school closures and dismissals in 2020 as a public health measure to reduce spread of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In Hong Kong, schools were dismissed after the Lunar New Year holiday in late January 2020 and remained dismissed until late May; during early July\u2013late September, schools were dismissed again in response to a surge in cases of COVID-19 , panel A>3 students in the same class each developing >2 symptoms of respiratory tract infection within 4 days  occurred in Hong Kong schools despite a wide range of infection control measures being in place. Staff and students wore face masks at all times; lunch hours were cancelled, desks were spaced out, and group activities were limited ("}
+{"text": "Scalds are the most common mechanism of burn in children, and a significant proportion of these injuries are associated with bathing. Burns sustained while bathing present a unique opportunity for injury prevention; previous studies have examined lowering water heater temperatures, however reputable infant bathing educational resources do not explicitly recommend avoiding running water and the risks that it could pose. In an effort to inform prevention programs, this study seeks to determine the incidence and circumstances of running water in bathing scald burns at our institution.A retrospective review was performed of records from an American Burn Association verified center over a ten year period (1/1/2010 to 12/31/2019). This center treats both children and adults and is affiliated with an academic hospital in a major urban center. The burn database was queried for scald injuries in children less than three years involving bathing. The Child Advocacy and Protective Services team provides inpatient consultation for all children less than three years old with burn injuries allowing us to analyze the specific events surrounding the bathing scald burns in this cohort.A total of 123 patients met inclusion criteria. Three bathing safety risk factors were specifically noted in the chart review: (1) running water, (2) lack of caregiver presence for duration of bathing, and (3) failure of caregiver to check water temperature before bathing. Of the cases identified, 107 (87%) had clear documentation of running water as part of the history of injury, 66 (54%) cases involved failure of caregiver to check the water temperature before bathing and 53 (43%) cases did not have a caretaker present for the duration of the bath. In cases with only one risk factor, running water was identified in 34 (94%) out of 36 cases, and in cases with one or two risk factors, running water remained the primary risk factor with 38 (90%) out of 42 cases. When looking at the combination of risk factors, only three (2%) cases had no risk factors while 77 (63%) involved two or more risk factors.The vast majority of bathing burn injuries in this series involved running water. In addition, a significant number of scald burns occurred from running water alone, even without the other identified risk factors. Conversely, only 2% of scald burns associated with bathing featured none of these three risk factors, suggesting that these injuries could be greatly impacted by safe bathing education."}
+{"text": "Genetic networks that regulate meristem transitions were recurrent targets of selection during crop domestication and allow fine-tuning of plant architecture for improved crop productivity. Solanum lycopersicum) and that were recurrent targets of selection during crop domestication and breeding. Fine-tuning the activity of conserved regulators of meristem transitions allows re-balancing vegetative to reproductive growth to customize plant architecture for improved crop productivity.Flowering plants display enormous architectural diversity that mainly results from differences in the position and organization of branches within vegetative and reproductive shoot systems. Where and when branches develop are tightly linked to the onset of flowering, which triggers the release of lateral buds from apical dominance and the outgrowth of additional branches. The transition to flowering depends on the activity of apical meristems, which are small groups of stem cells located at the growing tips of shoots. During vegetative growth, apical meristems produce vegetative organs including leaves and stem until endogenous and environmental signals prompt the transition to reproductive development, which often culminates in the production of an inflorescence, the flower-bearing shoot. It becomes clear that the rate at which meristems transition from the vegetative to the reproductive phase determines the number and pattern of branches in shoots and inflorescences . Not surConserved regulators of meristem transitions were recurrent targets of crop domestication and breeding.Changes in the activity of conserved meristem regulators result in quantitative variation in shoot and inflorescence architecture.Tuning the expression of conserved meristem regulators by genome editing allows engineering plant architecture for crop improvement.de novo domestication of wild species.Targeting conserved meristem regulators by genome editing facilitates the rapid improvement of underutilized crops and Meristem maturation and plant architecture are omnigenic traits and dependent on genotypic context and environmental conditions.vegetativeness that changes gradually during plant development  and pepper (Capsicum annuum)) and multiflowered inflorescences (e.g. tomato and related wild species). The evolution of Solanaceae inflorescence diversity involved changes in the rate of meristem maturation, which are driven by an increased transcriptional divergence of conserved regulatory genes during a critical developmental window that marks the transition to reproductive development  that is released in the axil of the last leaf. This process of floral termination and sympodial meristem release is reiterated indeterminately and results in the production of modular structures  that consist of a shoot with a terminal flower, resulting in a compound shoot that is characteristic for sympodial plants. In tomato, sympodial growth is recapitulated in inflorescences where each inflorescence meristem releases a sympodial inflorescence meristem at its flank before terminating in a flower, which results in the zig-zag arrangement of flowers on the tomato inflorescence.self-pruning (sp) mutation, which transformed indeterminate tomato vines into determinate bushes with concentrated fruit set that allows mechanical harvesting in large-scale field production  and belongs to the CETS  gene family (SP encodes an antiflorigen that acts as a repressor of flowering and antagonizes the activity of SINGLE FLOWER TRUSS (SFT), another CETS gene and homolog of Arabidopsis FLOWERING LOCUS T (FT). SFT encodes the universal flowering hormone florigen and triggers the transition of meristems to reproductive growth , the ortholog of Arabidopsis LEAFY , a flowering repressor that belongs to the CETS gene family  and other closely related wild species rapidly transition to flowering  is associated with higher SFT expression and accelerated flowering in short days  and antiflorigen (TFL1) takes place through competition for bZIP transcription factors that are bound to cis-regulatory elements of floral identity genes -engineered sp null mutants  to obtain highly compact and early yielding varieties that are optimized for indoor cultivation  by genome editing transforms sympodial meristems into inflorescence meristems that terminate in single flowers  and MACROCALYX (MC) are mutated  mutants carry mutations in the homeobox transcription factor gene S/SlWOX9, a homolog of Arabidopsis WUSCHEL-RELATED HOMEOBOX9, WOX9 , which is a homolog of Arabidopsis UNUSUAL FLORAL ORGANS and encodes an F-box protein that interacts with the transcription factor FA to form a floral specification complex and trigger floral differentiation  develop highly branched inflorescences with dozens of flowers but have been largely avoided by breeders due to low fruit set . These nX9, WOX9 . Naturaled genes . This derescence . Completntiation . S/SlWOXntiation . Loss ofAN depends on the activity of TERMINATING FLOWER (TMF), which encodes an ALOG (Arabidopsis LSH1 and Oryza G1) transcriptional regulator that directly represses AN expression  genes and the quadruple tmf tfam123 mutant was shown to develop single-flowered inflorescences on all shoot systems  transcriptional regulators (BOP1\u20133), which are co-expressed with TMF during vegetative meristem stages and decline toward floral identity  mutation induces strong inflorescence branching and reduced fruit set in specific genetic backgrounds (j2 mutation is caused by a Rider transposon insertion in a SEPALLATA (SEP) class MADS -box transcription factor gene and induces inflorescence branching in genetic backgrounds that carry a secondary mutation in the homologous gene ENHANCER OF JOINTLESS2 (EJ2)  results in flowers with elongated sepals while complete loss of EJ2 activity from CRISPR null mutations lead to leaf-like sepals. Importantly, j2 and ej2 single mutants develop unbranched inflorescences, but epistasis between the homologous genes causes excessive inflorescence branching and low fertility in j2 ej2 double mutants. Expression analyses of j2 ej2 double mutants uncovered misexpression of meristem stage-enriched marker genes at transition and floral stages of meristem maturation suggesting that j2 ej2 branching results from delays in meristem maturation (LONG INFLORESCENCE (LIN) also affect inflorescence architecture and lead to inflorescences with additional flowers and longer internodes that weakly branch. Triple j2 ej2 lin mutants give rise to inflorescence meristems that fail to achieve floral identity and produce cauliflower-like inflorescence tissue similar to the an mutant, demonstrating that J2, EJ2, and LIN genes synergistically regulate inflorescence complexity. Interestingly, the Arabidopsis genome encodes four SEP gene homologs, which redundantly regulate floral organ differentiation , breeders reported that the causative kgrounds . The j2 S2 (EJ2) . The secanscript . The natturation . Mutationtiation . Hence, j2 andW ej2 mutations by selecting additional genetic loci that suppress inflorescence branching /SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1)-class MADS-box transcription factor gene (SISTER OF TM3 (STM3) leads to lower STM3 expression and suppression of branching. Both EJ2 and STM3 copy number variants were present as cryptic variants in the domesticated tomato germplasm before j2 andW ej2 collided during modern breeding, illustrating how standing genetic variation contributes to breeding. Complete loss of STM3 activity in CRISPR-induced stm3 null mutants leads to late flowering indicating that STM3 promotes meristem maturation toward the transition to flowering  branching in a gene dosage-dependent manner , determinate shoot growth from a mutation in CsTFL1 is modulated in a day-length sensitive manner by the homologous gene CsTFL1d (The genetic networks that regulate meristem transitions are highly plastic and tightly linked to environmental changes . Howevernditions . The del equator . However CsTFL1d . In toma CsTFL1d . The und CsTFL1d .de novo domestication has been tested in wild relative species of tomato and rice (cis-regulatory regions allows the generation of quantitative phenotypic variation, for example, allelic series of domestication genes that can be used to fine-tune agricultural traits (Understanding the genetic changes that were selected by humans for adapting plants to new climatic regions can outline strategies for the development of novel genotypes for agriculture during climate change. Pan-genomes of crops and their wild ancestors allow the identification of genes and networks that were altered during domestication and breeding to modulate architectural plasticity. The standing genetic variation that is preserved in crop germplasms already presents a rich resource for adapting crops to new growth conditions. However, introducing genetic variation to new genotypic backgrounds can be challenging due to genetic linkage with deleterious alleles and often leads to unexpected phenotypic outcomes due to genetic interactions . Genome and rice . By targand rice . Genome and rice . Finallyl traits . TogetheHow are the effects of conserved meristem regulators modified in different genetic backgrounds, and what is the identity of the interacting genes?How do we uncouple the gene networks that regulate successive stages of meristem maturation to independently exploit shoot and inflorescence architecture for crop improvement?Is architectural diversity in crop populations mainly established by quantitative variation in a small number of conserved regulators or rather by variation in a large and diverse set of genes?What is the genetic architecture of plasticity in meristem development that relays environmental change to plant architecture?What is the impact of domestication and breeding on plasticity in meristem maturation?"}
+{"text": "This Correction follows an Expression of Concern relating to this article previously published by Portland Press.Biosci Rep (2018) 38(6): BSR20181414; DOI: 10.1042/BSR20181414) would like to correct The Authors of the original article \u201cAntioxidative and antiphotoaging activities of neferine upon UV-A irradiation in human dermal fibroblasts\u201d (The Authors state that this error had occurred during the figure making process, and confirm that it does not affect the conclusions of their study. The correct version of"}
+{"text": "Little is known about the disparities in patient experience of home health (HH) care related to social vulnerability. This study examined the relationships of patient Medicare-Medicaid dual eligible status and race and ethnicity with patient experience of HH care. We analyzed national data from the Home Health Care Consumer Assessment of Healthcare Providers and Systems (HHCAHPS), Outcome and Assessment Information Set, Medicare claims and Area Health Resources File for 11,137 Medicare-certified HH agencies (HHA) that provided care for Medicare beneficiaries in 2017. Patient-reported experience of care star ratings (1-5) in HHCAHPS included 3 domains  with each dichotomized into high (4-5) and low (1-3) experience of care. The proportion of patients with dual eligibility and the proportion of racial/ethnic minorities were summarized at the HHA level. HHA with higher proportion of dual eligible patients were less likely to have high experience of care rating in professional care delivery , effective communication , and specific direct care issues . HHA with higher proportion of racial/ethnic minorities were also less likely to have high patient experience of care rating across all three domains . Disparities in patient experience of HH care exist and they are associated with low income and racial/ethnic minority status, indicating substantial unmet needs among these socially vulnerable patients."}
+{"text": "OBJECTIVES/GOALS: This study\u2019s goal is to examine the feasibility and acceptability of using VRM to impact the APP of adults in the inpatient setting. Aims include examining the: 1) feasibility of VRM for APP management; 2) acceptability of using VRM for APP management; and 3) experience of VRM for APP management. METHODS/STUDY POPULATION: To comprehensively examine participants\u2019 experience of using VRM for APP, this study will employ a convergent mixed-methods design in which living kidney donors (N = 45) will be recruited to serially use VRM during their hospital stay. Feasibility and acceptability will be evaluated using descriptive and inferential statistics evaluating patient-reported outcome (PRO) measures taken pre-, post- and 1-hour post-VRM, PRO measures extracted from the participant\u2019s electronic health record and data on VRM use. Semi-structured interviews will allow formulation of inferences based on participants\u2019 experience of VRM for APP management and their insights on content, deployment, and clinical use of VRM. RESULTS/ANTICIPATED RESULTS: This in-process study expects: 1) an adequate sample of participants undergoing living kidney donor surgery who agree to enroll with retention of >90% of participants (Aim 1); 2) participants to report VRM as an acceptable and suitable treatment, feel \u201cpresent\u201d and interested in the VR environment, and feel comfortable using VRM in the hospital (Aim 2); and 3) to provide insight into participants\u2019 experience of VRM for APP, understanding of extended VRM use for APP analgesia, examination of key variables affecting participants\u2019 experience of VRM for APP and feedback about VRM procedures and protocol to inform future VRM use for APP management (Aim 3). DISCUSSION/SIGNIFICANCE OF IMPACT: Results of the proposed study will inform future clinical testing and deployment of VRM, guide future use of VRM as an adjunct for inpatient APP management, and provide insight into inpatients\u2019 experience of VRM for APP analgesia."}
+{"text": "We examined cross-sectional and prospective associations of sleep duration and insomnia symptoms with measures of cognitive function among older adults aged 45-75 y from the Boston Puerto Rican Health Study, a longitudinal cohort of 1500 participants of Puerto Rican ancestry. We found, statistically significant cross-sectional associations of sleep duration (hours) and an executive function domain before  and after  controlling for covariates ; between sleep duration and global cognition before  and a trend after controlling for covariates . In longitudinal associations, sleep duration (time2) was significantly associated with global condition at time3  after controlling for time2 global cognition. In conclusion, we found hours of sleep and insomnia symptoms significantly associated with various cognitive factors. A public health focus on sleep hygiene may improve cognitive health outcomes in older Puerto Rican adults."}
+{"text": "ABSTRACT IMPACT: Better understanding how clinicians make decisions about pain management, particularly since our prior research has demonstrated that opioids prescribed at discharge is the strongest predictor of opioids taken, is critical to decrease high-risk medication prescribing while preserving high-quality care. OBJECTIVES/GOALS: (1) Identify major biological, psychological, and social determinants of medical and surgical residents\u2019 pain management decisions; (2) Determine salient themes regarding the experience of residents in the management of acute and chronic pain METHODS/STUDY POPULATION: Focus groups of internal medicine and general surgery residents at an academic, tertiary care training hospital located in an urban setting were conducted. Due to the COVID-19 pandemic, all focus groups were conducted virtually and occurred during required didactic sessions to facilitate participation. All interviews were recorded and transcribed. Two reviewers independently reviewed and coded the data following the principles of constructivist grounded theory. RESULTS/ANTICIPATED RESULTS: 42 residents participated in ten focus groups ranging in size from two to five individuals. Six themes emerged demonstrating salient BPS factors in pain management decisions: (1) patient and clinician expectations determine what is considered normal/acceptable; (2) inability of pain scales to reliably capture patient pain; (3) desire for more objective methods of pain assessment, while simultaneously recognizing that pain is an inherently subjective experience; (4) difficulty in determine when pain is 'real\u2019 or 'legitimate'; (5) lack of education and protocols regarding pain management; (6) the importance of engaging other services such as acute pain service or nurse educators in complicated situations. Junior residents often expressed doubt in the appropriateness of their approaches and decisions. DISCUSSION/SIGNIFICANCE OF FINDINGS: Surgical and medical trainees routinely treat pain and may struggle, particularly in the early phases of training, to determine if pain levels are appropriate. There is also a lack of education and/or best practices for assessing and managing pain. These areas represent high-value, clinician-focused targets for future interventions to improve care."}
+{"text": "Psychosocial care for residents with serious mental illness (SMI) requires understanding of co-morbidities and careful attention to needs, rights, and preferences. Analyses of social services directors (SSDs) responses (n=924) to the National Nursing Home Social Service Director Survey considered perceived roles and competence to provide care stratified by the percentage of NH residents with SMI. Depression screenings and biopsychosocial assessments were common roles regardless of the percentage of residents with SMI. About one-quarter lacked confidence to train colleagues in recognizing distinctions between depression, delirium and depression (23.4% unable) or to develop care plans for residents with SMI (26% unable). A bachelor\u2019s degree  or less  was associated with less perceived competence in care planning compared to those with a master\u2019s degree. SSDs reported less involvement in referrals or interventions for resident aggression in homes with a high proportion of residents with SMI."}
+{"text": "With the development of real-time and visualized neuroimaging techniques, the studies on the central mechanism of acupuncture analgesia gain increasing attention. The experimental pain models have been widely used in acupuncture-analgesia neuroimaging studies with quantitative and controlled advantages. This review aimed to analyze the study design and main findings of acupuncture neuroimaging studies to provide reference for future study. The original studies were collected and screened in English databases  and Chinese databases . As a result, a total of 27 articles were included. Heat stimulation and electroacupuncture were the mostly used pain modeling method and acupuncture modality, respectively. The neuroimaging scanning process can be divided into two models and five subtypes. The anterior cingulate cortex and insula were the most commonly reported brain regions involved in acupuncture analgesia with experimental pain models. Acupuncture has been used for alleviating pain in China and other oriental countries for thousands of years. It has been accepted as an alternative or complementary therapy for pain in western countries. Nearly half of the 64 recommended indications of acupuncture by WHO , Chinese Biomedical Literature Database (CBM), the Chongqing VIP Database (VIP), and the Wanfang Database (WF). The literature search was conducted from database inception 11th Nov 2020. Details of search terms were modified for each database and depicted in The article was included if (1) it was an original article, (2) experimental pain stimulation was conducted on participants, (3) participants received acupuncture as intervention, and (4) the study was performed with neuroimaging techniques . ArticleThe process of the data selection is described in Information including the year of publication, the corresponding author , the trial place, the method of modeling, the acupuncture intervention , the pain assessment, the neuroimaging techniques, and the results of brain regions involved in acupuncture analgesia were extracted.A total of 27 neuroimaging studies with experimental pain models performing on healthy participants were included in this review.The first study was published in 1980 in Chinese. Sixteen of these 27 studies were conducted in China, and 9 studies in the United States. There were 13 corresponding affiliations mentioned; the top two were Massachusetts General Hospital (6 studies) and Peking University (4 studies).The pain modeling methods included heat stimulation (11 studies), electrical stimulation (4 studies), pressure stimulation (3 studies), injections of hypertonic saline (2 studies), potassium iontophoresis stimulation (2 studies), cold pain stimulation (1 study), video stimulation (1 study), tactile stimulation (1 study), stabbing stimulation (1 study), and capsaicin allodynia stimulation (1 study) on healthy participants .Thirteen studies chose manual acupuncture (MA), and 12 studies chose electroacupuncture (EA) as the intervention method. Besides, the transcutaneous electrical nerve (TENS) and transcutaneous electric acupoint stimulation (TEAS) were applied in one study, respectively .Hegu (LI 4) (9 studies), Zusanli (ST 36) (8 studies), and Sanyinjiao (SP 6) (4 studies) were the most frequently used acupoints in these studies .Fifteen studies assessed the pain with the Visual Analogical Scale (VAS), and three studies applied the Gracely Sensory and Affective Scales (GSAS). Other pain assessment scales are shown in Twenty-one studies applied fMRI, two studies used event-related potentials (ERP), two studies used electroencephalogram (EEG), one study used arterial spin labeling (ASL), and one study used both fMRI and PET as neuroimaging techniques .Similar scanning processes were sorted together regardless of the scanning time and repetition times. Scanning processes can be divided into model 1 and model 2 based on whether the pain stimulation was a part of task scanning. Subsequently, according to the sequence of pain stimulation, model 1 was divided into three subtypes [model 1-A .The reported deactivated/activated brain regions are shown in This review mainly described the current status of the central mechanism research of acupuncture analgesia based on the experimental pain model and neuroimaging techniques.Since early 1980, researchers have applied the electrical experimental pain model to investigate the central mechanism of acupuncture analgesia based on the ERP technique  (Hegu (LI 4) (9 studies)  were theThis review showed that VAS is the preferred scale for assessing pain. Using VAS was previously recommended in both research and clinical practice with the advantages of its simplicity and adaptability  was the most used technique of these 27 studies. fMRI indirectly measures brain activity by detecting associated changes in blood flow (hemodynamic response) , affective , and cognitive factors   The selection of the types of experimental pain could be broadened but not limited to the neuropathic pain on the skin. (2) Researchers can evaluate the pain from multimodal dimensions and using more objective assessment methods to guarantee the objective results and profoundly shape the experience of pain. (3) Researchers can use the neuroimaging technologies to compare the central mechanisms of EA and MA at different acupoints, different stimulations, and different intensities, to give the reference for the selection of the clinical treatment.ZF and LS designed the study. MP, CS, and QY participated in screening studies. YT and XK extracted the data from the included studies. HZ and CS performed the analysis plan. MP, SR, and YT drafted the article. ZF revised the draft. All authors have read and approved the publication of the final article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Remarkable advances have been reached in the understanding of the genetic basis of Parkinson\u2019s disease (PD), with the identification of monogenic causes (mPD) and a plethora of gene loci leading to an increased risk for idiopathic PD. The expanding knowledge and subsequent identification of genetic contributions fosters the understanding of molecular mechanisms leading to disease development and progression. Distinct pathways involved in mitochondrial dysfunction, oxidative stress, and lysosomal function have been identified and open a unique window of opportunity for individualized treatment approaches. These genetic findings have led to an imminent progress towards pathophysiology-targeted clinical trials and potentially disease-modifying treatments in the future.In this review article we will summarize known genetic contributors to the pathophysiology of Parkinson\u2019s disease, the molecular mechanisms leading to disease development, and discuss challenges and opportunities in clinical trial designs.The future success of clinical trials in PD is mainly dependent on reliable biomarker development and extensive genetic testing to identify genetic cases. Whether genotype-dependent stratification of study participants will extend the potential application of new drugs will be one major challenge in conceptualizing clinical trials. However, the latest developments in genotype-driven treatments will pave the road to individualized pathophysiology-based therapies in the future. Parkinson\u2019s disease (PD) is an age-related neurodegenerative disorder characterized by the progressive degeneration of nigrostriatal dopaminergic neurons and extranigral brain regions due to the accumulation of certain \u03b1-synuclein species , LRRK2 (Leucine Rich Repeat Kinase 2), and VPS35 (VPS35 Retromer Complex Component) cause an autosomal dominant form of mPD whereas mutations in PRKN (Parkin), PINK1 (PTEN-induced kinase 1), and PARK7 (oncogene DJ-1) (among others) are associated with autosomal-recessive mPD  gene are an unequivocal and frequent risk factor for the development of PD and a promising future drug target.PD is caused by complex interactions between genetic and environmental factors. Mutations in mPD Lill . Althoug Cookson . The ideGBA converge to distinct molecular mechanisms and can be divided into (i) \u03b1-synuclein aggregation  resulting in the formation of Lewy bodies  has already been proven useful in in-vitro, rodent, and primate models  against GBA gene encodes the protein glucocerebrosidase (GCase), a lysosomal hydrolase, which converts glucosylceramide to ceramide and glucose . Interestingly, GD patients have a higher incidence of parkinsonism, and heterozygous mutations in the GBA gene increase the risk of developing PD  and \u2018PD risk factor\u2019 GBA variants, which show an association with PD risk but are not considered causative for GD   are comparable with IPD whereas carriers of severe GBA variants (sGBA-PD) have a clearly increased risk of dementia with an earlier onset and a more rapid cognitive decline  substrate reduction (as often considered for the treatment of GD), (ii) external GCase augmentation, and (iii) the enhancement of GCase activity . Substrate reduction can be achieved by different mechanisms: Glucosylceramide synthase inhibitors decrease glycosphingolipid levels and are used to treat the hematological and visceral presentations of GD patients. The clinical trial GZ/SAR402671 (NCT02906020) showed that the glucosylceramide synthase inhibitor venglustat sufficiently crossed the blood brain barrier (BBB) in humans  and R15-006 (NCT02914366) tested the safety, efficacy, and tolerability of ambroxol in PD  phenotype, but show a relatively mild cognitive and motor decline during the overall disease course  with an increase of LRRK2 kinase activity. The LRRK2 protein has a complex multidomain structure and belongs to the family of protein kinases, which play a fundamental role in the control and regulation of complex cellular processes by transferring phosphate groups to target proteins. The kinase domain of LRRK2 shares similarities with mitogen-activated protein (MAP) kinases, which play a central role in mediating cellular stress. Even though the precise mechanism of LRRK2 is poorly understood, the disease-causing GOF mutations allows heuristic treatments by inhibition of its activity. Currently, two main strategies exist for LRRK2-targeted treatment strategies: (i) pharmacological inhibition of LRRK2 activity and (ii) silencing of the LRRK2 gene by the use of ASOs. Both options aim to reduce LRRK2 activity in the CNS whereby ASOs may bypass potential peripheral adverse effects of kinase inhibitors due to its intrathecal application  in blood. A trial with DNL151, a second LRRK2 inhibitor, is still actively recruiting healthy volunteers   the enhancement of PRKN or PINK1 expression, (ii) the prevention of Parkin or PINK1 inactivation, and (iii) the control of the downstream Parkin/PINK1 signaling pathway (Gaki and Papavassiliou PRKN or PINK1 mutation carriers) as listed in Table PRKN/PINK1 mutation carriers, heterozygous PRKN/PINK1 mutation carriers, and two IPD groups defined by the statistical extrema as determined by a mitochondrial PRS . Both studies have multimodal neuroimaging in common that will be applied as a surrogate marker for examining beneficial effects of in-vivo brain energy metabolism, i.e., by determining the change of energy equivalents using 31Phosphorus Magnetic Resonance Spectroscopy Imaging (31P-MRSI).Mitochondrial dysfunction is one of the main concepts in PD pathogenesis. Mitochondria play a fundamental role for a plethora of cellular processes relevant for the supply of energy, the overall cellular homeostasis, and neuronal survival. The first evidence for a role in PD derived from environmental studies illustrating the effect of neurotoxic agents in inhibiting the mitochondria's electron transport chain (ETC) . The disease-modifying management of PD is herewith more challenging due to the absence of validated and dynamic mechanism-based biomarkers.SNCA  and high energy phosphates such as ATP levels (31P-MRSI) (Bonvento et al. Biomarkers in clinical PD trials are mainly required to demonstrate target engagement and to quantify disease progression. Stratification of PD patients based on their primarily involved disease mechanisms is one substantial prerequisite for targeted therapies (Reden\u0161ek et al. The genetic discoveries in PD have aided the deepened understanding of clinical manifestations, underlying pathogenesis, and the potential for targeted therapies (Br\u00fcggemann and Klein"}
+{"text": "A 28-year-old primigravida with 22.3 weeks of gestation came for dedicated level II ultrasonography for anomaly scan to the antenatal clinic of AVBRH, Sawangi (India). The previous antenatal check-up was not done. The patient neither had a history of maternal systemic diseases like diabetes or hypertension nor history of any trauma or drug intake during pregnancy. There was no family history of congenital anomalies. On obstetric examination, the uterus was of about 20 weeks in size. On ultrasonography, single live intrauterine foetus with an average gestational age of 21 weeks 5 days corresponding to effective foetal weight of 396 grams showing right foot abnormality with persistent adduction and inward rotation suggestive of clubfoot with mild pylectasis of left kidney was noted. However, there was no obvious abnormality of left foot. There was amniotic band in right lower quadrant of gravid uterus."}
+{"text": "KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies  and other associated malformations . Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.Wiedemann\u2013Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the  Wiedemann\u2013Steiner syndrome  is a rare severe autosomal dominant disorder, characterized by intellectual disability (ID), developmental delay, hypertrichosis cubiti and distinctive facial features ,5,6,7,8.The introduction of next-generation sequencing (NGS) and the implementation of human phenotype ontology (HPO) have revolutionized diagnostics for rare diseases . ReverseKMT2A (lysine methyltransferase 2A) gene (MIM# 159555), located on chr11q23, previously known as MLL (mixed lineage leukemia). Germline and somatic KMT2A variants are, respectively, associated with WDSTS and multiple neoplastic diseases, along with gene structural rearrangements that are common in acute leukemia  and and22] ap-value < 0.01.In order to identify the regions that are differentially methylated between the subjects with WDSTS and controls, we used the DMRcate package  and seleKMT2A pathogenic variants may disturb the normal process of H3K4me3 deposition coupled at gene promoters. The methylome analysis did highlight a substantial change in the global methylation pattern in WDSTS samples, and resulted in 87% hypomethylated and 13% hypermethylated probes. Our studies reported that the expression of several homeobox containing genes (including HOX or HOX-related genes) is consistently altered in the blood of WDSTS patients. If also present in other tissues, dysregulation of normal methylation of homeobox gene expression may explain part of the ID, facies and associated malformations observed in WDSTS patients. These provide novel insights into the molecular etiology of WDSTS and likely explain the broad phenotypic spectrum of the disease.In conclusion, the identified WDSTS DNA methylation episignature is added to the list of Mendelian NDDs with known DNA methylation episignatures that can be used for screening and diagnosis of NDD patients."}
+{"text": "Biomarkers ideal for geroscience trials could be those simultaneously identified using targeted and discovery assays and which strongly associate with complementary disease (multimorbidity) and longevity  outcomes. To identify a tractable set of biomarkers for use in geroscience trials, we used the Cardiovascular Health Study (CHS), whose participant makeup closely aligns with the Targeting Aging with MEtformin (TAME) trial. In ~4800 CHS participants, quantitative assays of nine a priori-identified biomarkers were used to construct a biomarker index which strongly associated with the TAME primary outcome of mortality and multimorbidity over 6 and 10 years of follow-up. In ~3000 CHS participants, 1300 proteins were measured with unbiased aptamer proteomics and associated with survival to age 90 over 25 years of follow-up. Proteins in the biomarker index were identified as some of the strongest associated with survival to 90. This convergent evidence suggests these biomarkers may be well-suited for geroscience trials."}
+{"text": "An important quality marker for end-of-life services is congruence with patient\u2019s preferred place of care, but this congruence in place of care is less likely for those facing structural inequalities . As homelessness among older adults in the United States grows , the urgency in understanding place of care in palliative care with unhoused patients grows. This presentation illustrates results from an organizational case study  of a novel homeless palliative care team and focuses on a qualitative content analysis of charts of patients over 50 receiving care both before and during the COVID-19 pandemic (n=27). Findings highlight (1) the interplay between environmental factors, psychosocial resources and constraints, and medical acuity in determining where care can take place, (2) facilitators for care in marginal settings such as emergency shelters and encampments, and (3) where opportunities for more equitable age-friendly healthcare system interventions exist."}
+{"text": "BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 ( PSA decline of greater than 50% was observed in 50% of patients with BRCA1/2 and 3% of those with non-BRCA biallelic DDR gene alterations. Similar to olaparib, rucaparib was approved by the FDA for use amongst mCRPC patients with germline and/or somatic BRCA1/2 mutations undergoing prior progression on AR signaling inhibitor or taxane. Europe still awaits approval . Multiple phase I and phase II trials are evaluating immune checkpoint inhibitors in combination with treatments such as abiraterone and cabozantinib [NCT04477512], radiation therapy , and an experimental IL-8 directed monoclonal antibody [NCT03689699]. In addition, perioperative ipilimumab in combination with castration prior to radical prostatectomy has demonstrated feasibility with longer follow-up ongoing .DNA sequencing efforts have changed the molecular classification of prostate tumors and are leading to precision medicine strategies as well as defined prognosis and clinical features of molecular subsets of PC. Nevertheless, prospective studies demonstrating clinical value of biomarkers for prognostication or prediction of response are warranted. Somatic and germline DNA testing for patients with advanced PC should be considered in view of the therapeutic consequences for the patient and the possibility of pursuing targeted screening in this population. Metastatic tumor biopsies are recommended to obtain information regarding mCRPC tumor features. Germline samples are easily collected and analyzed, but still half of the patients with somatic DDR defects would not be identified. Liquid biopsies may be used to monitor for the detection of secondary mutations that may restore the function of a gene previously altered.PARP inhibitors represent one of the recent biggest therapeutic developments for PC patients. Combination of PARP inhibitor with AR-targeting agents is worthy due to the cross-regulation of both pathways and the central role of hormonal therapy in PC. Immunotherapy has shown still limited efficacy in these patients. However, immunotherapy combinations will probably overcome intrinsic resistance of PC to immunotherapy. Ongoing studies that assess the role of immunotherapy in PC are NCT04104893, NCT04019964 and NCT03570619."}
+{"text": "OBJECTIVES/GOALS: The aim was to examine whether nicotine patch was more effective in encouraging abstinence from cigarettes smoking compared to placebo. METHODS/STUDY POPULATION: Randomized controlled trials involving the general teenage age group smokers who were current smokers-\u201csmoked less than 100 cigarettes over their lifetime and smoked at the time of the interview. Databases were searched for relevant studies reported in English that employed a randomized design published since 2000. Two authors extracted data and assessed quality. The primary outcomes and prioritization were continuous abstinence at 3, 6 and 12-month follow-up or more for the number of patients who responded to treatment, defined as a reduction/abstinence. Heterogeneity between studies did not preclude combined analyses of the data. RESULTS/ANTICIPATED RESULTS: 4 of 266 publications were included. Four studies reported positive effects on smoking cessation at end of treatment: (1) nicotine patches improved continuous abstinence at 6 weeks \u2013 9 weeks months; (2) nicotine patch improved continuous abstinence at 3 to 6 months; (3) nicotine patches improved continuous abstinence 6 and 12 months; (4) nicotine patches improved continuous abstinence at 6 months \u2013 12 and 24 months (5). All studies showed, continuous abstinence at follow up differed in percentage between groups both at 6 weeks through 24 months, with NRT (Nicotine patch) intervention groups achieving higher rates in most of the studies compared to placebo intervention group. Conclusions: NRT intervention methods seem to increase smoking abstinence in those treated for smoking cessation. Further and larger sample size studies are required to make stronger the base of evidence. DISCUSSION/SIGNIFICANCE OF IMPACT: Four randomized controlled trials investigating the effectiveness of smoking cessation interventions, for teenagers who smoke cigarettes were identified for inclusion in this review. Four of the studies reported significant effects on smoking cessation, providing evidence of effectiveness of NRT (nicotine patch), behavioral support and combinations of the two, although not all trials intervention treatments found an effect. The four studies reported important intervention effects at both the short and long follow-ups required: 6 weeks up to the 24 months, thereby, providing stronger evidence to support the effectiveness of NRT intervention on smoking cessation. All studies showed some evidence of improved smoking abstinence outcomes. The four studies had in common that the smoking cessation interventions provided a combination of intent to treat prevention, and of all the clinical trials none of them suggested a negative effect of smoking cessation treatment on substance use outcomes using NRT. However, the studies used reliable methods and reported their cases properly, but the small number of studies reviewed for the systematic review makes the conclusion about the effectiveness of these interventions uncertain. The papers visibly stated how the trials protected against bias, as indicated by the Yes (low risk). No (high risk) and U as \u201cunclear risk.\u201d All four studies conducted a random sequence generation of participants enrolled into the study sample."}
+{"text": "This special issue is devoted to the celebration of the century anniversary of Xiamen University (XMU) (6 April 2021) and the establishment of the LSA Editorial Office in Xiamen (3 July 2021), a collection to highlight the recent exciting research works performed in XMU or by XMU alumni, from all aspects of optics and photonics, including basic, applied and engineering research and applications. The guest editors are three XMU alumni who are active researchers in these areas: Professor Minghui Hong from National University of Singapore, Professor Zhongqun Tian and Professor Junyong Kang from XMU.1; (2) Development of mode-locked fibre lasers towards visible-wavelength2; (3) A new route for stress recording based on the Force-induced charge carrier storage effect in mechanoluminescence materials3; (4) Identification of unconventional host\u2013guest complexation at nanostructured interface by surface-enhanced Raman spectroscopy4; (5) Quantification of electron accumulation at grain boundaries in perovskite polycrystalline films by correlative infrared-spectroscopic nanoimaging and Kelvin probe force microscopy5; (6) Improvement of detection in graphene/silicon heterojunction photodetectors through engineered tunnelling layer with enhanced impact ionization6; (7) Innovative approaches to determine the embedded electronic states at nanoscale interface via surface-sensitive photoemission spectroscopy7; (8) Development of AlGaN materials and optoelectronic devices that lead to the significant revolutions of solar-blind UV detection technology8; (9) Development of novel concepts and techniques in AlGaN-based LEDs for effectively controlling and tailoring the crucial properties of nitride quantum structures9; (10) Design of light-responsive and corrosion-resistant gas valve with non-thermal effective liquid-gating positional flow control10; (11) Design of nano/micro structures and macro-optical systems to enhance the detection sensitivity of surface-enhanced Raman and infrared spectroscopies11; (12) Demonstration of transmitting high-dimensional orbital angular momentum state at the single-photon level utilizing non-zero quantum discord12; (13) Development of hybrid laser processing technologies and their applications in the precision engineering of transparent hard materials13; (14) Demonstration of X-ray-charged bright persistent luminescence for multidimensional optical information storage by inkjet-printing NaYF4:Ln3+@NaYF4 nanoparticles14.XMU is a renowned university continuously featuring creativity and dedication. It was the first university established by an overseas Chinese (Mr. Tan Kah Kee) and has been selected for the \u201cDouble First-class Initiative\u201d Scheme, as one of the leading pioneers in achieving China\u2019s ambition of building world-class universities. XMU is also the first prestigious Chinese university to set up an overseas branch campus , which has been honoured as the \u201cshinning pearl\u201d of \u201cBelt and Road Initiative\u201d. Rooted in XMU, the motto \u201cPursue Excellence, Strive for Perfection\u201d, has been widely extended to all over the world through more than 400,000 of XMU graduates. During the century-long growth, XMU has achieved significant progress in the field of optics and photonics and become pioneers in several aspects: Development of laser holography that greatly promoted the anti-counterfeiting technology in China; study of entangled photon pairs that lead to quantum communications and optical micromanipulations, as well as the creation of facial recognition techniques based on the light beams; Development of surface-enhanced Raman spectroscopy (SERS) that not only conquers the material and surface limits of SERS, but also realizes the fast detection of trace hazards in the field of food safety; Improvement of efficiency for light-emitting diodes (LEDs) via creative pathways, including deep ultraviolet LEDs and high colour rendering warm-white LEDs. Research scholars across different disciplines in XMU are working on optoelectronic materials and devices, with interests in the designs and syntheses of luminescent materials, quantum dots, electrochromic materials as well as their applications in solid-state lighting, emissive displays, sensing, smart windows and photovoltaic cells. Experiments based on synchrotron-radiation light source as well as other advanced techniques are combined with computations/simulations to deeper understand the composition-structure-property coupling mechanism of functional materials, providing guidelines for developing high-performance materials and optoelectronic devices. This collection features some recent representative achievements in optical and optoelectronic sciences and technologies, contributed by XMU scholars and alumni. The innovative reports include: (1) Enhancement of deep ultraviolet emission by regulating the orbital state couplingEnlightened by Light, Xiamen University, this 100-year-old university will become more elegant with greater academic excellence, especially in optics and photonics research."}
+{"text": "The authors have demonstrated an exciting evolution of neoadjuvant chemotherapy (NAC) trends after radical cystectomy (RC) in the USA in the present study . During"}
+{"text": "We aim to investigate the effectiveness of repetitive Transcranial Magnetic Stimulation (rTMS) in reducing consumption and craving among patients with Substance Use Disorder (SUD) and comorbid depressive disorder.Dorsolateral prefrontal cortex (DLPFC) is greatly involved in SUD evolution (1). Research has turned to targeting this brain area with rTMS; a non-invasive brain stimulation technique that modulates cortical excitability by sending pulsatile electromagnetic fields through the skull and into the brain (2). rTMS is an FDA approved and safe treatment option for treatment-resistant depression (TRD) (3).Fifty-four patients were admitted over six-month period of time (June 2019- December 2019) to the inpatient unit of Erada center for treatment and rehabilitation of SUD in Dubai. All patients who fulfilled ICD-10 diagnoses of Depressive disorder and SUD were screened for further assessment.Positive drug screen was confirmed through urine analysis. Hospital Anxiety and Depression Scale (HADS) and Brief Substance Craving Scale (BSCS) were applied to all participants. Patients were contracted for 5-times weekly High frequency (10 Hz) rTMS for 4 weeks . Those who managed to complete their contracted TMS sessions were matched for age and sex with similar number of patients who received standard treatment as usual (TAU). Stimulation was as per FDA clearance for rTMS application in TRD.Eight patients were excluded (previous head trauma). A total of 46 patients had TMS mapping; nine of whom completed 20 sessions.Opioids was the most commonly used drug in almost 52% of patients (n = 14), followed by amphetamines in almost 30% (n = 8) and Cannabis in 18.5% (n = 5).Among those who completed 20 rTMS sessions; HADS scores on anxiety and depression fell by 85% and 78% respectively. BSCS score fell by 98%. Relapse rate (defined by positive drug screen) at 3 months was 33%.For those who completed 10 sessions; there was only 50% reduction on BSCS scores and 66% relapse rate. There were no data available on their HADS scores (only collected at baseline and at completion of 20 sessions).Those who only had TAU; there were no reduction in their BSCS (average score of 7 at both baseline and after 2 weeks).Our findings suggest that rTMS may be an effective and safe treatment for both depressive disorder and craving for SUD which is supported by other studies .Our study is probably the first of its kind within Middle East population with addiction problems."}
+{"text": "CDHR1 alleles, and compare the associated phenotypes with previous reports.To describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG).The clinical records of patients with macular dystrophy and biallelic variants in CDHR1: p.(Gly188Ser), p.(Met1?), or p.; one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5\u20136/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases.Seven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of This report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin. CDHR1\u2014OMIM 609502) is a transmembrane protein, expressed at the base of the rod and cone outer segments, and maintains outer segment structure , has been associated with adult-onset macular dystrophy.The present study corroborates the association between the p.[Pro261=] variant and macular dystrophy and presents novel alleles associated with the macular dystrophy phenotype.Our study adds CDHR1 to the list of candidate genes to screen in patients with likely autosomal recessive macular dystrophy.Figure S1_legendFigure S1"}
+{"text": "Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole > Oxfendazole > Nocodazole > Mebendazole > Albendazole > Oxibendazole > Fenbendazole > Ciclobendazole > Thiabendazole > Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate. Microtubules play a key role in the invasion and metastatic spread of tumor cells, depending on its crucial roles in mitosis, signaling, trafficking, proliferation, and migration of eukaryotic cells . Drugs tThe success rate for new anticancer drugs from Phase I trial to commercial use by FDA approval is estimated to be around 6.7% from 2003 to 2011, taking about 8.3 years as an average . The ovede novo drug compounds and constitutes nowadays 30% of the newly marked drugs in the United States  . DespiteIn vitro and in vivo studies revealed the potential of some members of benzimidazole anthelmintic drugs to suppress tumor progress through inhibition of multiple biological targets such as tubulin polymerization and angiogenesis (Benzimidazole anthelmintic drugs having over 40 years of safe use as over the counter medications . They arogenesis .Nocodazole (NZO) is a benzimidazole-based experimental drug targeting both protein kinases and microtubules. It is used as a lead compound for the discovery of novel CBSIs . In thishttps://pubchem.ncbi.nlm.nih.gov/). The nine tested compounds underwent energy minimization after examining the structure and the formal charges on atoms using a 2D depiction model. The partial charges were also automatically calculated. Structure of the co-crystallized NZO obtained from two subunits of the target tubulin protein (B and D subunits) and the nine tested benzimidazole drugs were imported together in the same database and saved in the form of MDB file to be docked in two separate processes for each subunit pocket, B and D, respectively.Docking studies using the Molecular Operating Environment (MOE) software package  were perhttp://www.rcsb.org/). All steps for the preparation of the target protein for docking calculations were done. The addition of hydrogen atoms with their standard 3D geometry to the system, automatic correction to check for any errors in the connections and types of atoms, and fixation of the potential of the receptor were also performed. The selection of the same active site of co-crystallized inhibitor in the protein structure was done by using Site Finder where dummy atoms were created at the same binding site of the pocket.The X-ray structure for tubulin protein (PDB: 5CA1) complexed with the native NZO was obtained from the Protein Data Bank  were used to approximately describe the polarity of colchicine binding pocket. All simulations were performed using GAUSSIAN 09 Revision C.01  based Becke\u2019s three-parameters Lee-Yang-Parr hybrid functional (B3LYP)  was emplion C.01  on Swinb2O616). Hydrophobic interactions were also observed between Leu253 and the benzene and imidazole moieties. The 2D graphic views of binding interactions between studied benzimidazole ligands and NZO with the target protein are deposited in Crystallographic data of co-crystallized NZO complexed with tubulin protein (PDB: 5CA1) revealed the existence of two binding sites for NZO inside the protein, subunits B and D, respectively. It was obvious that subunit D is larger than subunit B in size. By analyzing the binding modes (3D graphic views) of NZO inside the two subunits , it was By studying the binding site in both B and D subunits, it was concluded that the crucial amino acids for binding interactions between CBSIs and the two subunits are Glu198 and Val236, besides Asn165 for B subunit and Cys239 for D subunit. The refined NZO was also docked among other studied benzimidazole drugs into subunits B and D to validate the molecular dynamic model used in conducting the current study. For the B subunit, the docked NZO showed almost a fingerprint binding mode as the original co-crystallized one. Interestingly, loss of binding interactions between the oxygen atom of its carbonyl group and Cys239 was also noticed. Furthermore, as expected, the binding interaction between N (3)-benzimidazole and Glu198 was lost in two subunits (B and D) as a result of using the neutral form of refined NZO in contrary to the protonated form of native NZO. The other nine benzimidazole drugs were refined and docked into NZO binding pocket subunits (B and D), respectively. Results revealed that all of the tested drugs, except for Thiabendazole (8) and Bendazole (9) members, showed very similar binding modes to the native NZO due to the great structural similarity. Regarding B subunit, Flubendazole (5) showed a nearly similar fingerprint binding mode compared to the native and docked forms of NZO. Concerning D subunit, surprisingly, Albendazole (2), Ciclobendazole (3), Flubendazole (5), and Oxfendazole (7) showed the binding interaction with Cys239 similar to the native NZO which was lost in the docked NZO itself. Especially Ciclobendazole (3) and Oxfendazole (7) showed a fingerprint binding interaction with Cys239 with the same direct and indirect pathways. It was concluded that Flubendazole (5) showed the highest similarity in binding modes compared to the native NZO in both B and D subunits of protein pocket. Furthermore, Thiabendazole (8) and Bendazole (9) lost some of the binding interactions compared to the native NZO due to the differences in the structure of side chains of their benzimidazole moieties but maintained the binding interactions with both Val236 and Asn165. By reviewing molecular dynamics scoring and other parameters listed in 2O616) calculated at 3.14\u00a0\u00c5 which is comparable to the same bond formed at 2.70\u00a0\u00c5 by the native NZO.Another confirmatory tool for validating the binding interactions between the tested ligands and the target protein is through measuring the lengths of H-bonds involved. By representing the 3D filling positions of our tested compounds inside the deep protein pockets of two subunits B and D compared to the co-crystallized inhibitor, we observed a very close similarity between all in each subunit confirming the same binding mode and structural similarity between them as shown in Moreover, the large size of the two pockets of subunits B and D, especially D subunit, gives us an idea about the possible drug modifications especially at the side chain of thiophene ring of NZO to obtain larger compounds that can occupy the binding pockets more efficiently maintaining the same essential binding interactions with the crucial amino acids and at the same time forming extra binding ones for better inhibition.It is well known that outermost electrons are those involved in the binding interaction between a ligand and target protein, we therefore, computed the electron density of the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), and the molecular electrostatic potential (MEP) map. Figures of the electron density distribution of HOMO, LUMO, and MEP are depicted in The electron density of HOMO in NZO was found to be localized mainly on benzimidazole moiety, while the electron density of LUMO was solely localized on the thiophene side chain. The electron density of HOMO and LUMO of all other studied drugs are delocalized except for Mebendazole (1), Fenbendazole (4), and Flubendazole (5) in the case of HOMO and Oxibendazole (6) in case of LUMO. The electron density of HOMO of Mebendazole (1) and Flubendazole (5) is quite similar to that of NZO which is consistent with the calculated binding affinities [Flubendazole (5) > Oxfendazole (7) > NZO (docked) > Mebendazole (1)]. Despite of this consistency, the binding affinity does not solely depend on the energies and the electronic density distribution of HOMO and LUMO, but also on other determinants such as hydrogen bonding, electrostatic interactions, hydrophobic and Van der Waals forces and presence of clusters of water. We also noted that the electrons of HOMO are localized mainly on the benzene moiety and the aromatic side chain of Fenbendazole 4) in a different pattern to that observed with NZO.The MEP maps of all studied compounds revealed that one of benzimidazole nitrogen acts as an electron donating site capable of forming H-bond with amino acids in colchicine binding sites. Whereas the other benzimidazolyl nitrogen is electrophilic moiety acting as H-donor group. Interestingly, the MEP map of Mebendazole (1), Albendazole (2) and Flubendazole (5) are quite similar which is also consistent with the calculated binding affinities, where Flubendazole (5) > Oxfendazole (7) > NZO (docked) > Mebendazole (1) > Albendazole (2) > Oxibendazole (6) > Fenbendazole (4) > Ciclobendazole (3) > Thiabendazole (8) > Bendazole (9). Lack of 5 (6) substitution on the benzimidazole pharmacophoric group leads to a significant change in the MEP of Thiabendazole and Bendazole. Weaker binding affinities of these two drugs can be ascribed to the change in electronic configuration due to the absence of 5 (6) substitution.Among the nine tested members of benzimidazole anthelmintic drugs, Flubendazole (5) exhibits the most similar binding interactions, scoring, electron density distribution, and electrostatic map to that reported for NZO in tubulin protein (PDB: 5CA1). This suggests that Flubendazole (5) would be the most active member exerting antitumor activity mainly at CBS. At the same time, more structural modifications are required for FDA approved benzimidazole anthelmintic drugs and the original NZO inhibitor to obtain larger compounds with better fitting and binding modes inside the two large pockets of subunits B and D respectively."}
+{"text": "This Correction follows an Expression of Concern relating to this article previously published by Portland Press.Fragaria ananassa methanolic extract in a rat model of cadmium chloride-induced neurotoxicity\u201d (Biosci Rep (2018) 38(6), DOI: 10.1042/BSR20180861) would like to correct The authors of the original article \u201cProtective effects of The authors have stated that the overlapping images had been selected from the same group in error, and further confirm that this error does not affect the conclusions of their study. The correct version of"}
+{"text": "An increasing number of people are affected by various neurodegenerative diseases each year, impacting the quality of life of millions of people worldwide. However, considerable knowledge gaps in the mechanistic understanding of these diseases present a challenge to address this threat to human life successfully. Recent endeavors in basic research, clinical trials, and other research areas have provided vital insights to discover novel biomarkers for improved diagnosis and better treatment options for patients suffering from such diseases. Articles published as part of the Special Issue \u201cBiomarkers in Neurodegenerative Diseases\u201d highlight the recent advances in this field and emerging strategies to counter such diseases in the future.Three research articles published in the Special Issue focused on molecular mechanisms involving Alzheimer\u2019s disease (AD). First, Paik et al. used human SH-SY5Y neuroblastoma cells to show the neuroprotective role of Somatostatin-14 (SST). The possible mechanism involves the ability of SST to regulate the intracellular calcium levels and Collapsin Response Mediator Protein 2 (CRMP2) phosphorylation . NaturalKessler and others show a correlation between dysregulation of Monopolar Spindle 1 Kinase (MPS1) and tumor aggressiveness in glioblastoma multiforme (GBM) patients . The resOne key aspect of neurologic disorders includes complications arising from traumatic brain injuries (TBIs). In this regard, Alam et al. investigated the role of quinpirole in dopamine D2 receptor (D2R) activation using a mouse model simulating TBI . This stFulgenzi et al. provide an excellent update in the investigation of chelation therapy involving EDTA as a potential treatment for neurologic disorders. They studied more than 300 patients from a broad age group to monitor their toxic metal burdens before and after receiving EDTA as part of the therapy . InformaOne of the critical challenges for better treatment outcomes is correctly identifying the causes behind indicators of different neurologic conditions. Chien and coworkers used an artificial neural network to distinguish between dopamine transporter single-photon emission computed tomography (DAT-SPECT) images obtained from patients with Parkinson\u2019s disease or parkinsonism resulting from other illnesses with high (more than 80%) accuracy .Apart from these original research papers, the Special Issue also contains an excellent collection of review articles highlighting recent progress, challenges, and future directions in the field. For example, the review articles published by Jacopo Meldolesi and B\u0103la\u0219a et al. are excellent resources summarizing the significant advances made in fluid and imaging biomarkers for the early detection of neurodegenerative disorders in recent times ,9. The aI hope that these excellent research works and review articles published as part of the Special Issue will provide an invaluable reference for further research to counter the menaces posed by neurologic disorders in the future."}
+{"text": "The presence of 2 ventricular signals caused by structures near the His bundle region is rare. Some associative and dissociative maneuvers for dissociating a certain electrical signal from others of known origin are used to ascertain the source of an unknown potential. Figure 1 was obtained. The arrow points to a signal after the ventricular potential on the His-bundle (HB) catheter that was consistently seen in sinus rhythm . What could be the origin of this second unexpected potential?A 64-year-old man with recurrent episodes of wide QRS tachycardia with the absence of overt structural heart disease underwent an electrophysiological evaluation. An echocardiogram showed mildly depressed left ventricular function. During an electrophysiological study, the electrogram in 2 A wide range of diagnoses are possible, including (1) intermittent accessory pathway (AP) conduction with an antegrade 2-for-1 phenomenon, (2) intermittent fused premature ventricular complexes (PVCs) arising from the diseased tissue near the HB region, (3) intermittent right bundle ectopy, (4) intermittent nodoventricular (NV) conduction, (5) intermittent atriofascicular (Mahaim fiber) conduction, (6) fragmented ventricular potential, or (7) basal septal or periaortic ventricular late potentials and local abnormal ventricular activities (LAVAs).3 Mahaim fibers or the NV pathway may also produce a second HB deflection after the ventricular potential on the HB catheter because of the retrograde conduction of the right bundle.2 Other antegrade-conducting unusual AP connections from the right atrial appendage to the right ventricular outflow tract may also cause complex signals on the HB catheter. A 2-for-1 phenomenon can occur when the atrial impulse simultaneously travels down the AP (activating the annular ventricular myocardium) and the atrioventricular node (AVN) and the HB . Afterward, the ventricular activation wavefront may travel back toward the base .1The presence of 2 ventricular signals caused by structures near the HB region is rare.5 The atrial extra-stimulus testing might give us some important clues. The timing of the extra potential is expected to correlate with either the degree of pre-excitation or the amount of fusion (if a PVC or fascicular beat occurs). If the candidate signal is ventricular or otherwise associated with pre-excitation , then causing a delay to signal activation would cause less pre-excitation.2 In the current case, there was a delay from the atrial signal to both the HB and the candidate potential without a change in the degree of pre-excitation an atrial extra-stimulus beat  that showed more decrement in conduction down the AVN. A relatively fixed relationship was seen with V to this potential (single arrows), with a further delay with S2 (double arrow) in activating the tissue responsible for the extra (unexplained) potential. However, it would be difficult to explain the phenomenon via the effects of atrial pacing with a Mahaim fiber.2 For this to occur, a very similar decrement in conduction down the Mahaim fiber and the AVN is needed. The delay to the extra potential despite AH prolongation excluded all AP-related diagnostic possibilities in the current case, including NV pathways.8 Electroanatomic mapping revealed periaortic fibrosis that was consistent with this unusual potential , and then 4 different ventricular tachycardia (VT) morphologies were induced .Some associative and dissociative maneuvers for dissociating a certain electrical signal from others of known origin are used to ascertain the source of an unknown potential.11 These VTs from small regions of the periaortic scar can mimic idiopathic VT but are suggested by multiple VT morphologies .12 Several methods have been studied to invoke dynamic substrate changes in critical regions to target ablation, including decrement-evoked potential mapping,5 which involves a drivetrain and an S2 pacing protocol identifying sites of decremental LAVAs. This small periaortic site was then targeted for radiofrequency ablation . During ablation, the amplitude of this potential decreased, and all VT morphologies were no longer seen. Electrophysiologists must have a thorough understanding of how unexplained potentials can be analyzed using pacing maneuvers and by observing changes of association and dissociation that occur between these unknown signals and other known potentials .1 These techniques are useful in identifying the culprit sites and targets for ablation for several arrhythmias.2Periaortic fibrosis is increasingly recognized as a distinct clinical substrate for scar-related VT in the presence and absence of overt structural heart disease."}
+{"text": "From th studies .Medline (Pubmed) search using the following: \u201cvascularization maxillary sinus cadavers\u201d, completed with the revision of the bibliographical references of the selected articles in order to identify further relevant studies. Inclusion criteria: (1) Published between 2008 and 2015. (2) Cadaver Studies. (3) Studies that evaluate the position of the anatomical position of the anastomosis between arterial branches of the posterior superior alveolar artery and the infraorbitary artery. Exclusion Criteria: (1) Non cadaveric studies. (2) Foetal and paediatric studies.Eight articles were selected.The vascular anastomosis is frequently found in the lateral wall of the maxillary sinus. Its position and depth are variable, as well as its trajectory and morphology. Pre-surgical determination of its precise anatomical variations is of the utmost importance to avoid vascular damage and complications during external sinus lifts osteotomies."}
+{"text": "The temporomandibular disorders (TMD) are one of the main concerns regarding orofacial pathologies and there are an ascending number of cases. They are characterised as a group of pathological conditions that may affect the temporomandibular joint (TMJ), the masticatory musculature and/or other adjacent anatomical structures, leading to pain and dysfunction . The mulA 24-year-old female patient with a history of temporomandibular disorder and bruxism she presented an non-assisted mouth opening (UMO) of 28\u2009mm and an assisted mouth opening with pain in the masseter and TMJ bilaterally of 29\u2009mm, after the clinical assessment with the DC/TMD protocol we arrived at a diagnosis of disc displacement without reduction (DDwR) with limited opening, degenerative joint disease in the left TMJ, arthralgia (II), myofascial pain (III) in the masseter with pain referred to other anatomical regions. All the assumptions of the Helsinki Declaration have been fulfilled and an informed consent for clinical case of Clinica Dent\u00e1ria Egas Moniz approved by the ethic commission of Instituto Universit\u00e1rio Egas Moniz. The treatment plan consisted of cognitive behavioural therapy (CBT), prescription of muscle relaxants, occlusal splint especially for reduction of overload due to bruxism, infiltration with 1\u2009ml of hyaluronic acid of high molecular weight in the TMJ bilaterally followed by articular mobilisation techniques and neuromuscular and myofascial techniques. The patient was instructed to continue with the physiotherapy.The follow up was made 2\u2009months after with 8 sessions of physiotherapy and 1 more hyaluronic acid infiltration bilaterally as protocoled session, we could observe an absence of temporomandibular joint pain, UMO of 42\u2009mm, decreased crepitation, decreased intensity of myofascial pain (I) and (DDwR) without limited opening.The multidisciplinary dentist-physiotherapist team combines inputs from different professions with the aim of promoting the best patient care and represents an added value for the management of the signs/symptoms of patients with temporomandibular dysfunction."}
+{"text": "Health and social care providers are ill-equipped to address the complex needs of individuals growing older with IDD and their families when dementia is suspected or diagnosed. Addressing the growing need for professionals to acquire practical diagnostic, treatment, and management methods requires an interorganizational and interprofessional approach. A consortium of aging and IDD organizations developed a successful Project ECHO  model to create a virtual community of practice connecting a hub team and participating spoke sites. This paper reviews reasons for the model\u2019s success, including: (1) curriculum providing practical solutions to complex problems, (2) integration of interprofessional team approach, (3) \u201call teach, all learn\u201d model promoting sharing among participants, and (4) the inclusion of case studies engaging participants in developing solutions and strategies to improve the quality of life of clients and families. Implications of this model and recommendations for future professional educational programs are presented."}
+{"text": "For people living with HIV, there are multiple barriers to engagement with care. This study qualitatively examines the role of use of alcohol and other drugs (AOD) on the health and management of Human Immunodeficiency Virus (HIV) disease among older African Americans (\u226550 years). It draws on interviews conducted with twenty-seven older African Americans living with HIV in the Louisville, Kentucky area. Interviews were transcribed verbatim and then analyzed using constructivist grounded theory analytic techniques. Participants\u2019 understandings of their AOD use fell on a continuum of problematic use to use for self-care. Regardless of where participants fell on this continuum, they faced a) environmental impacts of AOD use and b) current or historic discrimination from the health care system. The analysis focused on gaining a deeper understanding of the intersection of AOD use and engagement in the HIV care continuum. This revealed six major phases, which occurred at various stages of the continuum: (1) Linking AOD use as the cause of HIV diagnosis (2) Having AOD use facilitate denial of HIV, (3) Experiencing problematic use, (4) \u201cTesting the Waters,\u201d (5) Relying on AIDS Service Organizations (ASO) and medical providers and (6) Maintaining health and/or using AOD for self-care. We discuss the ways that stigma along the lines of race, gender, and age intersect with co-occurring conditions such as substance use disorders in complex and multifaceted ways. Recommendations include assessing a patients\u2019 AOD use in relationship to the HIV care continuum to assess patients\u2019 experiences and barriers within systems of care."}
+{"text": "Following publication of the original article , the autThe incorrect author name is:Chayma (given name) Saheli (family name)The correct author name is:Sahli (given name) Chaima (family name)The author group has been updated above and the original article  has been"}
+{"text": "Dear Editor,Our immune gene model is of great help to predict the prognosis of colon cancer patients. The model genes could be used as prognostic markers and potential new targets for colon cancer patients.Colon cancer is a common tumor with high incidence worldwide.Different genes were analyzed by colon cancer data from TCGA database, and immune\u2010related genes were extracted. The immune differential genes were combined with the clinical data, and the model was constructed and evaluated. The model genes were enriched and analyzed. Single\u2010cell expression data of model genes were extracted, grouped according to the amount of each gene expression, and the percentage of infiltration of each cell phenotype in different groups was observed. The model genes were compared with immune checkpoints and immune cells. Analyzing the relationship between the key genes of the model and clinical information and using HPA database to verify model genes.Three hundred ninety\u2010six immune differential genes were screened, and the corresponding heatmap and volcanic maps were plotted  Correlation analysis between the expression of model gene CD19 and patient age. (B) Correlation analysis between model gene expression and tumor anatomical location. (C) Correlation analysis between model gene expression and occurrence of mismatch repair. (D ) Correlation analysis between the expression of model gene UCN and the occurrence of lymphatic invasion. (E) Correlation analysis between the expression of model gene and the occurrence of microsatellite instability. (F) Correlation analysis between model gene expression and tumor TNM staging. (G) Correlation analysis between model gene expression and lymphatic metastasis. (H) Correlation analysis between model gene expression and distant metastasis. (I) Correlation analysis between model gene expression and clinical stage of patients. (J) Correlation analysis between CD3E gene expression and tumor recurrence after treatment. (K) Correlation analysis between UCN gene expression and initial treatment effect. (L) The expression of prognostic\u2010related immune differential genes in colon cancer tumor tissues and normal tissuesClick here for additional data file."}
+{"text": "The application of femtosecond lasers in ophthalmology has enabled precise and reproducible tissue cutting, which is expected to improve the outcomes of surgical treatment, particularly in anterior segment surgeries such as cornea, cataract, and refractive surgery.As we have introduced in the call for papers for this Special Issue, the articles published cover topics focused on the application of femtosecond lasers in anterior segment surgery, including the development of the technologies behind femtosecond lasers and their application in ophthalmic surgery, the efficacy and safety of anterior segment surgery using femtosecond lasers, and imaging techniques associated with the application of femtosecond lasers.Femtosecond lasers have been increasingly used in cornea and refractive surgery. The laser can be used to create customized trephination edges for deep anterior lamellar keratoplasty and penetrating keratoplasty and for allowing ultrathin cut for Descemet stripping automated anterior lamellar keratoplasty. It can also be helpful for improving the consistency and reproducibility of refractive surgery, including laser-assisted in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE), intrastromal corneal ring segment implantation, and astigmatic keratotomy.Femtosecond laser cataract surgery (FLACS), in which a femtosecond laser is employed for corneal incision, anterior capsulotomy, lens fragmentation, and liquefaction, is also expected to improve the reproducibility and safety of cataract surgery. In this Special Issue, the authors contributed 10 original papers and one review article regarding the use of femtosecond lasers in anterior segment surgery.The authors have reported the results of their research on various topics related to femtosecond lasers in anterior segment surgery: (1) extrusion of femtosecond laser-implanted intrastromal corneal ring segments in keratoconic eyes: prevalence, risk factors, and clinical outcomes; (2) clinical observation of silicon hydrogel contact lens fitted immediately after SMILE; (3) preliminary results of a novel standardized technique of femtosecond laser-assisted deep anterior lamellar keratoplasty for keratoconus; (4) long-term evaluation of capsulotomy shape and posterior capsule opacification after low-energy bimanual femtosecond laser-assisted cataract surgery; (5) anatomical and visual outcomes after LASIK performed in myopic eyes with the WaveLight\u00ae refractive suite ; (6) correlation analysis of refractive and visual quality after wavefront-optimized laser in situ keratomileusis for 50% and 100% angle kappa compensation; (7) comparison of femtosecond laser-assisted cataract surgery and conventional phacoemulsification in shallow anterior chambers and glaucoma; (8) characteristics of facial asymmetry in congenital superior oblique palsy according to trochlear nerve absence; (9) a modified femtosecond laser technique for anterior capsule contraction syndrome; and (10) evaluation of astigmatic correction using a vector analysis after combined femtosecond laser-assisted phacoemulsification and intrastromal arcuate keratotomy. This Special Issue also includes one review article on the application of femtosecond lasers in anterior segment surgery.We believe these papers will provide readers with valuable information on the application of femtosecond lasers in anterior segment surgery and new ideas for research on related topics."}
+{"text": "The COVID-19 pandemic has renewed interest in endemic human coronaviruses (HCoV), which are responsible for an estimated 5-10% of acute respiratory infections (ARI) in temperate climate zones A total of 4,375 specimens from children and adults, who had presented with acute respiratory symptoms to a sentinel physician between October 2019 and September 2020, were examined by qPCR see . EndemicBB wrote the manuscript with support from DYO and RD; BB is responsible for data acquisiton; BB and DYO analysed the data; RD is responsible for the virological section of the sentinel system; TW and RD supervised the project.The authors declare that no competing interests exist."}
+{"text": "Typhoid fever, also known as typhoid, is a life-threatening bacterial infection that remains a global health concern. The infection is associated with a significant morbidity and mortality rate, resulting in an urgent need for specific and rapid detection tests to aid prevention and management of the disease. The present review aims to assess the specificity and sensitivity of the available literature on the immunodiagnostics of typhoid fever. A literature search was conducted using three databases  and manual searches through the references of identified full texts to retrieve relevant literature published between 1 January 2011 and 31 December 2020. Of the 577 studies identified in our search, 12 were included in further analysis. Lipopolysaccharides (LPS) and hemolysin E (HlyE) were the most frequently studied antigens. The specimens examined in these studies included serum and saliva. Using blood culture as the gold standard, anti-LPS IgA gave the highest sensitivity of 96% (95% CI: 93\u201399) and specificity of 96% (95% CI: 93\u201399) for distinguishing between typhoid cases and healthy controls, whereas the combination of anti-LPS and anti-flagellin total IgGAM gave the highest sensitivity of 93% (95% CI: 86\u201399) and specificity of 95% (95% CI: 89\u2013100) for distinguishing typhoid cases and other febrile infections. A comparably high sensitivity of 92% (95% CI: 86\u201398) and specificity of 89% (95% CI: 78\u2013100) were shown in testing based on detection of the combination of anti-LPS (IgA and IgM) and anti-HlyE IgG as well as a slightly lower sensitivity of 91% (95% CI: 74\u2013100) in the case of anti-50kDa IgA. Anti-50kDa IgM had the lowest sensitivity of 36% (95% CI: 6\u201365) against both healthy and febrile controls. The development of a rapid diagnostic test targeting antibodies against lipopolysaccharides combined with flagellin appeared to be a suitable approach for the rapid detection test of typhoid fever. Saliva is added benefit for rapid typhoid diagnosis since it is less invasive. As a result, further studies could be done to develop additional approaches for adopting such samples. Salmonella enterica serovar Typhi (S. Typhi). The life-threatening disease has been a public health problem in developing and underdeveloped countries for generations. A systematic analysis by typhoid and paratyphoid collaborators estimated that 10.9 million cases of typhoid fever occurred globally in 2017, resulting in 116.8 thousand deaths  AND [\u201cantigen\u201d OR \u201cantibody\u201d] AND [\u201cdiagnosis\u201d OR diagnostic\u201d] AND [\u201cspecificity\u201d OR \u201csensitivity\u201d]. An additional search was conducted by manually screening the references of the retrieved literature.The literature search was conducted in January 2021 according to the modified preferred reporting items for systematic reviews and meta-analyses guidelines . The seaArticles were excluded if (i) the studies were published before 1 January 2011, or after 31 December 2020; (ii) the studies were published in languages other than English or Malay; (iii) the studies did not mention the types of antigens used. We limit the studies to post 2011 (10 years) as the older literatures are not relevance to represent current diagnostic performance of the newly developed assays. Only studies that analyzed samples of at least two groups consisting of healthy controls and typhoid patients confirmed by positive blood culture were included in this systematic review. The retrieved literature was downloaded into Mendeley reference manager and duplicates were identified and removed. The references were distributed to four authors, who independently reviewed the titles and abstracts. A satisfactory agreement for the screening process was assessed between the reviewers. All four reviewers performed full-text screening and summarized the findings. Data from the selected sources were collated and summarized using a standard charting table consisting of six domains: (i) detection assays; (ii) biomarker; (iii) biological specimens; (iv) sample size; (v) specificity and sensitivity; (vi) year of publication.The number of true positives (TF), true negatives (TN), false positives (FP) and false negatives (FN) was independently retrieved from each article by three investigators and entered into an Excel datasheet. Discordant findings were assessed through discussion and when in doubt, the authors sought verification. Using blood culture as the reference standard, we calculated the sensitivity and specificity for each of the studied biomarker. Sensitivity was calculated by dividing the number of true positive outcomes with the sum of true positive and false negative outcomes. Specificity was calculated by dividing the number of true negative outcomes with the sum of true negative and false positive outcomes. Performance comparison of the immunodiagnostic assays was presented using forest plots based on control groups.The risk of bias for all included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool . The QUAThe present systematic review provides an overview of the performance of immunodiagnostic tests for typhoid fever and found that tests based on anti-LPS in combination with anti-flagellin offered the best diagnostic performance for the diagnosis of typhoid fever and that anti-HlyE could be an alternative option with a performance comparable to that of anti-LPS. Our results highlight the limitations of the ongoing immunodiagnostic development and provide baseline information for future studies to select appropriate biomarkers in the development of RDTs for typhoid fever. Based on the good performance of anti-LPS and anti-HlyE, these two antigens appear to be suitable options for the development of future POCTs for typhoid fever. The currently low number of studies using saliva samples for detection suggests that more studies could explore the development of alternative approaches implementing such samples, which have the advantages of less invasive sample collection, which would help to boost accessibility and facilitate efficient testing in a community, especially during a disease outbreak and in areas where access to laboratory-based testing is not available."}
+{"text": "This study aimed to assess the impact that the COVID-19 pandemic has had on the Hertfordshire Community Perinatal Team (CPT) group interventions and the innovations made.The CPT is a multidisciplinary mental health service that runs three groups: Circle of Security (CoS), Emotional Coping Skills (ECS) and a peer support group - Wellbeing and Lifestyle. The service has received an increase in referrals during the COVID-19 pandemic.Methods: Team member and client semi structured interviews were conducted with answers transcribed in real time and analysed. Patient clinical records were accessed via PARIS and analysed in order to identify patient demographics within each group and whether these had changed during the pandemic. Clinical outcome measures and client feedback were evaluated to see whether the change in groups is impacting their clinical effectiveness.Results: Innovations made by the CPT include: groups becoming virtual, launching of the new Circle of Security Group which helps women tackle the \u2018Ghosts in the Nursery\u2019 and strengthen maternal bonds, restructuring existing groups, breakout room forums and incorporating communication platform apps such as Whatsapp. The Wellbeing and Lifestyle Group increased in size and reach (7 women from 7 areas in 2019 vs 12 women from 12 areas in 2021) with an increased retention rate (71% in 2019 vs 100% in 2021) and a decreased attrition rate (29% in 2019 to 0% in 2021). The Emotional Coping Skills group experienced similar changes (10 areas represented in 2019 vs 15 different areas in 2021) with an increased retention rate (58% in 2019 vs 100% in 2021) and decreased attrition rate (42% in 2019 vs 0% in 2021).The Hertfordshire Community Perinatal Team has responded to the pandemic by innovating existing groups and creating new forums; many of which will continue on even after the pandemic ceases. The groups have acted as a lifeline for women breaking up the monotony and isolation of lockdown life and providing an invaluable space for women to be heard."}
+{"text": "Despite two decades of palliative care services, there remains numerous barriers to patient and caregiver use of palliative care. For many years, policymakers believed lack of funding for palliative care was the primary obstacle to accessing palliative care services. In 2017, we undertook a randomized controlled trial to test the effectiveness of a home-based palliative care (HBPC) program within accountable care organizations and in partnership with an insurance company that covered the cost of HBPC. After 20 months, we had recruited just 28 patients. This symposium will: (1) describe outcomes from various approaches undertaken to engage primary care physicians and recruit patients and their caregivers into this trial; (2) present barriers to HBPC referral identified from a qualitative study of primary care physicians; (3) present findings from a qualitative study of patient- and caregiver-identified barriers to HBPC; (4) describe physician and patient barriers to research participation; and (5) discuss implications of these findings for researchers and healthcare providers. Information presented in this symposium will inform researchers and policy makers about challenges and facilitators to recruiting patients, caregivers, and physicians to participate in research studies as well as inform healthcare practitioners of potential obstacles to increasing patient access to HBPC."}
+{"text": "Insomnia and obstructive sleep apnea (OSA) are two prevalent sleep disorders which share nocturnal sleep disturbances, impairments to daytime activity and quality of life, and high healthcare and social costs. The treatment of both disorders is often limited by the relatively low acceptance or long-term adherence to cognitive and behavioral therapy for insomnia (CBTi) or continuous positive airway pressure (CPAP) therapy, respectively.Unsurprisingly, the review published by Sweetman et al.  on comor(1)Refine the diagnosis and measurement of COMISA to assess both the independent and the shared symptoms of insomnia and OSA disorder.(2)Investigate the potential bi-directional relationships in COMISA in order to identify the predictors of the greatest response to insomnia or OSA treatments.(3)Examine the efficacy of the combined treatments for COMISA, administering both cognitive and behavioral therapy for insomnia (CBTi) and continuous positive airway pressure (CPAP) therapy.(4)Explore the mechanism(s) underlying the relationship between obstructive sleep apnea and insomnia.(5)Define the role of circadian rhythms in COMISA.(6)Clarify the moderating role of sex, race, age, and regional differences.(7)Assess the clinical evolution of insomnia during OSA treatments.Based upon recent randomized controlled trials, some issues that should be considered in the future research agenda include :(1)RefinCo-morbid insomnia and sleep apnea (COMISA) represent a clear model of bi-directional relationships between two different disorders. The review by Sweetman et al.  is able"}
+{"text": "When a trainee is unable to advance the tip of the tracheal tube through the vocal cords and the patient's pulse oximeter signals declining oxygen saturation (SpOThis oxygenation technique has proved consistently successful provided (1) the ETT tip is immediately supraglottic (retro-epiglottic) and (2) glottic closure (laryngospasm) has been prevented by prior administration of a muscle relaxant drug.In the late 1990s, members of our department began employing NLPAWS to ventilate adult patients (following anesthetic induction or cardiac arrest) via an orally inserted tracheal tube when PPV could not be administered because of a large leak at the facemask-skin interface. Such occurrences most often resulted from (1) the patient having a full beard or sunken cheeks, (2) the anesthetist having small hands or a lack of experience, or (3) use of a missized facemask .1 In approximately 20% of these cases, however, PPV failed because of airway obstruction (not air leak). A solution to this problem was found to be using a laryngoscope to guide the ETT tip to the same immediately supraglottic position that had always been a part of NLPAWS use during nasotracheal intubation.2 Two advantages of this technique of rescue ventilation compared to similar use of a laryngeal mask airway (LMA) are (1) faster access to an ETT and (2) suitability of almost any ETT size.At first, we used NLPAWS to permit ventilation through an oral ETT inserted a distance approximating the length of an appropriately sized oral airway.2 and PEEP 20 cm H2O) to reverse a rapid decline in blood oxygenation (SpO2 88% \u2192 42%) and elevate it to 58% during the time required for a replacement ETT to be brought to the patient's negative-pressure intensive care unit room.Very recently, members of our department have learned to use NLPAWS to enable PPV (1) in the presence of a leaking LMA (5 cases); (2) via a nasal airway fitted with an ETT adaptor during upper GI endoscopy ; and (3) via a correctly inserted ETT (4 cases). In 3 cases in the last category, the problem was simply that that the air syringe reserved for inflating the ETT cuff had been misplaced. In the fourth case, however, NLPAWS use may have been lifesaving. ETT cuff rupture occurred (probably from contact with a prominent incisor) during intubation of a patient with severe COVID-19 pneumonia. NLPAWS enabled sufficient Ambu ventilation (100% OWe are not aware of any instance of gastric aspiration occurring during NLPAWS use by a member of our department. Risk of this complication may be similar to risks associated with PPV performed using a facemask plus oral airway."}
+{"text": "Inflammation is originated by tissue injury and triggers several biochemical reactions that sensitize the nervous system for pain perception. Chronic inflammation induces adaptive changes that can cause altered pain signal processes. Indeed, inflammatory mediators provokes structural and functional changes in the peripheral or central sensory circuits, resulting in pain like behaviors, such as hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence suggests that central sensitization is driven by neuroinflammatory processes mediated by activation/proliferation of resident microglia and glial cells with the consequent release of inflammatory mediators; furthermore, several recent studies are relating the role of non-neuronal cells of the peripheral nervous system with the modulation of neuroinflammation involved in the development and maintenance of chronic pain.Boccella et al.).Currently treatments for chronic pain are quite unsatisfying. Therefore, there is a need for research aimed at discovering novel biological targets for new pharmacological approaches. Recently the authors collectively participated in the study of neuropathic pain and the role of HCAR2 expressed by Schwann cells in a sciatic nerve ligation model.  in arthritis by using different mouse models mimicking pathophysiology of rheumatoid arthritis in humans and integrative methodology  with special emphasis on pain. They provide the first evidence that HK-1 mediates several arthritic inflammatory mechanisms and pain by direct activation of primary sensory neurons not via its classical NK1 receptor.\u27a2 Li et al., summarize the current knowledge of the role of microglia during sepsis by showing the contribute of these cells in long-term sensorial and cognitive deficits. The Authors appropriately illustrate the activation of microglia in the Central nervous system by describing specific neurotransmissions and molecular pathways which may promote the cognitive damage and chronic pain during sepsis.\u27a2 Pacini et al. test the effects of the natural antioxidant thioctic acid which is clinically used as racemic mixture. The Authors report preclinical and clinical evidences suggesting positive properties of thioctic acid in the treatment of low back pain with a more relevant efficacy of (+)-thioctic acid as compared to (+/\u2212)-thioctic acid on pain, on time of onset of therapeutic effects.\u27a2 De Caro et al., show the anti-inflammatory and analgesic properties of Perampanel, the selective non-competitive AMPA receptor antagonist in acute (tail flick and hot plate tests) and chronic pain (Chronic constriction injury). They also suggest the involvement of the cannabinergic system  in Perampanel actions.\u27a2 Scuteri et al., provide a systematic review and meta-analysis assessing the efficacy of essential oils in pain. They describe the literature search conducted on databases relevant for medical scientific literature, i.e., PubMed/MEDLINE, Scopus, and Web of Science following the PRISMA  criteria. Among a total number of 30 studies included, three investigated neuropathic pain conditions.\u27a2 Borges et al., review recent clinical and preclinical studies investigating the epidermal growth factor receptor (EGFR) signaling pathway in chronic pain states. EGFR inhibitors are known for their use as cancer therapeutics however recent evidence suggested their clinical use for treating chronic pain. Here, the Authors provide an overview of EGFR signaling, highlighting possible mechanisms by which EGFR and its ligands may influence pain hypersensitivity and modulate inflammatory mediators of pain.\u27a2 Brik et al., investigate the behavioral and biochemical changes after intra-articular injection of sodium monoiodoacetate (MIA). This model mimics the degenerative changes observed in osteoarthritic patients. The Authors have characterized grading changes after injection of 1, 2 or 3\u00a0mg of MIA over a 28-day period. They report significant dose- and time-dependent changes in both gene expression and protein secretion levels of inflammatory factors.\u27a2 Mazzitelli et al., provide a direct evidence for the modulation of pain-like behaviors and spinal neuronal activity by basolateral amygdala-central nucleus (BLA\u2013CeA) signaling and central nucleus-corticotropin releasing factor (CeA\u2013CRF) neurons on under normal conditions and in an arthritis pain model.\u27a2 Ma et al., reveal the (fat-mass and obesity-associated protein) FTO-triggered epigenetic mechanism of matrix metallopeptidase 24 (MMP24) upregulation in the spinal cord after spinal nerve ligation (SNL). They show that blocking the SNL-induced increase of MMP24 in the spinal cord mitigate pain hypersensitivity both in the development and maintenance phase without altering the basal/acute responses or locomotor functions. The Authors suggest that MMP24 may be an endogenous initiator of neuropathic pain and could be a potential target for this disorder\u2019s prevention and treatment.\u27a2 Bruno et al., indicate that \u03b2-adrenergic receptors (\u03b2-ARs), mainly \u03b22-and \u03b23-ARs, contribute to tumor proliferation and progression and cancer-associated pain in a mouse model of cancer pain generated by the para-tibial injection of K7M2 osteosarcoma cells. This study highlights the ability of \u03b2-ARs antagonists in modulating both tumor growth and the neuroinflammation, showing a new therapeutic targets for cancer therapy and associated pain.\u27a2 In this Research Topic, different signaling implicated in neuroinflammation and chronic pain and possible therapeutic approaches have been described:"}
+{"text": "Natural disasters and COVID-19 likely add complexity to caregiving efforts, yet little is known about these effects. We will discuss our findings exploring additional needs and challenges experienced by caregivers during hurricanes, floods, and COVID focused on US Gulf Coast states. We interviewed caregivers of both Veterans (n=13) and non-Veterans (n=11). The presentation will include an overview of 1) types of resources needed or used related to storms and to COVID, including social support and access to information for both emergency planning and recovery; 2) caregiver experience before, during, and after the disaster including psychological effects on caregivers and addressing special health needs; 3) comparisons of challenges during storms versus COVID including emotional impact and access to health and specialty care; and 4) additional resources used by caregivers of Veterans. We will also address how these data are informing national caregiver support programs."}
+{"text": "Public health measures implemented to mitigate the spread of COVID-19 have transformed the physical and social environments in which we live. The effects of these policies on persons living with dementia (PLWD) and their care partners (CPs) are not fully understood. This study explores the experiences, attitudes, and perceptions of caregiving dyads during the COVID-19 pandemic. Cross-sectional survey data were drawn from a larger longitudinal study examining the relationship between PLWD aged 65+ and their CPs being conducted in a metropolitan city significantly affected by COVID-19. Interviews with were conducted remotely via videoconferencing and telephone. Data on sources and types of care provided for the PLWD, relationship quality and conflict, and caregiver stress were collected and analyzed using descriptive statistics and tests of independence. Preliminary results from PLWD (n=8) and CPs (n=13) confirmed a reduction in social interaction with family members and friends. CPs reported they (n=5) or other family members (n=2) changed their schedules to provide care for the PLWD. CPs reported increased conflict with the PLWD regarding care provision, going out or welcoming visitors, and home management. In contrast, PLWD reported a lack of conflict among household members (n=6) and the perception of good changes (n=2) and increased quality time with CPs. Preliminary findings provide empirical evidence of the effects of pandemic public health policies on dyads enrolled in this study and reveal differences in perceived relational conflict between PLWD and their CPs. Further research is needed to better understand the experiences of dyads and develop supportive interventions."}
+{"text": "Service users of secure forensic units can be prone to weight gain due to various reasons including medications, physical illnesses, sedentary habits and mental health difficulties. They in turn are at greater risk of obesity related health problems like Diabetes, Hypercholesterolaemia, Ischaemic Heart Disease, Depression among others.Our project was aligned with government's plan to improve prevention and screening for the obesity and metabolic syndrome among the patients of medium secure facilities by 2020.Our primary objective was to gather and analyse the data on current metabolic parameters such as weight, body mass index (BMI), blood pressure (BP) and biochemistry markers of the service users on a 18 bedded Male medium secure long term rehabilitation ward.Our secondary objective was to suggest healthy weight interventions that would help patients to loose weight and to explore the effects of these interventions on biochemistry markers and vital signs parameters.We collected cross sectional data in given period of time (mid-March 2020). Seventeen service users were included in the final sample. Following initial data collection, we suggested various healthy weight interventions for the patients and repeated data collection after four months (July 2020).Interventions offered:Healthy eating group1:1 sessions with doctors and pharmacistsGym referralsDietician referralsRelaxation groupBaselineFourteen patients on the ward (n = 14) were found to be either overweight or obese. Two patients (n = 2) had high BP, twelve patients (n = 12) had deranged lipid profile, six (n = 6) had high blood glucose (existing Diabetes).Following interventionFourteen patients (n = 14) remained either overweight or obese. Nine patients (n = 9) lost weight following the intervention. Eight patients (n = 8) gained weight over 4 months. In both of the patients (n = 2) with raised BP the readings came back to normal after the intervention. One (n = 1) patient with normal BP at the baseline had high blood pressure following intervention.Our service evaluation projects revealed that majority of the patients on the ward had deranged metabolic parameters such as increased BMI, abnormal blood tests and high BP.Following our intervention more than a half of the patients lost weight whilst other half gained weight during the period of observation, which we suspect is associated with significant physical activity restrictions during the coronavirus pandemic. In both patients with high BP at the baseline it has improved following the intervention.We would continue implementing healthy weight interventions on the ward and across the unit."}
+{"text": "Public health measures implemented to mitigate the spread of COVID-19 have transformed the physical and social environments in which we live. The effects of these policies on persons living with dementia (PLWD) and their care partners (CPs) are not fully understood. This study explores the experiences, attitudes, and perceptions of caregiving dyads during the COVID-19 pandemic. Cross-sectional survey data were drawn from a larger longitudinal study examining the relationship between PLWD aged 65+ and their CPs being conducted in a metropolitan city significantly affected by COVID-19. Interviews with were conducted remotely via videoconferencing and telephone. Data on sources and types of care provided for the PLWD, relationship quality and conflict, and caregiver stress were collected and analyzed using descriptive statistics and tests of independence. Preliminary results from PLWD (n=8) and CPs (n=13) confirmed a reduction in social interaction with family members and friends. CPs reported they (n=5) or other family members (n=2) changed their schedules to provide care for the PLWD. CPs reported increased conflict with the PLWD regarding care provision, going out or welcoming visitors, and home management. In contrast, PLWD reported a lack of conflict among household members (n=6) and the perception of good changes (n=2) and increased quality time with CPs. Preliminary findings provide empirical evidence of the effects of pandemic public health policies on dyads enrolled in this study and reveal differences in perceived relational conflict between PLWD and their CPs. Further research is needed to better understand the experiences of dyads and develop supportive interventions."}
+{"text": "The effects of the COVID-19 pandemic on both those experiencing homelessness  and those with life-limiting illnesses  is of great public health concern. This presentation details the findings from an organizational case study  aimed at investigating COVID-related changes to the service environments in which unhoused palliative care patients receive care. Through ethnographic field observation  and interviews with a homeless palliative care team and their community partners , findings included 1) decreased staff capacity due to de-congregated care; 2) efforts to extend care in community settings due to relocation barriers; 3) conflict between reducing viral risk and honoring unique population needs; and 4) provider perceptions of COVID-19 as an \u201cequalizer.\u201d Findings illustrate the impact of emergency response within housing and healthcare systems on unhoused patients\u2019 care and offer potential pathways to quality end-of-life care for homeless populations."}
+{"text": "Previous research has established the role of lifelong learning in promoting psychological wellbeing and active aging. Population aging necessitates an understanding of the unique opportunities and challenges around formal and informal learning in later life. This paper will share findings from a mixed methods study with the MIT AgeLab 85+ Lifestyle Leaders, a panel comprised of octogenarians and nonagenarians from across the United States. Drawing on an online survey and virtual focus groups with 29 Lifestyle Leaders from January 2021, findings suggest the Lifestyle Leaders most often learned new things from talking with others (46%) and reading print (54%) or online (54%) sources. The majority were familiar with attending in-person lectures or classes (89.7%) and were now using videoconferencing to do these (78.6%). A majority (56.7%) had or are currently participating in a lifelong learning program. Most consider themselves lifelong learners and described this around remaining curious and engaged with life, choices around what one learns, and greater enjoyment of learning. In the survey, a plurality of Lifestyle Leaders indicated the top two challenges affecting their ability to learn were sensory burdens  (35%) and their energy level (32.4%); focus group data revealed that recall also is a barrier. Focus group data further highlighted generational experiences around early life learning and career paths, specifically how gender roles, diagnoses of learning disabilities, and evolving digital technology have affected these and changed over the course of their lifetimes."}
+{"text": "Herein we reportthe first alkynylation of quinolones with terminalalkynes under mild reaction conditions. The reaction is catalyzedby Cu(I) salts in the presence of a Lewis acid, which is essentialfor the reactivity of the system. The enantioselective version ofthis transformation has also been explored, and the methodology hasbeen applied in the synthesis of the enantioenriched tetrahydroquinolinealkaloid cuspareine. A) derivativessuch as ciprofloxacin B are well known as broad-spectrumbacteriocidal agents6 -catalyzed alkylations usingorganomagnesium and organoaluminum reagents -catalyzed alkynylation ofquinolones has not been accomplished so far.31On the contrary, the use of readily available and structurallydiverse terminal alkynes as pronucleophiles, along with the mild reactionconditions, offers an attractive strategy for the synthesis of structurallydiverse quinolone derivatives. Several examples of this approach,including Cu(I)-catalyzed alkynylations of (thio)chromonesHerein we report the first example of the direct Cu(I)-catalyzedalkynylation of 4-quinolones with terminal alkynes as pronucleophiles1c. This 1a and phenylacetylene 2a in the presence ofbase DIPEA and catalytic amounts of Cu(I) salt. On the basis of ourgroup\u2019s experience with Lewis-acid-promoted Cu(I)-catalyzedconjugate additions,35 we evaluated the effect of severalLewis acids to enhance the electrophilicity of the quinolone substrate 1a. Excellent conversion to the desired addition product 3a was observed in the presence of a stoichiometric amountof tert-butyldimethylsilyl triflate (TBDMSOTf) afterstirring overnight (Supporting Information) confirmed the conditions in entry 1 as the mostoptimal. Next, we evaluated the effect of the protecting group ofthe quinolone substrate on the reaction outcome.At the start of this work, the optimization studies were carriedout for the alkynylation reaction between Cbz-protected quinolone 3a were obtained when trimethylsilylhalides were used instead (entries 9 and 10). The use of strongersilicon-based Lewis acids such as trimethylsilyl (TMS) and triethylsilyl(TES) triflates resulted in moderate reaction rates (entries 11 and12), whereas the boron-based Lewis acid BF3\u00b7Et2O did not improve the reaction outcome either (entry 13).The superiority of TBDMSOTf over other explored silyl triflates canbe rationalized by the higher stability of a possible TBDMS-enolateintermediate formed during the reaction.No conversion was observed whenunprotected or benzyl-protectedquinolones were used (entries 3 and 4). Moreover, replacing the Cbzprotecting group on the quinolone substrate by a Boc group resultedin a significant drop in the conversion (entry 5). Further studiesconfirmed that the presence of a copper salt and a stoichiometricamount of a Lewis acid are mandatory to promote the reaction to completion.No conversion of quinolone was observed in the absence of copper saltor using only a catalytic amount of a Lewis acid (entries 6\u20138).With silyl-based Lewis acids other than TBDMSOTf, a lower substrateconversion was obtained (entries 9\u201313). Only traces of theaddition product Having the optimizedconditions in hand (entry 1), we moved tostudy the scope of the reaction. For this purpose, various alkynesand quinolones were tested 2.3ab\u20133aj). An excellent yield was also obtained withheteroaromatic alkyne 3ak. Similar results were obtainedwhen using cyclopropyl-, isobutyl-, and ester-substituted alkynes. Surprisingly, the linearterminal alkyne 1-pentyne was unreactive under the optimized reactionconditions (3ao). The limited reactivity of alkyl alkynesand the lack of reactivity of linear alkynes are consistent with theliterature observations in other Cu-catalyzed reactions.37 Various quinolones can be usedwith this catalytic system. Excellent yields were obtained for quinolonesboth with activating and with deactivating groups present in the quinolonering (3eg\u20133ig) and for those withdisubstituted substrates (3jg and 3kg).The reaction was successfully extendedto several aromatic terminalalkynes bearing electron-donating and electron-withdrawing groupsand four-, three-, and two-substituted aromatic rings -cuspareine (5)without racemization, allowing the determination of the absolute configurationof the stereogenic carbon by comparing the optical rotation of cuspareinewith literature data.17The hydrogenation of In summary, an efficientmethodology for the alkynylation of quinoloneswith readily available terminal alkynes has been accomplished. Thismethodology tolerates the presence of several functional groups inboth the quinolone and alkyne reagents and complements the previouslydeveloped arylation and alkylation reactions of quinolones. We havealso demonstrated the feasibility of an enantioselective version andapplied the current methodology to the synthesis of the enantioenrichedHancock alkaloid (+)-cuspareine. Further studies are under way, aimingto improve the enantioselective variant and shed light on the underlyingmechanism."}
+{"text": "This study provides one of the first population-based studies investigating associations between social isolation, especially its two sub-dimensions (family isolation and friendship isolation), and sleep quality among older adults in China. We address three major research questions: 1) Does the risk of poor sleep quality vary by social isolation status? 2) Are the associations between social isolation and sleep quality mediated by mental disorders (depressive symptoms and loneliness) and physical impairments (pain and comorbidity)? and 3) Does the isolation from family members and friends differ in explaining sleep quality? We analyzed data from the 2014 wave of the China Longitudinal Aging Social Survey (CLASS), in which 7,597 respondents (aged 60-98) had complete information on measures of sleep quality (self-rated sleep difficulty), social isolation , and other analytical variables. Logistic regression models were estimated to predict the risk of sleep difficulty and Karlson-Holm-Breen (KHB) decomposition method was employed to test potential mediating effects. Results showed that social isolation, both family and friendship isolation, was significantly associated with higher risks of having sleep difficulty. The adverse effect of family isolation was found to be stronger than that of friendship isolation. Although both mental disorders and physical impairments mediated significant shares of associations between social isolation and sleep quality, physical impairments explained a lesser extent of them than mental disorders. These findings will be helpful for health policymakers and practitioners to design effective intervention strategies to help older adults with sleep problems."}
+{"text": "Salmonella typhimurium (HKST) on intestine against IR was investigated. Through mouse intestinal organoids and whole body irradiation of mice, we found that the pretreatment with HKST significantly preserved the structure of small intestine upon IR exposure and promoted the proliferation of intestinal cells post-IR. Further study revealed that the radioprotective effects of HKST were involved in DNA damage response (DDR) signaling. Moreover, the stimulation of DDR signaling by HKST upon radiation damage was mediated by Wnt signaling, in which the inhibition of Wnt signaling diminished the radioprotective effects of HKST. To sum up, our study suggested HKST as a potential radioprotectant used for prevention of IR-induced GI toxicity.Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) is a dose limiting factor in radiotherapy and a great threat for individual nuclear-related military missions. However, there are currently no available strategies to effectively prevent the damage on the intestine induced by IR. In the present study, the protective activity of Heat Killed  Patients received radiotherapy and victims from nuclear accidents unavoidably suffer from the damage induced by ionizing radiation (IR) . Acute rEscherichia coli O111: B4 LPS, the coagonist of TLR4 and TLR2, exerts stronger immune stimulation effects than that from TLR2 or TLR4 agonist used alone or in combination Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) appears to be a limited factor in radiotherapy and a great threat for those exposed to high dose radiation. However, there are currently no available strategies to effectively prevent or mitigate the damage on intestine induced by IR. Our study demonstrated that Heat Killed"}
+{"text": "My Sister\u2019s Keeper is an online education and support group created by women of color in response to disproportionate stresses related to COVID-19 experienced by women of color. The current study aims to examine the Stage 2 evidence that an online support group formed by members of the community may help mediate inequity-related stressors and increase receptiveness to health-related recommendations. To begin to develop this evidence, a thematic analysis of 8 in-depth individual interviews was performed. Resulting themes included: 1) feeling empowered; 2) solidarity in sisterhood ; 3) being focused (on women of color) yet being inclusive; 4) currency of knowledge ; and 5) preferring virtual accessibility to stay connected. Preliminary data suggest that social support offered through an online platform dedicated to women of color can promote health during the pandemic and possibly beyond."}
+{"text": "The current study examines how cohort differences across two age-matched groups of midlife and older women from the Health and Retirement Study are associated with well-being and self-perceptions of aging (SPA). Women aged 51\u201360 (n=2318) and 61\u201370 (n=1650) were selected from the 2008 and 2018 waves. No significant cohort differences were identified for life satisfaction  or positive SPA . The 2008 cohort of midlife women reported significantly higher negative SPA compared to 2018 (p<.05). Linear regression analyses find that cohort and SPA are significantly associated with life satisfaction in both age groups, and that the association of negative SPA differs by cohort for the midlife women (p<.01). Implications are discussed within the life course developmental framework."}
+{"text": "Tumour cells maintain a local hypoxic and acidic microenvironment which plays a crucial role in cancer progression and drug resistance. Urease is a metallohydrolases that catalyses the hydrolysis of urea into ammonia and carbon dioxide, causing an abrupt increase of pH. This enzymatic activity can be employed to target the acidic tumour microenvironment. In this study, we present the anticancer activities of urease mimetic cobalt (III) complexes on A549 cells. The cells were treated with different doses of cobalt (III) complexes to observe the cytotoxicity. The change in cellular morphology was observed using an inverted microscope. The cell death induced by these complexes was analysed through ATP proliferation, LDH release and caspase 3/7 activity. The effect of extracellular alkalinization by the cobalt (III) complexes on the efficacy of the weakly basic drug, doxorubicin (dox) was also evaluated. This combination therapy of dox with cobalt (III) complexes resulted in enhanced apoptosis in A549 cells, as evidenced by elevated caspase 3/7 activity in treated groups. The study confirms the urease mimicking anticancer activity of cobalt (III) complexes by neutralizing the tumour microenvironment. This study will motivate the applications of transition metal-based enzyme mimics in targeting the tumour microenvironment for effective anticancer treatments. The last few decades have seen an upsurge in cancer research. Many developments and milestones have been achieved in discovering compounds with effective anticancer therapeutic properties. Although a lot of such potent drugs such as doxorubicin and cisplatin were discovered several years ago and are still used clinically to treat different kinds of cancers; they are often limited by severe side effects on healthy cells ,2. RecenRecently, some researchers have focused on targeting the microenvironment surrounding tumour cells ,15,16,17Urease  is widespread in nature and is present in various forms in several bacteria, fungi, and algae . It is c2\u00b76H2O , tris(2\u2013aminoethyl)amine , triethylaminetetramine , and urea  were used as obtained. The complexes were prepared following literature methods Cl (III) and [Co(tren)Cl2]Cl (IV)) was measured from the culture media of the treated and untreated groups. 100 \u03bcL of the culture media was withdrawn from treated and untreated groups at fixed time intervals and the urease mimetic activity was measured using the urease activity kit from Merck Sigma-Aldrich, MAK120, following the protocol provided.The urease mimetic activity of the chloro complexes, (Cl (II) and [Co(trien)Cl2]Cl (III). The crystals were analysed by SC-XRD analyses and were found to be structurally similar to the initial compounds. The crystal structures are presented in 2]Cl was similar to the starting material, the [Co(tren)(NO2)2]Cl crystallised as a polymorph in a different space group. The most prevalent polymorph for this compound exists in orthorhombic space group (Pbca), and the only reported monoclinic form (A2) was isolated serendipitously Cl (IV) induced cleavage of urea into ammonia was reported by some of us recently. The increasing alkalinity was monitored spectrophotometrically with the aid of a pH dependent indicator, phenolphthalein Cl (IV) and [Co(trien)Cl2]Cl (III) were found to be slightly basic as compared to the other groups. This prompted us to measure the urease mimetic activity of the chloro complexes under treatment conditions. Therefore, confluent cells in culture dishes were treated with the optimised dose of the cobalt (III) complexes (32 \u03bcM) in the presence of urea (2 mM). The results were compared to cells treated with urea alone (2 mM) (untreated group) to negate any background absorbance that may arise due to the culture medium or urea. A total of 100 \u03bcL of the culture medium was withdrawn at fixed time intervals, and the urease mimetic activity was measured using the urease activity kit from Sigma Aldrich as per the protocol available with the test kit. The increase in absorbance at 670 nm at fixed time intervals for the cobalt treated groups was compared to the untreated group. The results are presented in 2]Cl (IV) and [Co(trien)Cl2]Cl (III) depicted a gradual increase in absorbance at 670 nm, and after 24 h of treatment, the absorbance, and hence the urease mimetic activity for [Co(tren)Cl2]Cl (IV) was significantly higher than [Co(trien)Cl2]Cl (III). Similar trends have been reported for catalytic studies as well [2]Cl (IV) performing better than [Co(trien)Cl2]Cl (III) for A549 cells.The ammonia generated because of urease mimetic activity in treatment groups was ascertained by pH measurements of the cell culture media after 24 h of treatment of A549 cells with the cobalt (III) complexes. Interestingly, the culture media from the cells treated with Cl (IV) and [Co(trien)Cl2]Cl (III) over 24 h  complexes for MCF7 cells were completely surprising and conflicting. There was no appreciable change in absorbance at 670 nm for the cells treated with [Co(tren)Clver 24 h . The abs2]Cl (III) and [Co(tren)Cl2]Cl (IV) complexes outperformed other Co complexes (2)2]Cl (II) and [Co(trien)(NO2)2]Cl (I) complexes exhibit poor catalytic urease activity as well, owing to the strong affinity and poor lability of the nitro group towards cobalt [The WS1 cells in the control and treated groups were seen to be healthy with no significant difference observed in growth and proliferation . The LDHomplexes A. The [Cs cobalt .2]Cl (III) and [Co(tren)Cl2]Cl (IV), while the nitro complexes were dropped out. To ascertain the urease-like anticancer activity of the cobalt complexes, the cells were treated with the complexes alone and with the addition of urea. The resulting alkalinity of urease activity has been shown to enhance the activity of weakly basic anticancer drugs, such as doxorubicin. Such drugs\u2013enzyme combinations and conjugates are gaining increasing attention in recent times Cl (III) and [Co(tren)Cl2]Cl (IV))\u2013urea combination as well as the combinations with doxorubicin, induced profuse toxicity in cells and reduction of ATP. These findings further support our claim that urease mimetic activity of the cobalt complexes induces anticancer effects by facilitating doxorubicin action, as observed in the LDH assay. The results are presented in A similar trend was observed with ATP of WS1 and A549 cells. No significant ATP proliferation was observed in WS1 cells depicting the safety of complexes against normal cells ; howeverThe A549 cells which were incubated with the cobalt complexes alone and in combination with urea and doxorubicin for 24 h showed distinct morphology in a concentration dependent manner compared to the control. The cells showed signs of cell death, with deformed membrane integrity, losing inter-cellular contact, vacuolation, rounding of cells and detachment from the culture plates . The toxAs observed in LDH and ATP assays, cell viability significantly reduced in A549 cells on treatment with the cobalt complexes and the urea and doxorubicin combinations . The celIII and IV) in combination with urea and doxorubicin. The luminescent signals elevated in these groups compared to control and authenticate the role of caspases in inducing cell death  complexes towards cancer cells. Such altering of the microenvironment can also be manipulated to enhance the activity of weakly basic drugs. Under acidic conditions, basic drugs, such as doxorubicin, tend to sequester in the acidic extracellular environment, thus failing to diffuse into the hydrophobic cell membrane. This often results in loss of therapeutic activity and drug resistance. In this study, we report a combination therapy of the cobalt (III) complexes with doxorubicin. The combination is proposed to be working synergistically, wherein the cobalt (III) complexes hydrolyse urea to generate ammonia, thus neutralizing the acidity in the tumour microenvironment. This subsequently, enhances the diffusion of doxorubicin into the cells, thereby, improving the overall cytotoxic activity. The cobalt complexes do not directly target the cancer cells; rather, they act on the extracellular microenvironment, disrupting the physiological factors that enable tumour growth. Thus, they exert a target specific cytotoxic action controlled by the surrounding pH. This can also be attributed to the low toxicity of the complexes towards normal cells that operate under strictly controlled pH conditions. To further confirm the mechanism of apoptotic action, caspase 3/7 expression was determined in treated groups. Even though the cell death stimulus induced by caspase 3 and 7 differs, they are yet considered universal executioner caspases ,53,54. AUrease activity was long viewed as detrimental, and research was mainly focused on inhibiting the enzyme\u2019s activity; however, the undesirable urease activity can be utilized to neutralize the acidity in tumour microenvironments, thereby leading to enhanced therapeutic efficiency. We have presented the preliminary results of the cytotoxicity induced by urease mimetic cobalt (III) complexes on lung cancer cells. The cytotoxicity results correlate well with the observed urease mimetic activity. The complexes reported in this study are found to be nontoxic towards normal cells, making them an ideal drug candidate for treating cancer cells. To further understand the application of these complexes as anticancer drugs, their dose responses on MCF-7 and HKESC-1 were also studied. With moderate toxicity on MCF-7 but commendable action against HKESC-1 cells, it can be concluded that the active complexes (III and IV) were not cell line specific and further research is warranted to understand the reason behind these specificities. Moreover, synthetic enzyme mimics based on transition metal complexes serve several advantages over the actual enzyme; they are robust, with long shelf life, and often can greatly reduce the cost of manufacturing. The urease, like the action of the cobalt (III) complexes, also improves the therapeutic activity of weakly basic drugs, such as doxorubicin, by inducing apoptosis as seen by the expression of caspase3/7 in treated groups; however, the conflicting results obtained with MCF7 cell lines warrant further investigation using in vivo and clinical models. The concept introduced in this article is worthwhile and deserves further investigation."}
+{"text": "ABSTRACT IMPACT: Being explicit about the prevention of falls throughout an older adults\u2019 episode of care may further help reinforce the role of physical therapy providers in falls prevention and improve dissemination of this knowledge. OBJECTIVES/GOALS: The purpose of this study was to determine older adults\u2019 awareness of and perspectives about the role of physical therapy providers for falls prevention and determine potential barriers and facilitators to utilization of preventive rehabilitation services METHODS/STUDY POPULATION: We used a qualitative descriptive phenomenological approach to emphasize participants\u2019 perceptions and lived experiences. Four focus groups were conducted with 27 community-dwelling older adults (average age = 78 years). Focus groups were recorded, transcribed, condensed, and coded using thematic analysis. RESULTS/ANTICIPATED RESULTS: Surveys indicated 37% of participants experienced a fall in the last year and 26% reported suffering an injury. Four main themes and six subthemes surrounding older adults\u2019 perceptions of physical therapy providers\u2019 roles for falls prevention emerged: (1) Awareness of Falls Prevention ; (2) Being Able to Get Up from the Floor; (3) Limited Knowledge about the Role of Physical Therapy Providers in Falls Prevention ; and 4). Barriers to Participating in Preventive Physical Therapy Services . DISCUSSION/SIGNIFICANCE OF FINDINGS: Older adults lack awareness about the role of physical therapy services in falls prevention, perceiving services are only to treat a specific problem or after a fall. Physical therapists should be explicit about the role of physical therapy in falls prevention for all older adults undergoing rehabilitation, regardless of the reason."}
+{"text": "Using whole-genome sequencing and combining genome sequence data derived from national surveillance databases, we identified additional emm12 GAS clones similar to those associated with prior SF outbreaks, emphasizing the need for continued surveillance for epidemic emergence in the USA.Scarlet fever (SF) has recently been associated with group A streptococcal (GAS) strains possessing multidrug resistance and specific streptococcal exotoxins. We screened a local surveillance collection of GAS  All raw genome sequences generated in this study are publicly available from the National Center for Biotechnology Information (NCBI) under BioProject accession number PRJNA608028. In addition, sequences from BioProjects PRJNA471864, PRJNA395240, PRJNA416675, PRJEB2675 and PRJNA13551 were used in comparative phylogenomics analysis, as indicated in Streptococcus (GAS) was an important cause of morbidity and mortality in children during the 19th and early 20th centuries [emm type 12 (emm12) and harbour two mobile genetic elements (MGE): an integrative and conjugative element (ICE-emm12) encoding tetracycline and macrolide resistance and a prophage (\u03d5HKU.vir) encoding two exotoxins (SSA and SpeC) and the DNase Sda1 [emm12 SF clone [emm12 SF outbreaks have been identified in additional emm types, including emm1 GAS strains [emm12 background to enhance colonization in a mouse model [emm12 clones is warranted, given their persistence in multiple outbreaks.Epidemic scarlet fever (SF) caused by group A ase Sda1 . SubsequSF clone . MGE ass strains . Several strains . Most reemm12 isolates. Molecular typing of GAS isolates from January 2013\u2013July 2018 was performed to determine emm type. A total 300 emm12 GAS isolates were identified and underwent antimicrobial susceptibility testing to tetracycline and erythromycin using disc diffusion [emm12 isolates (n=22) and any isolate resistant to both erythromycin and tetracycline using an Illumina MiSeq (300\u2009bp PE). Raw sequencing reads were assembled using SPAdes and queried for the presence of exotoxin, DNase and resistance genes using a custom algorithm as previously described [emm12 strains (n=22) and previously sequenced emm12 GAS strains from the Centers for Disease Control and Prevention (CDC) Active Bacterial Core Surveillance (ABCs) , Hong Kong/PR China  and the UK   see .emm12 GAS isolates from Houston, TX screened for antimicrobial resistance, a total of 14 (5\u200a%) were identified with resistance to erythromycin or tetracycline and a single isolate (TSPY1687 \u2013 pharyngitis from 2018) was identified to be resistant to both antibiotics. Consistent with previous reports on GAS [emm12 GAS isolates sequenced by the CDC ABCs and discovered three additional isolates with erythromycin and tetracycline resistance genes  demonstrated a close relationship of all four US isolates to groups of strains from previous SF outbreaks in Hong Kong and PR China  and tet(M), and differed by a single prophage that was devoid of any exotoxin or DNase genes  and emm1 (17.1\u200a%) lineages [emm12 GAS strains similar to the original outbreak strains in Asia [emm12 GAS strains more closely related to those from the UK were identified in Australia [emm12 SF-like clone in the USA using our local GAS strain surveillance and shown additional clones circulating within the US population using publicly available national surveillance databases. SF is a notifiable disease in many Asian countries and the UK but not the USA. Interestingly, none of the four emm12 SF-like clones identified in our study were derived from SF cases. TSPY1687 was isolated following a case of pharyngitis in an 8-year-old child in 2018 but lacked rash or other symptoms (e.g. strawberry tongue) associated with SF. Likewise, the three CDC ABCs emm12 SF-like strains were from cases of invasive disease in 2015 but at opposite ends of the country . Unlike in our local surveillance, we are unable to further query electronic medical records for additional signs and symptoms in the CDC ABCs cases. Inasmuch as GAS whole-genome sequencing analyses have shown that invasive strains are derived from the population of pharyngeal strains [emm12 SF clones in the US population. At this time, it is unclear if more robust prospective surveillance for GAS pharyngitis would identify additional cases in the USA. Alternatively, it is also possible that the small number of emm12 SF-like clones identified in our analysis represent individual importation events from outbreak regions. Importantly, our data confirm a worldwide spread of emm12 SF clones and suggest that additional factors apart from GAS strain contribute to the development of SF. In summary, our findings emphasize the role of GAS surveillance, antimicrobial susceptibility profiling and heightened awareness of possible SF in Houston and the USA.A rapid rise in the incidence of SF in the Republic of Korea, PR China and Hong Kong marked the beginning of an epidemic in Asia. Extensive surveillance identified GAS strains of primarily emm12 76.\u200a% and em in Asia . Most reustralia . We have strains , our finClick here for additional data file."}
+{"text": "Here, we present the results from a population study that evaluated the performance of massively parallel sequencing (MPS) of short tandem repeats (STRs) with a particular focus on DNA intelligence databasing purposes. To meet this objective, 247 randomly selected reference samples, earlier being processed with conventional capillary electrophoretic (CE) STR sizing from the Austrian National DNA Database, were reanalyzed with the PowerSeq 46Y kit (Promega). This sample set provides MPS-based population data valid for the Austrian population to increase the body of sequence-based STR variation. The study addressed forensically relevant parameters, such as concordance and backward compatibility to extant amplicon-based genotypes, sequence-based stutter ratios, and relative marker performance. Of the 22 autosomal STR loci included in the PowerSeq 46GY panel, 99.98% of the allele calls were concordant between MPS and CE. Moreover, 25 new sequence variants from 15 markers were found in the Austrian dataset that are yet undescribed in the STRSeq online catalogue and were submitted for inclusion. Despite the high degree of concordance between MPS and CE derived genotypes, our results demonstrate the need for a harmonized allele nomenclature system that is equally applicable to both technologies, but at the same time can take advantage of the increased information content of MPS. This appears to be particularly important with regard to database applications in order to prevent false exclusions due to varying allele naming based on different analysis platforms and ensures backward compatibility.The online version contains supplementary material available at 10.1007/s00414-021-02685-x. Throughout the past decades, short tandem repeat (STR) loci have become the most important genetic markers in forensics. They can be analyzed at a reasonable cost/time ratio and provide high enough statistical discrimination power to identify individuals in the majority of crime and human identification cases . TraditiHere, we evaluated the performance of an MPS-based STR-typing system consisting of the PowerSeq 46GY panel  analyzed on a MiSeq FGx sequencer  for DNA intelligence databasing purposes using a random subset of the Austrian National DNA Database as an example. The PowerSeq 46GY kit includes all loci required for national and international DNA intelligence databasing in the United States and Europe. We evaluated concordance and backward compatibility to extant CE-based genotypes, stutter display, and heterozygote balance and provide new population data to increase the body of STR variation that is currently being collected and catalogued in various environments e.g., , 10)..10]).All 248 buccal swab reference samples included in this study derived from the Austrian National DNA Database in accordance with the Austrian Data Protection regime. They were analyzed in line with Austrian legislation and with permission of the Austrian Federal Ministry of the Interior. Legal requirements with respect to sample storage  as well as the permission to go back to DNA extracts for re-testing are regulated by the Austrian Federal Security Police Act, which also contains specific legal provisions for scientific purposes to provide biometric data, including DNA data, in anonymized form to universities for research. The samples were randomly selected by executive authorities of the Austrian Federal Ministry of the Interior. The selection criteria were based on male sex, Austrian nationality, and birthplaces. The samples were made anonymous to the analyzing laboratory by using barcode information.DNA was extracted from buccal swab samples using the Chelex 100  method , and stoTo determine the amount of genomic DNA, a real-time quantitative PCR (qPCR) assay targeting specific AluYb8 sequences was used . A spikeSTR analysis was performed using the AmpFlSTR NGM SElect Express kit (TFS)  and the The PowerSeq 46GY kit (Promega) was used to co-amplify 22 aSTRs , 23 Y-STRs (data not shown), and amelogenin. This extended STR panel aims to target forensic markers to comply with the European Standard Set (ESS)  deletion Supplementary file2 (PDF 134 KB)Supplementary file3 (PDF 96 KB)Supplementary file4 (PDF 175 KB)Supplementary file5 (PDF 174 KB)Supplementary file6 (PDF 138 KB)Supplementary file7 (PDF 122 KB)Supplementary file8 (XLSX 1015 KB)Below is the link to the electronic supplementary material."}
+{"text": "Tuberous sclerosis, angiomyolipoma and lymphangioleiomyomatosis are a group of diseases characterized by mutation in tuberous sclerosis genes (TSC 1-2). TSC mutation leads to continuous activation of the mTOR pathway that requires adaptation to increased ATP requirement. With limited treatment options, there is an increasing demand to identify novel therapeutic targets and to understand the correlations between mTOR pathway activation and the lack of cell death in the presence of TSC mutation. In the current study, we demonstrate deregulation of p53 controlled and mitochondria associated cell death processes. The study also reveals that treatment of TSC mutant cells with the drug candidate Proxison combined with reduced concentration of rapamycin can increase production of reactive oxygen species (ROS), can modify miRNA expression pattern associated with p53 regulation and can reduce cell viability.The online version contains supplementary material available at 10.1007/s10495-021-01670-4. RecentlIn a previous study of lymphangioleiomyomatosis (LAM)  TSC mutaTSC mutations are particularly disruptive in the phosphoinositide 3 kinase (PI3K)/Protein kinase B (PKB or AKT)/mTOR pathway, as the mTOR pathway is inhibited by the complex of two proteins Hamartin (TSC1) and Tuberin (TSC2). Mutation in the TSC genes allows continuous activation of mTOR resulting in slow growing neoplasms . The mTOBased on the above we theorized that investigation and modulation of p53 and mitochondrial function associated cell death pathways might provide a better understanding of the molecular background of TSC mutation induced diseases and the results might lead to identification of additional targets for therapy.Materials and methods are detailed in the Supplementary material . Briefly, LAM tissue samples were obtained from lung transplant donors for generation of cell lines . ParaffimTOR is downstream of the PI3K and AKT enzymes that transduce signals from growth factor activated receptor kinases . To inveTo understand the significance of the results, a linear regression-based prediction algorithm analysis  was usedTo confirm that deregulation of the pro- and anti-apoptotic pathways are not a unique feature of the AML derived S102 cell line, 4 primary LAM tissue derived cell lines  in TSC2 mutant cell lines revealed a distortion in the pro- and anti-apoptotic balance. The cell death processes are blocked in TSC mutant cells despite p53 activation  combined with the drug candidate Proxison (3\u00a0\u00b5M) can result in cell death. Although further studies are required, combined inhibition of the mTOR pathway and TRXR can potentially lead to a more effective therapy.Supplementary file1 (DOCX 7450 kb)Below is the link to the electronic supplementary material."}
+{"text": "The purpose of this study was to generate a selective radiosensitising effect by the intra-hepatic-arterial infusion of misonidazole (MISO). MISO (10 mg) was infused after transcatheter hepatic-arterial embolisation into the livers of rabbits bearing VX2 liver cancer. This procedure was followed by 15 Gy electron irradiation. Evaluation of tumour volume and histological examination was carried out on the 7th day after treatment. The greatest tumour response was obtained in the group which received MISO followed by radiation and was characterised by extensive fibrosis around the tumour and nearly complete tumour necrosis. Liver cell regeneration was also noted in adjacent liver tissue. The advantages of regional infusion of MISO following hepatic-arterial embolisation are: (1) Selectivity increased radiosensitivity of liver cancer alongside very low drug concentration in the plasma. (2) Reduced or absent deleterious side effects of MISO with higher tumour/normal tissue ratios of drug concentration. (3) Reduced cost due to the lower dosage of MISO required for regional infusion."}
+{"text": "ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. This syndrome is infrequent and corresponds to a peculiar small subgroup of patients with symptomatic gallstone disease. The patients with the LPAC syndrome present typically with the following main features: age less than 40 years at onset of symptoms, recurrence of biliary symptoms after cholecystectomy, intrahepatic hyperechoic foci or sludge or microlithiasis along the biliary tree. Defect in ABCB4 function causes the production of bile with low phospholipid content, increased lithogenicity and high detergent properties leading to bile duct luminal membrane injuries and resulting in cholestasis with increased serum gamma-glutamyltransferase (GGT) activity. Intrahepatic gallstones may be evidenced by ultrasonography (US), computing tomography (CT) abdominal scan or magnetic resonance cholangiopancreatography, intrahepatic hyperechogenic foci along the biliary tree may be evidenced by US, and hepatic bile composition (phospholipids) may be determined by duodenoscopy. In all cases where the ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with ursodeoxycholic acid (UDCA) should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. Cholecystectomy is indicated in the case of symptomatic gallstones. Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatations filled with gallstones. Patients with end-stage liver disease may be candidates for liver transplantation.Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of  Low phospholipid associated cholelithiasisABCB4 gene mutationCholelithiasis with ABCB4 gene mutation-associated cholelithiasisABCB4 mutations with symptomatic and recurring cholelithiasis in young adults (e.g. <40 years).Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations in the whole population of patients with cholelithiasis.The exact prevalence of LPAC remains unknown. The disease is more common in young adults, the usual age at the onset of the symptoms is typically lower than 40 years. The male to female ratio is estimated at approximately 1:3. However, at present, the literature data and our results did not allow to determine the frequency of Up to 10% of the European and American population carry gallstones, approximately 25% of cases have symptoms and less than 2% present with severe complications (cholangitis or pancreatitis). Based on previous epidemiological data, we consider that LPAC syndrome is infrequent and corresponds to a peculiar subgroup of patients with symptomatic gallstone disease [LPAC presents as a peculiar form of cholelithiasis characterized by cholecystitis, cholangitis and intrahepatic gallstone disease, and/or acute pancreatitis associated with biliary microlithiasis. Most patients report a history of cholesterol gallstones amongst their first-degree relatives. Intrahepatic hyperechoic foci are characteristic sign of the LPAC syndrome. Intrahepatic gallstones or sludge and increased serum gamma-glutamyl transferase (GGT) activity are frequently present. It suggests that the biliary symptoms experienced by these patients are probably caused by cholesterol crystal deposits and bile duct inflammation but not directly and exclusively related to the presence of detectable gallstones. Increased cholesterol saturation index and a defect in the hepatic transport and biliary secretion of phospholipids in patients with an intrahepatic cholesterol gallstone disease or an acute pancreatitis associated with biliary microlithiasis have been shown in another studies ,4.ABCB4 mutations presented also with an history of intrahepatic cholestasis of pregnancy and 14% had fetal complications) [The typical biliary pain in patients with LPAC syndrome  often leads to decision of cholecystectomy. The majority of patients is our series (90%) underwent cholecystectomy but recurrence of the symptoms was observed in half of them, despite cholecystectomy . The onscations) . Prophylcations) . Of noteMDR3 (now referred to as ABCB4) gene, the phosphatidylcholine translocator across the canalicular membrane, are thought to be responsible for progressive intrahepatic cholestasis type 3 (PFIC 3) [Phospholipids are the major carrier and solvent of cholesterol and they exert a protective effect against bile salt-induced biliary mucosa injury. Homozygous and heterozygous mutations in the (PFIC 3) , and het(PFIC 3) -11. DefeABCB4 gene mutations in 60 consecutive adult patients who had been referred to our liver unit because of symptomatic or complicated cholelithiasis and we characterized more precisely the clinical phenotype associated with these mutations [ABCB4 gene analysis because of clinical history compatible with the syndrome that we previously described . Multivariate analysis showed that among patients with cholelithiasis three independent factors were predictive of a mutation at the ABCB4 locus: a recurrence of symptoms after cholecystectomy (adjusted OR = 8.5), intrahepatic hyperchoic material (adjusted OR = 6.1), and age <40 years (adjusted OR = 3.0) [Among the 32 patients suspected of having the syndrome, 18  presented a point mutation at the Finally, more recent data shows that the LPAC syndrome is more frequent in females and that biliary symptoms occur earlier in female who present a nonsense mutation .ABCB4 gene using polymerase chain reaction (PCR) amplification and DNA sequencing of exons 2 to 28 and all splice junctions. We identified 14 heterozygous and homozygous point mutations amongst these 18 patients. None of these mutations was detected in a control panel of 140 chromosomes demonstrating that they did not correspond to polymorphisms (SNPs). Affected patients with heterozygous mutations exhibited 1bp-insertion, 1bp-deletion, nonsense mutations or missense mutations resulting in a frameshift predicted to cause premature messenger RNA termination, a loss of protein function and single-nucleotide substitutions, while affected patients with homozygous mutations demonstrated only missense mutations. Most mutations were localized in the central part of the molecule, close to nucleotide binding domain 1 (NBD1), or in adjacent transmembrane domains and intracellular loops .Patients were screened for mutations in the st intracellular loop and resulted in a substitution in a conserved cluster of four amino-acids at position 169\u2013172, required for the adenosine triphosphatase activity of the molecule. This mutant resulted in a complete loss of drug-induced P-gp ATPase activity. The Phe165Ile mutation was localized in the same part of this intracellular loop and may therefore give rise to a similar defect. The Glu528Asp mutation was localized close to the NBD1. The glutamic acid is included in a small amino-acid cluster localized before the walker B motif which is required for drug-induced ATPase activity. These mutations indeed induced a loss of function of the molecule in vitro. It should be noted that the two unrelated patients in whom the Thr175Ala mutation was identified originated from Northern Europe, so they may have inherited a founder mutation from a shared ancestor. This mutation has also been recently identified in adults with cholangiopathy and intrahepatic cholestasis of pregnancy [The definition of a disease-causing mutation (DCM) is problematic when functional assays to determine the phenotypic effects of specific variants are not available or have not been performed. To date, two of the missense mutations (Glu528Asp and Thr175Ala) detected in patients with the LPAC syndrome had been analyzed previously in a homolog of ABCB4  in yeast ,14. The regnancy . The mutregnancy .ABCB4 sequence alterations leading to predicted premature truncation of the protein, small deletions or insertions and non-conserved missense mutations were considered as potential DCMs. Even if this restriction was taken into account, a certain number of arguments strongly supported a pathogenic role for ABCB4 gene mutations. These mutations are indeed detected at high frequency in patients with LPAC syndrome; they affect only highly conserved amino acids between human and rodent homologues of the gene and no mutation was detected in an independent control panel of 140 chromosomes. In addition, LPAC syndrome was observed in patients exhibiting the same or similar nonsense or missense mutations: in a mother and her elder son with an identical heterozygous nonsense mutation (1327insA); in independent patients from non-consanguineous families with the same homozygous missense mutation (Ser320Phe or Ala934Thr), while their heterozygous parents were asymptomatic; in patients with a similar nonsense mutation (1006-1016insT and 1006-1016delT) and in unrelated patients with the same missense mutations (Pro1161Ser). For all these reasons, these mutations could be considered as causing the LPAC syndrome.Only ABCB4 mutations may lead to cholesterol cholelithiasis when residual ABCB4 activity and subsequent biliary phospholipid secretion fall below a critical threshold which may depend on the type of mutation and on other host or environmental factors, including probably bacterial infection of the bile ducts .These results and data in the literature therefore strongly suggest that ABCB4 gene point mutation, defects in the promoter region or large DNA rearrangements might also be involved in some patients presenting with LPAC syndrome. Alternatively, defects in other regions of the gene or in other genes may also be involved, and some evidence from animal studies has pointed to Abcb 11 , Abcc 2  or Abcg5/Abcg8 as other possible candidate genes underlying susceptibility to cholelithiasis [The mutation screening method used in our two studies was unable to detect major DNA rearrangements, and nor did the analysis include the promoter or other potential regulation regions of the gene. As 44% of LPAC patients did not present ithiasis -19 or phithiasis .in vitro to enhance cholesterol crystallization. This mechanism explains the early and higher prevalence of gallstones in female Mdr2 -/- mice and provide a rationale for substitution of more hydrophobic bile salts with ursodeoxycholic acid in LPAC patients [It has also been shown that substantial amounts of cholesterol are secreted by Mdr2 (-/-) mice on a cholate-supplemented diet and microscopic examination of the gallbladder reveals massive amount of cholesterol crystals and that after 12 weeks, 50% of the Mdr2 (-/-) mice on chow also developed gallstones composed of needlike \"anhydrous\" cholesterol crystals and mucin ,22. Indepatients .ABCB4 gene mutations and sequence diversity in 34 consecutive patients with primary sclerosing cholangitis. We found no ABCB4 gene mutations and no abnormal SNP frequency in these unselected PSC patients [ABCB4 from that observed in healthy Caucasian controls [ABCB4 genetic variation in the pathogenesis of the PSC, although an implication of ABCB4 cannot be ruled out in a subgroup of these patients.As a recent study reported that Mdr2 KO mice develop liver lesions mimicking sclerosing cholangitis characterized by biliary strictures and dilatations , we alsopatients . These dcontrols . Thus, tCholesterol cholelithiasis was also demonstrated in patients with progressive familial intrahepatic cholestasis-3 (PFIC3) and some of their relatives ,26, and etc.) should remind of this rare monogenic form of cholelithiasis (e.g. LPAC syndrome) for which genetic testing may be offered by several genetic laboratories.In patients with symptomatic cholelithiasis, the presence of additional hepatobiliary manifestations , computing tomography (CT) abdominal scan or magnetic resonance cholangiopancreatography;\u2022 Intrahepatic hyperechogenic foci along the biliary tree by US;\u2022 Hepatic bile composition ;ABCB4 gene analysis.\u2022 Other inflammatory bile duct diseases which may lead to biliary symptoms and/or intrahepatic gallstones .ABCB4 genotyping should be used to confirm the diagnosis of LPAC syndrome in young adults who present with a symptomatic cholelithiasis and should allow familial screening.ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with UDCA should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. UDCA was shown to up-regulate the expression of the protein at the canalicular membrane, minimize the toxicity of the endogenous hydrophobic bile acids and increase the pool of protective hydrophilic bile acids.Special diet is not required. In all cases where the In the case of associated hypercholesterolemia, statins should be preferred to fibrates which increase the lithogenicity of the bile.Cholecystectomy is indicated in the case of symptomatic gallstones but not when only sludge is present in the gallbladder.Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatation filled with gallstones.Patients with end-stage liver disease may be candidates for liver transplantation.Drugs that may induce ABCB4 expression.Typically, the clinical course is progressive, with multiple recurrence despite the operative intervention(s) until UDCA treatment is started.The majority of patients with LPAC syndrome described in the literature do not develop recurrence or end-stage liver disease under medical treatment.ABCB4 gene defect in LPAC syndrome and replace it in the context of ABCB4 gene-associated liver diseases in adults including attenuated form of PFIC 3, \"atypical intrahepatic cholestasis of pregnancy\", LPAC syndrome which might lead to adulthood biliary cirrhosis or bile duct dilatations associated with gallstones. A genetic test based on the present results may permit the molecular diagnosis of LPAC syndrome and the screening of high-risk subjects. Depending on the results, long-term curative or prophylactic UDCA therapy may be initiated early to prevent the occurrence or recurrence of this syndrome and its severe complications.In summary, our results strongly support the role of an"}
+{"text": "Exogenous purines M) can modulate the cytotoxicity of methotrexate (MTX) in cultured cells, protecting cells at low MTX concentrations  M) and markedly potentiating its effect at higher concentrations. The ability of hypoxanthine (HX) to modulate the effects of two antifolates-ICI 198583 (an inhibitor of thymidylate synthetase) and piritrexim -was investigated using cultured mouse leukaemic cells, L1210. HX (10(-4) M) was found to potentiate only the cytotoxicity of DHFR inhibitors (MTS and PTX), increasing cell kill by 20-70 fold to the level achieved by an equivalent concentration (10(-5) M) of ICI 198583 alone. Agarose gel electrophoresis of DNA extracted from cells exposed to antifolates for 24 h demonstrated that the chromatin was cleaved into multimers of 200 base pairs. This pattern of DNA cleavage indicates cell death via apoptosis. The degree of DNA fragmentation was found to be closely linked to cytotoxicity. DNA fragmentation increased from 50% in cells treated with 10(-5) M MTX or PTX to 70% when HX was added with the drugs, a level achieved by 10(-5)M ICI 198583 alone. HX potentiation of cytotoxicity was correlated with a substantial increase in dATP in conjunction with low dTTP pools. The specific potentiation of DHFR inhibitors by HX may be due to their inhibition of purine synthesis with a concurrent rise in PRPP levels. Addition of HX with MTX substantially raised intracellular purine levels via the salvage pathway as indicated by ribonucleotide pool measurements. ICI 198583, on the other hand, stimulated de novo purine synthesis with or without added HX. Treatment with MTX plus HX or ICI 198583 (with or without HX) caused a reduction of dTTP pools to 8% of untreated control and excess dATP accumulation. The subsequent elevation (to 300% of control) of the dATP pool may provide a signal for endonucleolytic fragmentation of DNA and subsequent cell death."}
+{"text": "Eighty-four patients with breast cancer at high risk of bone metastases were investigated with magnetic resonance imaging (MRI) of the thoracolumbar spine. Of 58 patients with normal limited skeletal surveys (LSS) and bone scans (BS), 4 (7%) had MR images compatible with malignant infiltration. Fourteen patients had abnormal bone scans with normal or non-diagnostic plain films; 7 of these patients (50%) had MR images compatible with malignant infiltration. Twelve patients had single or multiple wedge collapses of uncertain aetiology on plain film; MR demonstrated metastatic disease as the cause of wedge collapse in 7 (58%). MRI may define a group of patients with extra-osseous relapse who have occult metastatic disease. Although the detection rate in patients with primary breast cancer is low (4/45), MRI is of value in determining the cause of wedge collapse in postmenopausal women with breast cancer and may elucidate the cause of an abnormal bone scan with normal or non-diagnostic plain films."}
+{"text": "Between January 1991 and December 1992 a phase I trial of superficial photodynamic therapy (PDT) using topical application of 5-aminolaevulinic acid (ALA) was undertaken to treat Bowen's disease, superficial basal cell carcinomas (BCCs) and metastatic skin secondaries from breast (adenocarcinoma) or pinna (squamous cell carcinoma). Promising results were obtained with 36 areas of Bowen's disease, with a complete response rate of 89% at a median follow-up of 18 months. The treatment of BCCs was less successful, with 50% complete responses in 16 lesions at a median follow-up of 17 months. Metastatic nodules responded poorly. The treatment was well tolerated and discomfort during light irradiation could be reduced by prior application of 'Emla' cream. Lesions wept for 1-2 weeks following treatment and healed over a period of approximately 2 months. For large areas of Bowen's disease, particularly in anatomically difficult areas and in elderly patients, PDT using ALA may constitute a single simple alternative outpatient treatment to existing therapies. Further work is required to improve the results with BCCs."}
+{"text": "The oncogenicity of Duck hepatitis B virus (DHBV) is unclear since hepatocellular carcinomas (HCCs) have been reported only in domestic ducks in Qidong, an area of China where hepatitis B virus (HBV) and aflatoxin B1 (AFB1) are risk factors for liver cancer in man. In order to better define the association between DHBV infection, AFB1 and HCC we analysed a series of 16 duck liver samples collected from local farms in Qidong. HCC was found in eight and cirrhosis in one of these samples. Furthermore bile duct proliferation, characteristic of AFB1 exposure in ducks and other animal species, was found in these ducks. Integration of DHBV DNA into cellular DNA was observed in only one out of four DHBV positive HCCs, indicating that viral integration is not prerequisite for tumour development. In four remaining HCCs the polymerase chain reaction (PCR) failed to show any DHBV DNA suggesting that liver tumours do occur in polymerase chain reaction (PCR) failed to show any DHBV DNA suggesting that liver tumours do occur in these ducks in the absence of DHBV infection. In addition, AFB1-DNA adducts were detected by hplc-immunoassay in one such DHBV-negative tumour. In summary we demonstrate that risk factors other than DHBV, including AFB1 exposure, may be important in duck liver carcinogenesis in Qidong."}
+{"text": "Electrophoretic isoenzyme separation provides much more precise information than measurement of alkaline phosphatases (AP). Use of this technique for 83 patients with Hodgkin's disease revealed that the presence of the alpha 1 fraction  was very significantly correlated with the stage of disease extension (P less than 0.01) and above all with the presence of general symptoms (P less than 0.001). Repeat measurements performed during patient follow-up demonstrated a close association between presence of alpha 1 AP and existence of progressive disease. While the mechanism of appearance of this abnormal alpha 1 AP fraction is not linked to Hodgkin-specific liver lesions, this test provides much more interesting data than classical measurement of total alkaline phosphatases (TAP)."}
+{"text": "For the exceptional self-renewal capacity, regulated cell proliferation and differential potential to a wide variety of cell types, the stem cells must maintain the intact genome. The cells under continuous exogenous and endogenous genotoxic stress accumulate DNA errors, drive proliferative expansion and transform into cancer stem cells with a heterogeneous population of tumor cells. These cells are a common phenomenon for the hematological malignancies and solid tumors. In response to DNA damage, the complex cellular mechanisms including cell cycle arrest, transcription induction and DNA repair are activated. The cells when exposed to cytotoxic agents, the apoptosis lead to cell death. However, the absence of repair machinery makes the cells resistant to tumor sensitizing agents and result in malignant transformation. Mismatch repair gene defects are recently identified in hematopoietic malignancies, leukemia and lymphoma cell lines. This review emphasizes the importance of MMR systems in maintaining the stem cell functioning and its therapeutic implications in the eradication of cancer stem cells and differentiated tumor cells as well. The understanding of the biological functions of mismatch repair in the stem cells and its malignant counterparts could help in developing an effective novel therapies leaving residual non-tumorigenic population of cells resulting in potential cancer cures. Gurdon first introduced the concept of stemness state of the cells while successfully achieving the generation of all cell lineages of a living tadpole after transferring the nuclei from intestinal epithelial cells of feeding Xenopus tadpoles to activated enucleated eggs ,2. TheseThe multipotency of stem cells to maintain tissue homeostasis and its differentiation into mature cell types is under a tightly controlled system and is associated with restricted expression profile. The expression of transport proteins \u2013 ABC (ATP-binding cassette) transporter proteins and multidrug resistant proteins that protect cells against toxins and are associated with the efflux of xenobiotic toxins, low rate of cell division and active DNA repair are the innate properties of normal development of stem cells. Besides hormonal stimulation, DNA damage is one of the key factors for stem cell activation. DNA accumulates errors either from environmental factors, which could be the exposure to radiation, chemicals or drugs, viruses and bacteria or DNA replication errors . This woCancer stem cells (CSCs) were first identified in 1990s in hematological malignancies, mainly acute myelogenous leukemia (AML) and also in other subtypes like AML M0, M1, M2, M4 and M5 and chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and multiple myeloma . CSCs arIn the hematopoietic and solid tumors side population (SP) containing CSCs constitute the fraction of total population of cells that shows that CSCs is a common phenomenon for all the malignancies. SP can be identified by the efflux of fluorescent dyes by ABC transporter proteins which are the major multidrug resistant genes. In the absence of DNA repair capacity, the drug resistant pluoripotent cells accumulate mutations and show increased cell survival .To maintain the genomic integrity and normal functioning of stem cells, several DNA repair pathways come into interplay and provide the robust defense to the cell. Absence of these repair processes have a great impact on the diminution of stem cells and increased chance for stem cell differentiation and malignant transformation due to altered gene expression.AGT repair is a DNA repair protein encoded by MGMT (O6-methylguanine DNA methyltransferase) removes DNA adducts from O6 methylguanine. The failure in the repair system results in G to A transition and DNA strand break observed in hematopoietic tumors, breast, ovarian and retinoblastomas ,14.In NER, the damaged DNA bases are recognized by XPC (xeroderma pigmentosum complementation group C) and RAD23B whereas XPA, RPA (replication protein A), RNA polymerase II transcription factor 11A and XPG excise the fragment of 27\u201330 nucleotides surrounding the damaged bases. The gap is further restored by DNA polymerases and ligases and replaces it with the correct sequence. Defective NER leads to xeroderma pigmentosum (skin cancer) .It comprises of short and long patch pathways where DNA glycosylases generate apurinic/apyrimidinic (AP) followed by its 5' excision by AP endonucleases (APE-1) and remove damaged bases. Double-stranded breaks have the potential to be the most disruptive form of DNA damage ,17.Double-stranded breaks have the potential to be the most disruptive form of DNA damage. The DNA double strand breaks (DSBs) produced by free radicals generated during oxidative respiration, ionizing radiation, DNA replication, malfunction of recombination activating gene complex during V(D)J  recombination in T and B lymphocytes are brought in closed proximity by Ku70-Ku80 heterodimer and kinase activity by DNA dependent protein kinase catalytic subunit (DNA-PKcs) of DNA-PK complex followed by its ligation by XRCC4-DNA ligase IV, SCID (Severe Combined Immunodeficiency) is associated with defective NHEJ repair system .The DSBs are repaired by misalignment, deletions, and rearrangement. ATM, a PI-3 Kinase binds DNA and phosphorylates multiple proteins. BRCA1 activated by ATM (ataxia telangiectasia) facilitates BRCA2 and RAD51 binding of the overhang followed by the attraction of RAD52/RAD54 with the help of BLM/WRN proteins. The homologous recombination is facilitated by large protein complexes at the DSBs. High incidence of leukemia, breast-ovarian, Werner's and Bloom's syndrome with severe premature aging and cancer is seen in defective HR repair system ,19.It is a genome surveillance system in bacteria, yeast and mammals by maintaining genomic integrity. The MMR pathway is the form of DNA repair responsible for the elimination of specific mismatched and/or unmatched bases and insertion-deletion loops (IDLs) where DNA synthesis is liable to errors, either as a part of DNA replication before cell division, or as part of DNA repair (unscheduled DNA synthesis) . AlthougMismatch in eukaryotic DNA is recognized by two heterodimeric complexes of Mut S related proteins \u2013 MSH2/GTBP (Mut S\u03b1) and MSH2/MSH3 (Mut S\u03b2) . Mut S\u03b1 Proliferating cell nuclear antigen (PCNA) has been identified as DNA polymerase processivity factor and has a role in repair at or prior to excision steps as a strand discriminating factor . Bi \u2013 diDNA exonuclease and helicase unwind, nick and degrade the error \u2013 containing strand. After dissociation of MMR complex, PCNA, which still binds at the end of error containing primer strand, recruits replication complex and thus re-initiation starts with the help of DNA polymerase.The mutations characterized by point mutations, insertions or deletions in the length of DNA microsatellite repeat sequences throughout the genome resulting in microsatellite instability (MSI) is a hallmark of defective DNA MMR system which result in malignant transformation .The maintenance of MMR system decreases the error rates by 100 to 1000 fold during DNA replication. Since it has tremendous importance in the carcinogenesis, this review presents a discussion on the role of DNA mismatch repair system as a therapeutic potential in eliminating the cancer stem cells.The maintenance and longevity of stem cell phenotype is characterized by the presence of efficient MMR system, which result in accurate DNA replication, restore normal DNA after its damage and remove replication defects at microsatellite sequences by repairing the DNA polymerase slippage products.-/- and Mlh2-/- phenotype, mice develop stem cell-derived-lymphoid malignancies and all lymphoid tumors show MSI [-/- primary murine hematopoietic cells with wild type into lethally irradiated mice with temozolomide, a methylating agent. MMR deficiency as evident by MSI was observed in early progenitor colony forming unit (CFU) and Sca+Kit+Lin- derived clones, which explain the alteration in growth and survival of hematopoietic stem cells and its long-term repopulation capacity because of accumulation of genomic instability [-/-, Msh2+/+, Msh2-/+ mouse embryonic stem cells following prolonged low level radiation treatment. The cells deficient in active MMR system survive promutagenic genomic insults by alkylating and oxidating agents that contribute to neoplastic transformation as in hereditary non-polyposis colorectal cancer (HNPCC) [The MMR deficiencies because of the mutations in wild type MMR allele with Msh2show MSI . The sertability . In anot (HNPCC) . The six (HNPCC) .The loss of MMR genes directly or indirectly alters signal pathways, loss of strictly regulated expression of cytokine receptors, transcription factors and cell cycle regulation . Unlike The mitotic homologous recombination can result in chromosomal translocations, deletions or inversions with deleterious consequences in the adult or during development. Loss of MMR adds up an additional level of genetic instability in a form of chromosomal rearrangements commonly observed in hematological malignancies. High incidence of lymphoma is reported in Msh2 deficient mouse embryonic stem cells .-/- mouse ES cells after exposure to temozolomide but not cisplatin and contributed to failed repair mechanism and apoptosis in a p53 dependent manner [The Msh2 low and deficient mouse ES cells showed poor or complete elimination of repair function and demonstrated the resistance against the toxic effects of an ethylating agent, N-ethyl-N-nitrosourea (ENU). The ENU-induced mutagenicity under the fully or partially deficient conditions accelerated the lymphomagenesis . Toft ett manner .-/- mouse embryonic stem cells showed two-fold resistance to the cytotoxic effects of cisplatin as compared to wild type cells [In a study by Fink et al., Msh2pe cells . On the pe cells . Howeverpe cells , increasIn most of the malignancies CSCs constitute less than 1% of total cell population. They are in quiescent state and most of the conventional chemotherapeutic drug therapies are effective in actively dividing cells, so for complete eradication of CSCs, the therapeutic agents either should kill cells independently of the cell cycle or selectively induce cycling of cancer cells. Moreover, therapy should target pathways uniquely used by CSCs. CSCs express various drug transporter proteins which efflux the cytotoxic drugs and protect them from damage. The inhibitors to these transporters make the CSCs sensitive to chemotherapy. Since normal stem cells also express some of these transporters so non selective inhibition of these multidrug resistant genes also kill normal stem cells. The characterization of stem cells markers would help in identification of CSCs from normal stem cells have important implications in elimination of CSCs by specifically targeting the tumor cells . Table 2The wild type MMR expression blocks the homologous recombination between the diverged DNA sequences throughout the genome and thus prevent the stem cell to accumulate further genetic instability. Hematological malignancies and lymphoma arise due to chromosomal rearrangements because of loss of MMR proteins . The effMost of the human cancers are identified having mismatch repair deficiency that result in defect in cell cycle and altered growth as in case of hematological malignancies. The defective MMR status in a damaged cell directly contributes to the resistant phenotype against the cytotoxic effects of chemotherapeutic drugs and thus these CSCs survive chemotherapy Fig . The actThe maintenance of genomic stability is the prime requirement for the stem cell phenotype and its normal functioning. The increased mutation rate and absence of MMR may give rise to stem cell failure, a proliferative advantage and cancer stem cells formation. The cancer stem cells having MMR deficiencies make them insensitive to the treatments against the cytotoxic agents and would increase the risk of relapse and metastasis. The importance of MMR in designing the therapeutic strategies specifically targeting the tumor cells is being explored and pursued in the clinical trials.The author(s) declare that they have no competing interests.The manuscript was written and finalized by the author."}
+{"text": "Ploidy and cell proliferation determined by flow cytometry were assessed on colorectal cancers from patients admitted to two Italian cancer research centres. A total of 181 patients were followed prospectively for 4 years at the Istituto Regina Elena (IRE) of Rome and at the Istituto Nazionale Tumori (INT) of Milan. Fresh (at the IRE) or frozen (at the INT) tumour material and similar procedures were used for subsequent sample preparation. Similar frequencies of aneuploid tumours (63% vs 66%) and superimposable median DNA indices (1.6) were observed for the two case series. In both series, DNA ploidy was generally unrelated to clinico-pathological factors, except for a higher frequency of aneuploid tumours in Dukes' D (88%) than in Dukes' A stage (33%) in the IRE experience. DNA ploidy was a weak prognostic indicator at 3 years but not at 4 years in the IRE case series, and it never exhibited a clinical relevance in the INT experience. Conversely, multiploidy was an indicator of worse relapse-free and overall survival at 4 years in the IRE and INT case series."}
+{"text": "Some environmental factors of possible aetiological importance for primary liver carcinoma (PLC) in males were analysed in a case-control study including 83 cases of hepatocellular carcinoma (HCC), 15 cases of intrahepatic cholangiocellular carcinoma (CC), 3 cases of haemangiosarcoma and 1 case of unspecified sarcoma in the liver--102 cases in total. Two matched controls were used in each case. One case with haemangiosarcoma was exposed to polyvinyl chloride. The case with unspecified soft-tissue sarcoma was exposed to phenoxy acids. A 4-fold increase in the risk of HCC was seen in alcoholics, and regular drinking gave a 3-fold increase in the risk. Exposure to organic solvents gave a 2-fold increase in the risk of HCC. No increased risk was observed for cases exposed to various other chemicals. Three cases of HCC had a previous diagnosis of porphyria acuta intermittens (PAI), versus no control. Six cases of HCC had a previous diagnosis of porphyria acuta intermittens (PAI), versus no control. Six cases with PLC had polyphyria cutanea tarda (PCT) which in 4 cases was related to alcoholism and in one case to haemochromatosis."}
+{"text": "Cervical intraepithelial neoplasia (CIN) grades I to III lesions (n = 94) and squamous cell carcinomas of the uterine cervix (n = 27) were analysed for MHC class I and II expression and presence of HPV genotypes. MHC class I and II expression was studied by immunohistochemistry and HPV typing was performed by general primer- and type-specific primer mediated PCR (GP/TS PCR). Both techniques were performed on paraffin embedded tissue sections. Results show disturbed MHC class I heavy chain expression in CIN I to CIN III, as well as in cervical carcinomas. Upregulated MHC class II expression on dysplastic epithelial cells was also found in the different CIN groups and carcinomas. Prevalence of HPV genotypes increased with the severity of the lesion, mainly due to the contribution of the HPV types 16 and 18. No correlation could be established between the presence of specific HPV genotypes and any MHC expression pattern in the different CIN groups or cervical carcinomas. In some cases these data were confirmed by RNA in situ hybridisation showing HPV 16 E7 transcripts in the same dysplastic/neoplastic cells from which MHC status was determined. The results indicate that local differences may exist in the type of cellular immune response to HPV induced lesions."}
+{"text": "Cremophor EL, a pharmacologically inactive solubilising agent, has been shown to reverse multidrug resistance (MDR). Using flow cytometric evaluation of equilibrium intracellular levels of daunorubicin (DNR), we found that eight other surface active agents will also reverse MDR. All the active detergents contain polyethoxylated moieties but have no similarities in their hydrophobic components. The properties of three polyethoxylated surfactants that showed the lowest toxicities, Cremophor, Tween 80 and Solutol HS15, were examined in more detail. The concentrations of Tween 80 and Solutol required to reverse DNR exclusion were 10-fold lower than for Cremophor. However while concentrations greater than or equal to 1:10(2) of the former two surfactants resulted in breakdown of cells, even 1:10 of Cremophor did not lyse cells. Studies of the effects of Cremophor on the uptake and efflux of DNR in normal and MDR cell types showed that Cremophor increases intracellular DNR primarily by locking the rapid efflux from the cells. This blockage of drug efflux may be mediated by a substantial alteration in the fluidity of cell membranes induced by Cremophor, as shown by decreased fluorescence anisotropy of a membrane probe. Consistent with these data, coinjection of adriamycin plus Cremophor into mice carrying a multidrug resistant P388 transplantable tumour significantly increased the survival time of the mice compared with adriamycin treatment alone."}
+{"text": "Human papillomavirus (HPV) typing and quantitation by polymerase chain reaction was performed on exfoliated cells from 133 women referred for colposcopy because of an abnormal smear. High levels of HPV 16 correctly predicted cervical intraepithelial neoplasia (CIN) grade II-III in 93% of its occurrences, but only 59% of cases of CIN III were associated with high levels of this type. Eighty-four per cent of CIN III lesions contained high levels of at least one of HPV types 16, 18, 31, 33 and 35, but the other types were less specific for CIN III than HPV 16. Overall HPV testing compared favourably with cytology for predicting high-grade CIN lesions, but it would appear that some combination of the two modalities will produce better performance than either alone. In particular, HPV testing appears to be helpful in determining which women with mildly abnormal smears have high-grade underlying lesions in need of immediate referral for colposcopy."}
+{"text": "The chemosensitising effect of the nitroaromatic radiosensitiser misonidazole (MISO) on the alkylating agent cyclophosphamide (CTX) has been investigated in a C3H mammary carcinoma in CDF1 mice. The selective cytotoxicity against aerobic and hypoxic cells was measured indirectly, using a local tumour control (TCD50) assay. The hypoxic fraction was calculated from the dose difference between the TCD50S for tumours irradiated either in air or under clamped conditions. The relative survival of tumour cells after drug therapy was expressed as a surviving fraction (SF). CTX (100 mg kg-1) was found to be considerably more toxic towards hypoxic than aerobic cells (SF 4% versus 52%). MISO (1000 mg kg-1) was almost exclusively toxic to hypoxic cells (SF 22%). When MISO and CTX were administered simultaneously a decrease in the surviving fraction was observed. The effect on aerated cells was found to be 10-fold more than expected from addition of toxicities, suggesting a chemosensitising effect on these cells by MISO when used in combination with CTX. No synergistic effect was found on radiobiologically hypoxic cells. The exact role of hypoxia for the development of chemosensitisation seems to be complex and requires additional research in the future."}
+{"text": "A large body of theoretical work suggests that analyses of variation at the maternally inherited mitochondrial (mt)DNA and the paternally inherited non-recombining portion of the Y chromosome (NRY) are a potentially powerful way to reveal the differing migratory histories of men and women across human societies. However, the few empirical studies comparing mtDNA and NRY variation and known patterns of sex-biased migration have produced conflicting results. Here we review some methodological reasons for these inconsistencies, and take them into account to provide an unbiased characterization of mtDNA and NRY variation in chimpanzees, one of the few mammalian taxa where males routinely remain in and females typically disperse from their natal groups. We show that patterns of mtDNA and NRY variation are more strongly contrasting in patrilocal chimpanzees compared with patrilocal human societies. The chimpanzee data we present here thus provide a valuable comparative benchmark of the patterns of mtDNA and NRY variation to be expected in a society with extremely female-biased dispersal. Human societies show significant variation in post-marital residence practices. About 70% of human societies practice some form of patrilocality, with men remaining in and women migrating from their natal household, clan, lineage, village, or other cultural unit subsumed within a larger group of people sharing a common culture and language, often termed a `trib\u00e9 in traditional societies One study of Hill tribes of northern Thailand showed the predicted differences between patrilocal and matrilocal tribes in patterns of mtDNA and NRY variation At least three factors may contribute to the discrepant findings of prior research comparing contemporary patterns of genetic variation and post-marital residence practices. First, analyses of mtDNA and NRY variation have been performed at a broader scale of social organization than that at which sex-biased migration actually takes place. For example, the different patterns of mtDNA and NRY diversity shown by matrilocal and patrilocal tribes in Thailand versus India may occur because only in Thailand do members of the migrating sex sometimes move out of their own tribe to join another. Migration outside the tribe is actually a rare event in traditional societies, as different tribes can have very different languages and cultures A second factor complicating attempts to compare patterns of mtDNA and NRY variation is that estimates of genetic differentiation between populations are sensitive to variables that reduce the level of within-group variation, with decreased variation resulting in larger genetic differentiation. For example, an early study of global genetic variation found that genetic differentiation among continents was larger for the NRY than the mtDNA Finally, a third possible reason for the contradictory findings of prior research is that we do not know for how long and how consistently each of the sampled societies has practiced their particular form of post-marital residence. One of the societies in the Central Asian study has practiced its contemporary form of post-marital residence for several centuries In contrast to the complex situation in human populations, patterns of sex-biased migration in animals are often well known from long-term behavioral observations. The currently available genetic studies of animal populations, however, furnish limited insights into how sex differences in migration affect mtDNA and NRY variation. Long-term behavioral observations indicate that migration out of bonobo groups is extremely female-biased Here we examine patterns of mtDNA and NRY variation in four groups of wild chimpanzees located in Uganda and separated by 10\u2013165 km. Chimpanzees live in communities consisting of 20\u2013150 individuals, and as a result of over 180 total years of human observation at multiple field sites, their migration patterns are well understood ST based genetic differentiation estimates, we use the recently developed standardized measure of genetic differentiation We compare the patterns of variation in chimpanzees with those inferred from published data on patrilocal human tribes belonging to five different larger cultural/geographic regions, hereafter termed \u2018tribal groups\u2019  P\u200a=\u200a0.008, two-tailed)  . Chimpanzees thus have reduced levels of NRY diversity relative to mtDNA diversity compared with patrilocal humans.We found that the average NRY haplotype diversity of the four chimpanzee communities  was significantly lower than that of the 20 patrilocal human tribes   . However-tailed) , suggestWe found extensive sharing of mtDNA variants among chimpanzee communities that strongly contrasted with complete community specificity of NRY haplotypes . In contStandardized genetic differentiation produced broadly similar results, with chimpanzees showing significantly larger standardized NRY genetic differentiation than three of five patrilocal human tribal groups . HoweverThe more similar standardized than unstandardized NRY/mtDNA genetic differentiation ratios between chimpanzees and patrilocal human tribal groups suggest that in addition to differences in the extent of female-biased migration, other factors which reduce NRY relative to mtDNA within-group variation have affected chimpanzees more strongly than the patrilocal human tribal groups. One possibility is that the effective population size of males relative to females may be smaller in chimpanzees than it is in humans. To test this hypothesis, we used parentage assignments in the chimpanzee communities and published human data sets to compare sex differences in effective population size in both species. We found that the ratio of male to female variance in lifetime reproductive success (LRS), an important factor influencing sex differences in effective population size, is actually similar in chimpanzees and in humans living in traditional societies . Taken tWhatever the reason for the discrepancy between unstandardized and standardized NRY/mtDNA genetic differentiation ratios, standardized NRY and mtDNA genetic differentiation were still more strongly contrasting in chimpanzees than in patrilocal human tribal groups. This suggests that migration is more female-biased between chimpanzee communities than between patrilocal human tribes within a tribal group. Additional analyses of patrilocal humans which are conducted on the scale over which sex-biased migration actually occurs, e.g., villages within a tribe rather than tribes within a tribal group, will be necessary to test this hypothesis. Alternatively, the recent history of patrilocality in most human populations may have prevented the build-up of such extremely contrasting patterns of mtDNA and NRY variation. For humans, the absence of higher NRY than mtDNA genetic differentiation at the continental and global scale may indicate that migration is not female-biased at these broad geographical distances www.ncbi.nlm.nih.gov) accession numbers for the chimpanzee mtDNA sequences are EU077270-EU077418. Supplementary We examined mtDNA and NRY variation in four communities of chimpanzees (number of mtDNA/NRY-chromosomes sampled in parentheses): the Sonso (28/16) community of Budongo Forest Reserve, the Ngogo (94/41) and Kanyawara (20/10) communities of Kibale National Park, and the Mugiri (7/6) community of Semliki National Park. We also analyzed previously published data from five patrilocal Dravidian tribes from India (Vanne (32/23), Pokanati (59/25), Panta (37/21), Kapu (22/16) and Akhutota (32/21)), five patrilocal Mundari tribes from India , Munda (23/23), Kharia (21/13), Bhumij (40/39) and Asur (30/28)), three patrilocal Hill tribes from Thailand (Akha (91/21), Chiang Rae Lisu (53/9) and Mae Hong Son Lisu (42/22)), four patrilocal tribes from the lowlands of Western New Guinea (Awyu (12/10), Citak (40/28), Mappi (18/10) and Muyu (10/6)), and three patrilocal tribes from the highlands of Western New Guinea (Dani (21/12), Ketengeban (22/19) and Una (51/46). Subjects were sequenced at the first hypervariable control region of the mtDNA and genotyped at microsatellite loci on the NRY. The chimpanzees were sequenced at 473 bases and genotyped at 9 microsatellite loci following procedures described elsewhere U tests to compare average mtDNA haplotype diversity, NRY haplotype diversity, and the ratio of NRY/mtDNA haplotype diversity between the chimpanzee communities (N\u200a=\u200a4) and the patrilocal human tribes (N\u200a=\u200a20).We used Arlequin 3.10 Unstandardized genetic differentiation was calculated in an AMOVA framework, with the number of different alleles used as the distance metric for both mtDNA and NRY. We examined the overlap in the 95% confidence limits generated by bootstrapping genetic differentiation values in a locus-by-locus AMOVA to evaluate whether (a) genetic differentiation between the chimpanzees and each of the five patrilocal human tribal groups were significantly different and (b) genetic differentiation of NRY and mtDNA were significantly different within chimpanzees and patrilocal human tribal groups.a and b at a locus, in one of the populations these alleles were recoded as c and d), and calculated an AMOVA FST for this transformed data set . This transformation does not affect within-population variation, but maximizes between-population variation. We then calculated standardized genetic differentiation by dividing the original unstandardized AMOVA FST by the AMOVA FST obtained for this transformed dataset. We included only variable loci when calculating both unstandardized and standardized genetic differentiation. The inclusion or exclusion of non-variable loci does not affect the unstandardized AMOVA, but including non-variable loci when calculating the AMOVA for the transformed data set results in AMOVA values that are determined more by the ratio of variable to non-variable sites, and less by the levels of variability of the variable loci. This would push maximum genetic differentiation possible towards 1, and result in standardized genetic differentiation values that are nearly identical to their unstandardized counterparts. To determine 95% confidence intervals for the standardized genetic differentiation, we divided the lower 95% confidence limit of the original unstandardized genetic differentiation value by the upper 95% confidence limit of the transformed genetic differentiation, and divided the upper 95% confidence limit of the original unstandardized genetic differentiation by the lower 95% confidence limit of the transformed genetic differentiation. For all tests, loci had to have less than 5% missing data to be included in calculations.To calculate standardized genetic differentiation, we first transformed the data such that each population had its own set of unique alleles  and females (IF). IM and IF are commonly used to estimate variance in lifetime reproductive success when the sampling of male and female reproductive output is incomplete and the data indicate the sexes have different mean lifetime reproductive success, when in reality they must be equal To estimate variance in lifetime reproductive success, we calculated the variance in the number of offspring divided by the square of the mean number of offspring, for both males Click here for additional data file."}
+{"text": "A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free."}
+{"text": "The past ten years parallels have been drawn between the biology of cancer and pulmonary fibrosis. The unremitting recruitment and maintenance of the altered fibroblast phenotype with generation and proliferation of immortal myofibroblasts is reminiscent with the transformation of cancer cells. A hallmark of tumorigenesis is the production of new blood vessels to facilitate tumor growth and mediate organ-specific metastases. On the other hand several chronic fibroproliferative disorders including fibrotic lung diseases are associated with aberrant angiogenesis. Angiogenesis, the process of new blood vessel formation is under strict regulation determined by a dual, yet opposing balance of angiogenic and angiostatic factors that promote or inhibit neovascularization, respectively. While numerous studies have examined so far the interplay between aberrant vascular and matrix remodeling the relative role of angiogenesis in the initiation and/or progression of the fibrotic cascade still remains elusive and controversial. The current article reviews data concerning the pathogenetic role of angiogenesis in the most prevalent and studied members of ILD disease-group such as IIPs and sarcoidosis, presents some of the future perspectives and formulates questions for potential further research. The interstitial lung diseases (ILDs) are a heterogeneous group of diffuse parenchymal lung diseases comprising different clinical and histopathological entities that have been broadly classified into several categories ,2 includThe scope of this review article is to summarize the current state of knowledge regarding angiogenic and angiostatic activity in the most important and prevalent members of ILD disease-group such as IIPs and sarcoidosis, discuss its pathogenetic role and present some of the future perspectives and limitations based on authors' assessment or originated from the statements of original authors.de novo formation of blood vessels from angioblasts or endothelial progenitor cells, process that mostly occurs during embryogenesis [Angiogenesis is the process of new capillary blood vessels growth and is instrumental under both physiologic and pathologic conditions. Physiologic conditions include embryogenesis, growth, tissue repair after injury and the female reproductive cycle whereas pathologic angiogenesis can occur in chronic inflammatory and fibroproliferative disorders and tumorigenesis of cancer. Angiogenesis is similar to but distinct from vasculogenesis which describes the ogenesis . On the 2-terminus a three amino-acid motif (ELR) such as IL-8/CXCL8, epithelial neutrophil activating protein (ENA)-78/CXCL5, growth-related genes , granulocyte chemotactic protein (GCP)-2/CXCL6 and neutrophil activating protein (NAP)-2/CXCL7, originally promote angiogenesis [Molecules that originally promote angiogenesis include members of the CXC chemokine family, characteristically heparin binding proteins which on structural level have four highly conserved cysteine amino acid residues, with the first two cysteines separated by one nonconserved amino acid residue. CXC chemokines display unique diverse roles in the regulation of angiogenesis resulting from dissimilarity in structure. Therefore, members that contain in the NHogenesis ,12. Therogenesis ,12. Anotogenesis ,14. Its ogenesis . Finallyogenesis . In addiogenesis -19.By contrast, other members of the CXC chemokine family that do not contain the angiogenic ELR motif (ELR-) behave as potent inhibitors of angiogenesis. Platelet factor-4 (PF-4)/CXCL4 was the first chemokine described to inhibit aberrant angiogenesis. Furthermore, the angiostatic ELR- members of the CXC chemokine family include the interferon (IFN)-\u03b3 inducible protein (IP)-10/CXCL10, monokine induced by IFN-\u03b3 (MIG)-2 and IFN-\u03b3-inducible T-cell a chemoattractant (ITAC)/CXCL11 . The latSeveral transcription factors play instrumental role in promoting angiogenesis and sensing the environmental cues that drive this process. Strieter et al.  identifiThe past ten years parallels have been drawn between the biology of cancer and pulmonary fibrosis. The unremitting recruitment and maintenance of the altered fibroblast phenotype with generation and proliferation of immortal myofibroblasts is reminiscent with the transformation of cancer cells -37. A haThere is increasing evidence supporting the notion that vascular remodeling in fibroproliferative disorders appears to be regulated by an imbalance between angiogenic and angiostatic factors. Seminal observation implicating angiogenic activity as an important aspect of progressive fibrosis was originally made by Turner-Warwick in 1963, when she demonstrated the presence of anastomoses between the systemic and pulmonary microvasculature in lungs of patients with IPF . DespiteKeane and colleagues were the first addressing this crucial issue. They demonstrated increased angiogenic activity in a large number of IPF lung specimens ,42 and sOriginal attempt to prove an association between abnormal vasculature and regional heterogeneity characterizing IPF was performed by Renzoni and coworkers . Fueled Lappi-Blanco et al. addressed this crucial issue ,54. TheyThere is a great lack of knowledge regarding this issue which has been largely ignored. Renzoni et al.  were theTowards this direction, Simler et al.  performeA second attempt to correlate local and systemic expression of angiogenic mediators with clinical biomarkers of disease severity and activity was recently published by Pignatti et al . They inFinally, Strieter et al.  recentlyThe vascular remodeling phenomenon has been also described in the experimental model of bleomycin-induced pulmonary fibrosis. The role of neovascularization during the pathogenesis of experimental pulmonary fibrosis was originally raised by Peao and coworkers . In lineFueled by the prospect that anti-angiogenic treatment could be beneficial for pulmonary fibrosis, Hamada et al.  tested tThe latter results have clear therapeutic implications since inhibition of angiogenic mediators or administration of angiostatic chemokines reduced lung collagen deposition and attenuated the exaggerated matrix remodeling. On the basis of this concept, neutralization of proangiogenic environment should be pursued. However, the latter statement should be treated with caution for the following reasons: 1) Findings derived from the bleomycin model of pulmonary fibrosis may not be applicable to human disease since pathogenetic components seen in bleomycin-induced pulmonary fibrosis do not demonstrate areas compatible with fibroblastic foci, the leading edge of human fibrosis. In addition, there are clear limitations to this model in terms of its self-limiting nature, the rapidity of its development and the close association with inflammation that accompanies the lung injury . Regardi2 terminus. While CXCR3/CXCR3 ligands inhibit angiogenesis, CXCR3 ligands play a pivotal role in orchestrating Th1 cytokine-induced cell-mediated immunity via the recruitment of mononuclear and CD4+ T-cells expressing CXCR3 and consequently via the granuloma formation (1). So far, there are only few studies in the literature implicating angiogenesis in the immunomodulatory cascade of sarcoidosis and correlating its immunopathogenesis with members of the angiostatic group of CXC chemokines. These studies are discussed in the following lines.Recent immunological advances on sarcoidosis have revealed a T helper 1 (Th1) and T helper 2 (Th2) paradigm with predominance of the Th1 response in its immunopathogenesis ,68. The The concept of disparate activity of the IFN-\u03b3-induced CXC chemokines in the context of Th1-like immune disorders, such as sarcoidosis, was originally raised by Agostini et al.  who docuThe aforementioned studies substantiate the assertion that IFN-\u03b3-induced CXC chemokines are strongly involved in the immunomodulatory cascade of sarcoidosis implicating angiostasis with Th1 immune response. However, there are several arguments that should be addressed. The majority of the studies cited above have investigated the ability of CXCR3 ligands to promote Th1-dependent immunity and not to inhibit angiogenesis. Studies have shown that angiostatic CXC chemokines are more likely to contribute to the granuloma formation through their chemotactic rather than angiostatic properties. The contention of \"immunoangiostasis\" (promotion of Th1 response and at the same time inhibition of angiogenesis) as it has been coined out by Strieter et al.  may possIIPs are a heterogeneous group of diffuse parenchymal disorders resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis. On the other hand several patients with sarcoidosis develop irreversible lung damage and pulmonary fibrosis which culminates to a fatal outcome. Several theories and mechanisms have been delineated regarding the pathogenesis of fibrotic lung disorders. Recent evidence support the concept that inflammation is subsequent to injury and that fibrosis occurs as a polarization of the Th2 immune response of the body to repeated injury to the lung (\"multiple hits\" hypothesis) ,73.Putting the aforementioned data together, we tentatively present the three current theories regarding the role of aberrant vascular remodeling in the fibrogenic process. The first hypothesis is based on the idea that the hypervascularity observed in the least fibrotic areas has a role in the regeneration of the alveolar septa damaged by the fibrotic process and is a compensatory response to the decreased vascularity seen within the fibroblastic foci Figure . In thisAlternative hypothesis regarding the role of vascular remodeling during the process of ECM remodeling has also emerged. This theory supports the premise that newly formed microvessels enhance the exaggerated and dysregulated ECM deposition, support fibroproliferation and inhibit normal epithelial repair mechanisms . Human ,52 and aThe third theory supports the notion that the role of angiogenesis in the pathologic process of pulmonary fibrosis is overestimated and that aberrant vascular remodeling is just a bystander or a consequence of fibrogenesis. The latter idea is based on the assertion that CXC chemokines may exert their anti-fibrotic activities through pathogenetic pathways different from those of angiogenesis . The afoBased on the above data we can state that although several study groups have investigated aberrant vascular remodeling in the pathogenesis of pulmonary fibrosis, the relative roles played by new vessel formation and vascular regression in IPF and subsequently in other fibrotic lung disorders are still elusive and controversial. However, to address this issue further investigation in the context of large prospective multicenter studies using highly standardized techniques is sorely needed. The emergence of massive genome screening tools (DNA microarrays)  coupled Several lines of research have been proven inadequate to demystify the relative role of angiogenesis in the etiopathogenesis of chronic fibroproliferative disorders. The question originally raised still remains unanswered: \"A pathogenetic hallmark of just a bystander?\" However, the status of knowledge regarding the contribution of newly formed vessels in the initiation and/or progression of the sequential events of abnormal injurious response, paradoxical apoptosis and exaggerated matrix remodeling has been greatly elevated by several studies. So far, a number of investigations give credence to the view that a chemokine imbalance favoring angiogenesis supports fibroproliferation and inhibits normal repair mechanisms. Alternatively, the regional vascular heterogeneity in IPF can be explained as a compensatory response (vascular regression) to the striking hypovascularity described in areas of active fibrosis. Currently, angiogenesis represents one of the most fruitful applications in the therapeutic minefield of fibrotic lung disorders. The lack of an effective treatment option challenges chest physicians to think beyond conventional therapeutic strategies and apply fresh approaches. Blockage of multiple angiogenic mediators may provide a way forward. Whether our hopes will be fulfilled or disproved remains to be seen.Basic fibroblast growth factor (bFGF)Bronchiolitis obliterans-organizing pneumonia (BOOP)Bronchiolitis obliterans syndrome (BOS)Cryptogenic organizing pneumonia (COP)Epithelial neutrophil activating protein (ENA)-78Extracellular matrix (ECM)Farmer's lung disease (FLD)Granulocyte chemotactic protein (GCP)Growth-related genes (GROs)Hypoxia inducible factor-1a (HIF-1a)High resolution computed tomography (HRCT)Idiopathic pulmonary fibrosis (IPF)Interferon-\u03b3 (IFN-\u03b3)(IFN)-\u03b3 inducible protein (IP)-10(IFN)-\u03b3 inducible T cell-a chemoattractant (ITAC)Idiopathic interstitial pneumonias (IIPs)Interstitial lung diseases (ILDs)Matrix metalloproteinases (MMPs)Macrophage inflammatory protein (MIP)-2Monokine induced by IFN-\u03b3 (MIG)-2Natural killer (NK) cellsNeutrophil activating protein (NAP)-2Nuclear factor-\u03baB (NF-\u03baB)Non-specific interstitial pneumonia (NSIP)Platelet factor-4 (PF-4)Pigment epithelium-derived factor (PEDF)Systemic sclerosis (SSc)Usual interstitial pneumonia (UIP)Vascular endothelial growth factor (VEGF)von Willebrand factor (VWF)The author(s) declare that they have no competing interests.AT and DB were involved with the study conception. AT and SA performed the data acquisition and interpretation. AT prepared the manuscript. DB was involved in revising the article for important intellectual content. All authors read and approved the final manuscript."}
+{"text": "The effects of the major human serum bile acid, glycochenodeoxycholic acid (GCDC), as well as unconjugated chenodeoxycholic acid (CDC), on the MCF-7 human breast cancer cell line have been studied in vitro under oestrogen and bile acid deprived culture conditions. GCDC increased the growth of the breast cancer cells over the range 10-300 microM. At concentrations in excess of the bile acid binding capacity of the medium cell growth was prevented. In contrast 10 microM CDC tended to reduce cell growth. Oestrogen (ER) and progesterone (PgR) receptors, pS2 and total cathepsin D were quantified by monoclonal antibody based immunoassays. Ten to 100 microM GCDC and 10 microM CDC down-regulated ER protein and this was accompanied by induction of the oestrogen-regulated proteins PgR, pS2 and possibly cathepsin D, including increased secretion of the latter two proteins into the culture medium. All these changes were quantitatively similar to those observed with 10 nM oestradiol. The bile acid effects on ER and PgR were not due to interference with the assay procedures. Cells incubated with 50 microM GCDC or 10 microM CDC had higher pmolar concentrations of the bile acids than controls. This study suggests that naturally occurring bile acids influence the growth and steroid receptor function of human breast cancer cells."}
+{"text": "Somatostatin (SMS), a naturally occurring peptide is known to inhibit the production of certain protein molecules and to diminish the ability of peripheral blood mononuclear cells to proliferate. We tested the effects of three forms of SMS on the bioactivity of both lymphotoxin (LT) and tumour necrosis factor (TNF). We also tested the effects of these agents on production of cytotoxins by peripheral blood mononuclear cells. We found the 28 amino acid form of SMS significantly enhanced the bioactivity of both LT and TNF (10(-9) M concentration) when tested in mouse L cells. The 14 amino acid form of SMS enhanced LT (10(-9) M concentration) activity but not TNF activity. The first 14 amino acid form of SMS-28  did not affect bioactivity of the cytotoxin. In contrast, the naturally occurring 14 amino acid form of SMS (10(-8) M concentration) significantly diminished production of cytotoxin by human peripheral blood mononuclear cells. Cytotoxin produced by the latter was shown to be a combination of both LT and TNF. Similarly after SMS exposure, the cytotoxin produced remained a mixture of LT and TNF in roughly similar proportions. It thus appears that certain forms of SMS can enhance the bioactivity of cytotoxins, but at the same time decrease the production of these cytotoxins."}
+{"text": "Alterations in the p53 gene were analysed in 39 patients with locally advanced breast cancers (LABCs) (stage III-IV) with inflammatory signs in most cases (UICC stage T4d = 32 patients) by molecular and immunohistochemical (IHC) approaches. All patients were included in the same therapy protocol. Using polymerase chain reaction (PCR) and a single-strand conformational polymorphism migration technique (SSCP), the presence of mutations in exons 2-11, covering the entire coding sequence of the p53 gene, was evaluated. Using the mouse specific anti-human p53 monoclonal antibody (PAb 1801), we also looked for overexpression of the p53 protein in tissue sections. In 16 cases shifted bands were reproducibly identified by PCR-SSCP, and all but one  were in exons 5-8, the usual mutational hotspots. Fifteen of these 16 samples were sequenced and 14 of the suspected mutations (36%) were confirmed. Most of them (12) were single nucleotide substitutions, and transitions were more frequent (eight cases) than transversions (four cases). Fourteen of the tumour samples were positively stained with the monoclonal antibody PAb 1801, 11 with nuclear staining only, two with mixed cytoplasmic and nuclear staining and one with cytoplasmic staining only. Staining patterns were very heterogeneous in terms of the percentage of positive cells (10-75%) and their distribution in the tissue section (isolated foci or dispersed cells). In 11 of the 14 mutated cases a positive immunostaining was observed. The presence of a p53 mutation was significantly associated with larger tumour diameter  and the presence of clinical metastases (stage IV) . A non-statistically significant trend of association was observed between p53 mutation, negative oestrogen receptors and lower response rate to therapy. Our results in this group of patients and the heterogeneity of the staining of tumour cells in tissue sections suggest that p53 mutations could be a late event in this non-familial form of breast cancer."}
+{"text": "We have investigated the capability of differentiation of Ewing's sarcoma (ES) towards a neuronal direction through the establishment of four extraosseous ES cell lines and by in vitro stimulation with dibutyryladenosine cyclic monophosphate (db-cAMP) of eight ES lines. All except one of the lines expressed the molecule defined by 5C11, the antibody specifically reactive with ES. Two ES lines expressed a 200 kilodalton (kD) neurofilament protein (NFP) although their original tumours were negative for NFP. Elongation of cytoplasmic processes and increased NFP expression were observed after db-cAMP treatment of these lines and microtubules in the cytoplasmic processes were ultrastructurally demonstrated. Six lines were NFP negative, but three lines changed their morphology after induction of 200 kD NFP expression by db-cAMP treatment. The other three showed no definitive differentiation after db-cAMP treatment. Chromosomal analysis of the new ES lines showed the typical t in one line and a +der(22) in two lines. No correlation was observed between the chromosomal abnormality and the differentiation capability. We conclude that ES is a heterogeneous group of tumours with respect to capability of differentiation into the neuronal lineage, but it is clearly distinguished from peripheral primitive neuroectodermal tumours by its 5C11 reactivity."}
+{"text": "We report the natural killer (NK) and lymphokine activated killer (LAK) cell activities in peripheral blood lymphocytes (PBL) from untreated patients with Hodgkin's disease (HD) and from healthy donors. The frequency of LAK cell precursors was also studied using limiting dilution analysis (LDA). About 75% of the HD patients had normal NK activity. There was a higher percentage of low NK responders  in patients with lymphocyte depletion histologic grade of the disease and those who were in clinical stage IV, suggesting a correlation of decrease in NK activity with poor prognosis. We found efficient LAK activity against the NK-sensitive K562 cells and NK-resistant VIP (melanoma) and T-24 (bladder carcinoma) tumour targets in both low and normal NK responder HD patients, irrespective of the histopathological grade and clinical stage of the disease. In concordance with their good LAK cell activity, HD patients showed a frequency distribution of LAK cell progenitors in the PBL comparable to that of healthy donors."}
+{"text": "Intra-tumoural heterogeneity of proliferation has been assessed by taking multiple biopsies from 30 colorectal cancers. Following in vivo IUDR labelling, dual parameter flow cytometry was used to measure tumour DNA index (DI) and labelling index (LI) and to derive DNA synthesis time (Ts) and potential doubling time (Tpot). Heterogeneity was seen for all parameters under investigation. Overall coefficients of variation (CV) and logarithmic transformation of Ts and Tpot (due to their non-gaussian distributions) indicate that LI (CV 25%) was the most variable parameter. Intra-tumoral heterogeneity in Tpot (lnTpot CV = 22%) was less than inter-individual variation (CV = 63%), suggesting that this variation should not be a limitation to the possible usefulness of this technique as an independent prognostic indicator. Correlations of Tpot values were examined between the shortest, the median and the value for a pooled homogenate sample from a single tumour. Using an homogenate, it was possible to accurately predict classification of tumour Tpot values as being below the median ('fast tumours') in 15 of 19 cases (79%). The data suggest that assaying an homogenate may allow a more rapid analysis of a multiply sampled tumour."}
+{"text": "The reactivity of murine monoclonal antibodies (McAbs) directed against the monomorphic determinants of Class I and Class II antigens of the major histocompatibility complex (MHC), and against antigens expressed by discrete populations of leucocytes was studied using the indirect immunoperoxidase technique on serial tissue sections of 16 benign and 17 malignant primary human breast tumours. Class I antigens (detected by the McAb 2A1) were consistently associated with stromal leucocytes, fibroblasts and vascular endothelium, but expression on epithelial cells particularly of malignant provenance, was more variable. Class II antigens (detected by TDR 31.1) were present upon a variety of cell types which also included sporadic expression on malignant and benign epithelia. The distribution of leucocytes grossly monitored with 2D1 (reactive with a common leucocyte antigen) was largely interepithelial and periductal in benign lesions. Leucocytes were generally more numerous in malignant tumours, where they were largely confined to the stroma. The majority (approximately 75%) of leucocytes were T lymphocytes (reactive with UCHT1), some of which appeared to react with TDR 31.1 and were therefore activated. Ratios of helper/inducer (OKT4+) and suppressor/cytotoxic (OKT8+) subsets generally exceeded unity in malignant neoplasms. There was no correlation between the extent and distribution of T cells and the HLA status of the epithelial cells. Leucocytes detected by the monoclonal antibody OKM1 which reacts with monocytes/macrophages, granulocytes and large granular lymphocytes were numerically few and again mainly confined to the stroma. In a limited number of tests, leucocytes detected with HNKl, reactive with a differentiation antigen expressed on some cells which mediate natural and antibody-dependent cellular cytotoxicity in vitro although detectable interepithelially in benign tumours, were virtually absent from malignant tissue. HNK1 also cross-reacted with myoepithelial cells in the ducts of benign lesions."}
+{"text": "Small cell bronchial carcinoma (SCC) xenografts with differing sensitivity to cyclophosphamide (CY) were investigated using a variety of techniques. Two xenografts (HX78 and HX88) were relatively sensitive to CY, one xenograft (HX72) was inherently resistant to CY and a fourth xenograft (HX78Cy) was a CY induced resistant subline of HX78 and was unstable when maintained without CY exposure. Conventional light microscopy, cytology and electron microscopy examination of the xenografts revealed appearances consistent with SCC. An antikeratin antibody demonstrated the presence of keratin in the inherent and the induced resistant xenografts (and in the unstable revertant) but not in the two sensitive xenografts; the presence of keratin suggested squamous differentiation. Monolayer culture morphology of the sensitive HX78 and the unstable revertant was anchorage independent with the cells forming floating aggregates; the induced resistant subline of this xenograft (HX78Cy) showed, by contrast, flattened, angular adherent cells. Beta HCG production was detected in the monolayer culture supernatant of sensitive HX78 cells; the level of production of beta HCG was increased in the induced resistant HX78Cy cells. Karyotype and flow cytometry studies were also performed. The morphological responses of small cell lung cancer to treatment are discussed."}
+{"text": "We have examined the incidence of Harvey ras mutations in human squamous cell carcinomas (SCC) of the upper aerodigestive tract using the polymerase chain reaction (PCR) followed by direct sequencing. No mutations were detected at codons 12, 13, 59 or 61 of this gene in any of six papillomas, five erythroplakias, 56 squamous cell carcinomas, and 16 SCC cell lines. Some of the SCC were lymph node metastases (three) or tumours which had recurred following radiotherapy (seven). We conclude that Harvey ras mutations are not a common event in the pathogenesis or recurrence of SCCs from Caucasian subjects, in contrast to the situation with Indian populations ."}
+{"text": "We have examined two new oestrogen receptor (ER) assays--an enzyme immunoassay (EIA) and an immunocytochemical assay (ICA) in a large series of primary breast tumours to compare their potential as predictors of (1) response to endocrine therapy and (2) survival in patients developing advanced breast cancer. Response to endocrine therapy was categorised at 6 months (UICC criteria). ER-ICA appears the better predictor of response to endocrine therapy than ER-EIA. Combining ICA and EIA results did not improve the prediction of response. With both assays patients with ER positive tumours survived longer from the time of diagnosis of advanced disease than those with ER negative tumours. The predictive power of these assay for progression of disease appears slightly better for the ER-ICA."}
+{"text": "To evaluate the association between mood and anxiety disorders in Hashimoto disease and Euthyroid Goitre in a case control study.Cases included 19 subjects with Hashimoto disease in euthyroid phase, 19 subjects with euthyroid goitre, 2 control groups each of 76 subjects matched (4/1) according to age and sex drawn from the data base of a community based sample. Psychiatric diagnoses were formulated using the International Composite Diagnostic Interview Simplified, according to DSM-IV criteria. All subjects underwent a complete thyroid evaluation including physical examination, thyroid echography and measure of serum free T4 (FT4), free T3 (FT3), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase autoantibodies (anti-TPO). Results: Subjects with Hashimoto disease showed higher frequencies of lifetime Depressive Episode , Generalized Anxiety Disorders  and Social Phobia  whilst no differences were found between subjects with goitre and controls.The study seems to confirm that risk for depressive disorders in subjects with thyroiditis is independent of the thyroid function detected by routine tests and indicates that not only mood but also anxiety disorders may be associated with Hashimoto disease. Clinical and epidemiological studies seem to indicate that an association between high levels of thyroid autoantibodies may be implicated in the increased frequencies of mood disorders observed in thyroid disease, independently of impairment of thyroid function -3. A stuThe aim of the present study was to compare 2 clinical samples of subjects, one with Hashimoto disease (in euthyroid phase) and the second with euthyroid goitre versus controls drown from a community sample, in order to clarify whether the association of mood and anxiety disorder in Hashimoto disease is evident prior to impairment of thyroid dysfunction.Cases: 19 subjects, 18 females, mean age 39.7+/-12.6, with Hashimoto disease in euthyroid phase and 19 subjects, 16 females, mean age 38.1+/-10.4, with euthyroid goitre, all of whom were attending the Endocrinological Unit of the Department of Internal Medicine, University of Cagliari, Italy.Two control groups, each of 76 subjects aged 18\u201364 years, were obtained by matching each \"case\" with four \"controls\" randomly selected on the basis of demographic characteristics (sex and age) from the data base of a larger population enrolled during a previous epidemiological study aimed at defining the prevalence of psychiatric  and thyrTwo standardized forms were used to acquire information concerning: demographic data, state of health and use of social and health services. Psychiatric diagnosis was made using the Italian Simplified version of the Composite International Diagnostic Interview (CIDIS) . The comAll subjects underwent a complete thyroid evaluation including physical examination, thyroid echography and measure of serum free T4 (FT4), free T3 (FT3), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase autoantibodies (anti-TPO). FT4 and FT3 were measured by means of a chromatographic method based on separation of free T4 on Lisophase columns ; TSH was measured by a chemiluminescent method  with normal values ranging from 0.3\u20133.0 \u03bcU/ml. Thyroid echography was performed using a \"real time\" echograph , Generalized Anxiety Disorders , Social Phobia  and Primary Sleep Disorders ; a tendency towards an increased frequency of Panic Disorder was observed, although statistical significance was not reached . No differences were found in the evaluation of lifetime prevalence of DSM-IV Psychiatric Disorders between patients with Euthyroid goitre and controls (Table 1).This study seems to indicate an association between the presence of a lifetime diagnosis of mood or anxiety disorder and Hashimoto disease without functional thyroid impairment. No difference was observed in mood and anxiety disorders between goitre cases and controls.These findings are congruent with the results of a previous study  that indThe above-cited community survey found that subjects with at least one lifetime diagnosis of anxiety disorders presented anti-TPO+ more frequently than subjects without mood or anxiety disorders. However, no specific anxiety diagnosis was found to be associated with anti-TPO+, although General Anxiety Disorder showed a strong trend toward association (P < 0.058). Anxiety Disorder Not Otherwise Specified was more frequently observed with anti-TPO+, but this is only a sub-threshold condition. A previous research carried out on celiac patients indicated thyroid autoimmunity as possible risk factor for panic disorder . In the Indeed, these 3 surveys seem to indicate a congruent trend of possible risk for anxiety disorders such Generalized Anxiety Disorder, Social Phobia and Panic Disorder in Hashimoto Disease.To our knowledge, the data concerning the association between sleep disorders and Hashimoto disease is the first such evidence published in literature, although it may be consistent with a dysregulation of sleep architecture in subjects with sub-clinical thyroid impairment .A sub-clinical dysfunction of axis thyrotropin releasing hormone (TRH) thyroid stimulating hormone (TSH) with consequent alteration of circadian rhythms of TSH has been hypothesized in several depressive disorders. Indeed, this hypothesis may explain why some forms of mood disorders were associated with anti-TPO+ without hypothyroidism, as defined by blood routine tests. A slight reduction in thyroid hormone secretion such as that found in sub-clinical hypothyroidism may affect cognition and mood . At variAlternatively, autoimmunity may be implicated in some form of extra-thyroid disease associated (even indirectly) with the depressive symptomatology.In Hashimoto disease the onset of vasculitis is frequently observed and would seem to be directly correlated to the duration of the illness .In this disease brain perfusion modifications would appear to be of an aspecific nature; recently however, Spect examination revealed a marked compromising of the left cingulum posterioris, thus related in the etiology of associated affective disorders .Recent evidence suggests that thyroid autoimmunity may be affected by the Hypothalamic-pituitary-adrenal axis (HPA) through the balance of proinflammatory and antiinflammatory cytokines ,16. In lThe potential of this study is limited by the small sample size, particularly regard to psychiatric diagnoses less frequently observed in the general population, such as Panic Disorder; the extension of the findings is therefore rather limited.This study seems to indicate an association between the presence of a lifetime diagnosis of mood or anxiety disorder and sleep disturbance and anti-TPO+. The findings obtained suggest the need for further longitudinal studies aimed at clarifying the association between anxiety and depressive disorders and anti-TPO+."}
+{"text": "The prognostic role of drug-induced amenorrhea (DIA) was restrospectively evaluated in 221 out of 254 consecutive premenopausal patients treated with adjuvant CMF or a CMF-containing regimen; 33 patients were eliminated because of lack of menstrual data. All patients had metastatic axillary nodes; drug regimens were: CMF x 9 courses +/- Tamoxifen (TM) and CMF x 6 courses; median age was 43 (range 26-54). Premenopausal status was defined as last normal menses within the 6 weeks preceding initiation of chemotherapy: DIA as cessation of menses for at least 3 months not later than 3 months from the end of chemotherapy. DIA occurred in 166,221 (75.1%) patients and was strictly related to the age of the patients; also, the older the patients the shorter the time required to develop DIA. At median follow up of 69 months, Mantel-Byar analysis showed a longer disease free survival (DFS) for patients who developed DIA as compared with non amenorrheic women (P less than 0.001). DIA prognostic value was independent of age, number of involved nodes, tumour size and number of CMF cycles, as assessed by the Cox model , in which DIA was entered as a time dependent covariate."}
+{"text": "Nuclear deoxyribonucleic acid (DNA) content of hepatocellular carcinoma (HCC) in 41 South African and 47 Japanese patients at autopsy was analysed by dual-wavelength microspectrophotometry. The DNA distribution patterns were classified as type I, II, III or IV and as low ploidy  or high ploidy , according to the degree of dispersion. We found a significantly higher incidence of high ploidy in South African HCC than in Japanese HCC. Moreover, type IV was significantly more frequent among South Africans than among the Japanese. These findings demonstrate that large differences in biological characteristics and clinical behaviour of HCC between South Africa and Japan may reflect differences in DNA distribution patterns which we observed between these two races."}
+{"text": "The cell kinetics of 82 squamous cell carcinomas of the head and neck were studied by in vivo administration of the thymidine analogue, bromodeoxyuridine (BrdUrd). Ploidy, BrdUrd labelling index (LI), duration of S-phase (Ts), potential doubling time (Tpot) and S-phase fraction (SPF) were measured by flow cytometry on 50 microns paraffin embedded sections. The range of values obtained compared well with other in vivo cell kinetic studies of head and neck cancer. Aneuploid tumours had a significantly higher BrdUrd labelling index and SPF, and a short Tpot than diploid tumours. To validate the use of 50 microns sections for measuring cell kinetic parameters by flow cytometry a comparison of values obtained by 50 microns sections and small blocks of tissue was made. No significant difference was found between the two methods. Reproducibility of values between two consecutive thick sections was also good. We conclude that reproducible cell kinetic measurements can be made in tumour samples using 50 microns sections of BrdUrd labelled tissue."}
+{"text": "This study was designed to compare two different modalities of TBI which are currently used in clinical practice. The same dose of 750 cGy was given to CBA mice either in a single dose at a low dose rate (4 cGy min-1) (STBI) or in a fractionated regimen (six fractions of 125 cGy three times a day) at a higher dose rate (25 cGy min-1) (FTBI). After TBI completion we simultaneously studied the in vivo radiation response of bone marrow cells, two murine bone marrow clonogenic cells (CFU-S and GM-CFC) and peripheral blood lymphocytes and granulocytes for a period of 1 month. The percentage of spleen erythrocytic and granulocytic colonies was also determined. No significant differences were observed between the two groups in the first 48 hours after irradiation except in bone marrow cell numbers, probably due to differences in the overall treatment time between the two TBI schedules. After the first 48 hours the repopulation patterns of the different cells were very similar in both groups. These findings suggest that the different dose rates and fractionation used in this study caused similar radiation damage to the murine haemopoietic system. Moreover, no significant repopulation occurred during the longer overall treatment time of the fractionated regimen. These preliminary results must be corroborated with a larger range of doses before any firm conclusion can be drawn."}
+{"text": "Nine primary pulmonary carcinomas, one metastatic carcinoma, and two malignant pleural mesotheliomas have been analysed for the expression at the mRNA level of metalloproteinases (MPs) and tissue inhibitors of MPs (TIMPs). In situ hybridisation showed TIMP-1 and TIMP-2 transcripts predominantly over tumour stroma and gelatinases evenly distributed over both stromal and tumour cells. While both TIMP-1 and TIMP-2 were expressed in non-neoplastic lungs (NNL) as well as in carcinomas, stromelysin 3 (ST3), 92 kDa gelatinase and interstitial collagenase were expressed only by carcinomas. Expression of these MPs by carcinomas was independent of histologic type and such tumour features as fibrosis or necrosis. The consistent expression of ST3 by all of the carcinomas examined and absence of its expression in NNL indicates that ST3 production is likely associated with the malignant phenotype. However, since 92 kDa gelatinase and interstitial collagenase transcripts were found in some but not all tumour samples, their expression is not a uniform feature of pulmonary carcinomas. The possible prognostic significance of the expression of the latter two enzymes by carcinomas remains to be established."}
+{"text": "Antigenic modulation of major histocompatibility and tumour associated antigens was observed in neoplastic cells obtained from patients with pleural and abdominal effusions of breast and ovary carcinomas following a single intracavitary dose of 18 x 10(6) U recombinant IFN-alpha. This regimen resulted in antigenic modulation in seven out of 11 tested cases, suggesting a potential, although limited, responsiveness of at least a fraction of breast and ovary carcinoma cells to in situ biomodification with IFN-alpha."}
+{"text": "Drug resistance in haemopoietic cells may be partly related to the expression of the glutathione-s-transferase (GST) pi and mdr-1 genes. We have used RNA slot blotting techniques to investigate the expression of GST pi in peripheral blood and bone marrow of eleven normal subjects, nine patients with myelodysplastic syndrome (MDS), eighteen patients with acute myeloblastic leukaemia (AML), and thirty-two patients with chronic lymphocyte leukaemia (CLL). We found increased expression of GST pi in 8 of 9 MDS,  12 of 18 AML  and in the peripheral blood of 24 of 32 CLL  relative to normal controls. Increased expression of GST pi can occur at any stage of disease and shows no clear relation to mdr-1 expression except, possibly, in CLL. In 3 AML patients GST pi transcript levels were the same or lower on relapse compared to presentation. Upregulation of the GST pi gene could not be demonstrated in 2 CLL patients in response to treatment with intermittent chlorambucil."}
+{"text": "The QR regressor tumour (QR-32), a fibrosarcoma which is unable to grow progressively in normal syngeneic C57BL/6 mice, was able to grow progressively in 13 out of 22 mice (59%) when it was subcutaneously coimplanted with gelatin sponge. We established four culture tumour lines from the resultant tumours (QRsP tumour lines). These QRsP tumour lines were able to grow progressively in mice even in the absence of gelatin sponge. The ability of QRsP tumour cells to colonise the lungs after intravenous injection and to produce high amounts of prostaglandin E2 (PGE2) during in vitro cell culture was much greater than that of parent QR-32 cells. These biological characteristics of QR-32 cells and QRsP tumour cells were found to be stable for at least 6 months when they were maintained in culture. We also observed that QR-32 cells were able to grow progressively in five out of 12 (42%) mice after coimplantation with plastic non-adherent peritoneal cells obtained from mice which had been intraperitoneally implanted with gelatin sponge. These host cells reactive to gelatin sponge increased the production of high amounts of PGE2 by QR-32 cells during 48 h coculture. Preliminary in vitro studies implicated the involvement of hydrogen peroxide and hydroxyl radical as some of the factors necessary to induce QR-32 cells to produce high amounts of PGE2 and to accelerate tumour progression."}
+{"text": "We have found that elevation of preoperative serum sialyl-Tn antigen (STN) levels is associated with a poor prognosis for gastric cancer patients, and these high levels remain in the advanced stage of the disease. We have now examined findings with the combined assay of STN and carcinoembryonic antigen (CEA) levels with regard to prediction of the prognosis of gastric cancer patients. Serum CEA levels and STN levels were determined preoperatively in 349 Japanese patients with gastric cancer. The patients were divided into four groups: (A) the CEA (-) STN (-) group ; (B) the CEA (-) STN (+) group ; (C) the CEA (+) STN (-) group ; and (D) the CEA (+) STN (+) group . Clinicopathological features and the prognosis of these groups were examined. The distribution of two markers showed no significant correlation. The patients in the CEA (+) STN (+) group (group D) had more advanced disease than the patients in CEA (-) STN (-) group (group A); tumour size was larger, serosal invasion was prominent, lymphatic and vascular involvement was frequent and the tumour was more infiltrative. Lymph node metastasis and hepatic metastasis were more common. Total gastrectomy was usually performed, and the non-curative rate was higher. The 5-year survival of patients in the CEA (+) STN (+) (group D) was 14.5 +/- 9.5%, that is lower than that of patients in any other group . This combined assay of these markers will aid in estimating the prognosis and selecting appropriate drugs and care for gastric cancer patients."}
+{"text": "Growth in soft-agar bilayer cultures of human tumour cells derived from 4 in vitro continuous cell lines, from 21 xenografts carried in athymic mice, and from 197 samples of fresh human solid tumours of various histologic types was analyzed by computer-assisted image analysis. Replicate cultures for each specimen were assessed on successive days of incubation for the number and volume of growth units within multiple size categories. Our results confirm the recent finding of others that there is an upper limit of approximately 10(9) microns 3 to the cumulative growth unit volume obtainable in a 2 ml bilayer soft agar culture system. Since this upper limit to the carrying capacity of the closed culture system exists, the extent of growth within the cultures is determined in a fundamental way by the cumulative volume of growth units initially inoculated into cultures. A growth index of greater than or equal to 16-fold was only seen when initial cumulative growth unit volume was less than 10(7) microns 3 per culture dish. Computer-assisted volume analysis (CAVA) appears to be a useful quantitative method to study the growth of human tumour cells in soft agar cultures."}
+{"text": "As yet, there is no reported study of chromosome allele loss in fibrolamellar carcinoma (FLC), a distinct, rare variant of hepatocellular carcinoma (HCC). We searched for evidence of allele loss in FLC using 18 DNA probes for 10 chromosomes and compared the pattern of loss with our series of HCC. Two of the probes, lambda MS32 (1q42-43) and cMS621 (5p) showed allele losses in one tumour, while other probes showed no loss. The frequency of allele loss in FLC was much lower than in HCC, which may be associated with their different prognoses."}
+{"text": "Two hundred and twenty-two women with advanced cancer of the breast were asked to complete two previously validated self-assessment questionnaires  and the Rotterdam Symptom Checklist (RSCL) in order to determine the prevalence and persistence of affective disorders in this group of patients. Fifty-six (27%) of 211 women who completed the HADS and 33 (22%) of 204 who completed the RSCL rated as probable cases of an anxiety state and/or depressive illness. One hundred and fifty-five patients completed the questionnaires again 1-3 months later. Twenty-one (13%) were persistently anxious or depressed as judged by the HADS compared with 14 (10%) on the RSCL. When both questionnaires were considered together, approximately one third of patients had scores suggestive of an affective disorder and in one third of these it was persistent. Only 30 patients (43% of cases) were detected as 'cases' by both questionnaires and this finding warrants further investigation."}
+{"text": "Transcriptome data from quantitative PCR (Q-PCR) and DNA microarrays are typically obtained from a fixed amount of RNA collected per sample. Therefore, variations in tissue cellularity and RNA yield across samples in an experimental series compromise accurate determination of the absolute level of each mRNA species per cell in any sample. Since mRNAs are copied from genomic DNA, the simplest way to express mRNA level would be as copy number per template DNA, or more practically, as copy number per cell.Here we report a method (designated the \"Percellome\" method) for normalizing the expression of mRNA values in biological samples. It provides a \"per cell\" readout in mRNA copy number and is applicable to both quantitative PCR (Q-PCR) and DNA microarray studies. The genomic DNA content of each sample homogenate was measured from a small aliquot to derive the number of cells in the sample. A cocktail of five external spike RNAs admixed in a dose-graded manner  was prepared and added to each homogenate in proportion to its DNA content. In this way, the spike mRNAs represented absolute copy numbers per cell in the sample. The signals from the five spike mRNAs were used as a dose-response standard curve for each sample, enabling us to convert all the signals measured to copy numbers per cell in an expression profile-independent manner. A series of samples was measured by Q-PCR and Affymetrix GeneChip microarrays using this Percellome method, and the results showed up to 90 % concordance.Percellome data can be compared directly among samples and among different studies, and between different platforms, without further normalization. Therefore, \"percellome\" normalization can serve as a standard method for exchanging and comparing data across different platforms and among different laboratories. E. coli. Statistical approaches have been proposed for ratiometric data to improve inter-microarray variations, especially of non-linear relations : an Excel spreadsheet file containing 2 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 4 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 8 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 24 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 2 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 4 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 8 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 24 hr Percellome data (15 sample data) of the 60 samples of the TCDD study (cf. Figure Click here for fileExcel spreadsheet file containing 15 Affymetrix MG-U74v2 A GeneChip raw data of the uterotrophic response study (cf. Figure Click here for fileExcel spreadsheet file containing Percellome data of the same 15 samples of the uterotrophic response study (cf. Figure Click here for file"}
+{"text": "The morphological appearance, incidence and prognostic significance of human chorionic gonadotrophin (HCG)-containing cells in seminomas were examined in a retrospective series of 228 orchidectomy specimens, obtained between 1958 and 1972. Sections from each tumour were stained with haematoxylin and eosin (H & E) and immunocytochemically for HCG. In 33 (14.5%) of the tumours HCG-containing cells were observed, but in only 12 were these recognised in an initial study of the H & E stained sections. HCG staining was seen predominantly in syncytiotrophoblastic giant cells and rarely in \"mulberry\" cells and mononuclear seminoma cells. Of the patients whose tumours included HCG-containing cells 23% died of their disease within 2 years of orchidectomy, compared with only 8% of the patients whose tumours lacked this feature. It is concluded that immunocytochemical staining for HCG should form part of the routine histological assessment of seminomas, and that the presence of HCG-containing cells indicates a more aggressive disease."}
+{"text": "An analysis of the primary tumour histopathology was performed on 103 patients managed by orchidectomy and surveillance for stage I seminoma. Patients have been followed for 14-141 months (median 62 months) after orchidectomy. Seventeen patients relapsed, the probability of remaining relapse free at 5 years being 82% . No patients died of progressive germ cell tumours. The only significant histological factor predicting relapse was the presence of lymphatic and vascular invasion. Four of 42 patients with neither lymphatic or vascular invasion recurred, nine of 53 patients with either lymphatic or vascular invasion recurred and three of eight cases with both lymphatic and vascular invasion recurred (P = 0.05-trend). Though initial recurrence was usually of moderate volume and confined to para-aortic nodes, eight patients were treated with chemotherapy either because of the extent of their initial relapse (four cases), or because of subsequent relapse (four cases). In view of the difficulties of identifying patients at risk and of detecting early relapse, surveillance for stage I seminoma should remain a research protocol."}
+{"text": "The \"Sir Charles Bell Society (SCBS)\" is an inThe SCBS began as an informal group in 1992 during the VIIth International Facial Nerve Symposium in Cologne. At this initial meeting, 74 attendees confirmed the need for a multinational approach. The original 74 attendees were to be considered as \"Founding Members\" and they drafted a Statement of Purpose: \"The SCBS is to be an international forum for clinicians of all medical specialties and researchers in basic or clinical science who have a special interest in the facial nerve and its disorders. This unique international multi-disciplinary organization is dedicated to the collection, dissemination and exchange of ideas relating to the facial nerve and its diseases.\" Their first charge was to aid Professor Naoki Yanagihara in organizing the \"VIIIth International Facial Nerve Symposium\" to be held in Japan in 1997.The SCBS was officially recognized June 23, 1993, incorporated in the state of California as a non-profit mutual benefit corporation organized under the non-profit mutual benefit corporation law meeting the criteria of: Internal Revenue Code Section 501 C (6) with FEDERAL Employee Identification Number: 94-320802 and California Corporate Number; 1917755 SCOBS.Membership includes otolaryngologists, plastic-reconstructive surgeons, neurologists, neurosurgeons, basic science researchers, physiotherapists, audiologists, anatomists, psychologists, psychiatrists, radiologists, and internists. At present there are over 229 members from 32 countries.The scientific impact is based on the interdisciplinary discussion of problems dealing with the facial nerve. An international meeting is held every four years in different countries. Main topics of discussion and international exchange are:\u25b6 Facial nerve regeneration following different kind of lesions\u25b6 Changes of the Central Nervous System following different kind of nerve lesions\u25b6 Surgical and conservative methods for treatment of facial nerve diseases\u25b6 Evaluation of grading systems.An important aspect of the SCBS is that these problems are discussed on an interdisciplinary platform.The last meeting of the SCBS was held in 2005 in Maastricht/Netherlands during the \"Xth International Facial Nerve Symposium (Chairman: Hans Manni)\" with election of Rainer Laskawi (Germany), President; Jacqueline Diels (USA), Secretary; Paul Mulkens (Netherlands), Treasurer, Mihael Podvinec (Switzerland) is Webmaster and Kedar Adour (USA) President-Emeritus. The next meeting will be held in Rome  in 2009."}
+{"text": "Placental and placental-like alkaline phosphatase (PLAP) levels in the culture media of 87 cell lines of neoplastic and 'normal' origin were measured by a conventional immunosorbent enzymatic assay (IAEA) and by a new immunoradiometric assay (IRMA). The IRMA detected immunoreactive PLAP in 37 of 80 (46%) human epithelial and germ cell cultures, while the IAEA detected PLAP in only 25 (33%). Of the 52 non-germ cell tumour cultures, the IRMA detected expression in 24 (46%) and the IAEA in only 16 (31%). In 17 cases (21%) the IRMA recorded levels double that of the IAEA, while in five cultures (6%) the reverse was true. The IRMA was much more robust than the IAEA and had considerably lower inter- and intra-assay coefficients of variation (3.75-8.5% vs 5.2-46%). Detection of PLAP(-like) expression by IAEA is dependent on neoplastic expression of enzymatically functional molecules and quantification assumes constant enzyme kinetics. PLAP-like material has a higher catalytic rate constant than PLAP and thus will give higher values on a stoichiometric basis in an IAEA. The higher detection rate and levels of PLAP-like material in neoplastic cultures when measured by the IRMA clearly demonstrate ectopic expression of non-enzymatic PLAP and PLAP-like genes. The incidence of PLAP(-like) expression by non-germ cell and possible germ cell tumours has been underestimated and its utility as a tumour marker should be re-examined using assays which measure antigen mass rather than phosphatase activity."}
+{"text": "Inconsistent findings on the efficacy of psychosocial interventions in cancer may be due to their lack of specificity. The aim of this study was to identify priorities of psychosocial need among cancer patients currently receiving treatment in Western Sydney (NSW) as a prelude to targeted intervention. A sample of 188 patients , with various solid tumours, completed a self-report ranking questionnaire listing eight major areas of psychosocial need based on a literature search of relevant studies. The resulting ranking of priorities was: family (1), dealing with emotional stress (2), getting information (3), money (4), work (5), social life (6), sex life (7), and dealing with hospital staff (8). These priorities were independent of demographic characteristics, including time since diagnosis, suggesting that support in the areas of major need may be just as important during follow-up as it is at diagnosis. Males reported less distress than females, and patients with cancer of the head/neck or breast reported most distress. To be maximally effective, psychosocial intervention for cancer patients should focus on the principal areas of family interaction, effective stress management, and access to information."}
+{"text": "Helix pomatia agglutinin (HPA)- and Concanavalin A (Con A)-binding carbohydrate expression were studied on 32 tumour samples from primary adenocarcinoma of the breast and 12 samples from lymph node metastases. Live cells were spilled from each of the fresh samples and the extent of fluorescent-labelled HPA and Con A-binding was assessed by flow cytometry. The extent of brightness was expressed in a defined quantitative fashion and the percentage of positive cells was accurately determined from a sample of 10,000 cells per tumour. Correlation of binding with clinicopathological features showed that HPA but not Con A related to lymph node involvement (P = 0.001) in tumours of higher grade (II and III). Spilled tumour cells (non-lymphocytes) were selected from the lymph nodes and the presence of HPA binding cells in the involved lymph nodes was found to relate to positive HPA binding in autologous primary tumours (P = 0.002). Dual-label analysis of HPA and Con A binding showed characteristic features for each tumour. The study demonstrates the use of flow cytometry as a simple and effective technique in detecting differences in lectin binding in live spilled cells from fresh breast cancer tissues. This method may prove to be particularly useful if performed preoperatively on cells in fine-needle aspirates."}
+{"text": "The present investigation shows the effect of vitamin A deficiency on the initiation and postinitiation phases of benzo(a)pyrene-induced lung carcinogenesis in male Wistar rats. Lung tumours were induced by giving three intratracheal instillations, one week apart, of 10 mg benzo(a)pyrene per instillation. Maximum tumour incidence (100%) and tumour burden per rat was found in rats which were kept on vitamin A deficient diet for 4 weeks prior to the first administration and 8 weeks after the last administration of benzo(a)pyrene. Rats in which vitamin A deficiency was terminated after the last administration of the carcinogen had 83% tumour incidence, whereas corresponding control pairfed animals had 39% incidence of tumours. These data represent the values obtained 32 weeks after the last administered dose of the carcinogen and indicate the role of vitamin A, both in the initiation as well as in the postinitiation phases of lung carcinogenesis."}
+{"text": "The clinical significance of neuron-specific enolase (NSE) as a tumour marker was evaluated in 54 patients with seminoma. Before orchiectomy NSE was elevated in six out of 21 patients with stage I seminoma and 11 out of 16 patients with metastases. After orchiectomy NSE normalised in all evaluated stage I cases, but was still elevated in six out of 12 patients with metastatic disease. NSE monitored the effect of cisplatin-based chemotherapy in patients with metastases. In some patients, increased serum NSE was found together with raised levels of human choriogonadotropin (HCG) and lactate dehydrogenase (LDH), while in others only NSE was elevated. No false positive NSE values were observed. NSE seems to be a clinically worthwhile serum tumour marker for monitoring seminoma patients, with a sensitivity and specificity of the same order as HCG."}
+{"text": "Pancreatic ductal adenocarcinomas are characterised by a dense connective tissue reaction. To test the hypothesis that stroma components are synthesised and produced by the tumour cells themselves, eight cell lines as well as six xenografted tumours from human ductal adenocarcinomas of the pancreas were examined for the expression of extracellular matrix proteins (ECM), using cDNA probes and antibodies to collagen types I, III and IV, vitronectin, fibronectin, undulin and laminin. All tumour cell lines  and xenografted human pancreatic tumours expressed at least one of the examined ECM at the RNA (collagen type IV > laminin = fibronectin = vitronectin > collagen type III > undulin > collagen type I) or protein level (collagen type IV = collagen type III > vitronectin > laminin > collagen type I = fibronectin > undulin). In nude mouse tumours expression of laminin and collagen I was most pronounced in well-differentiated carcinomas. In a few tumours, collagen type III, vitronectin and undulin were expressed on the luminal side of the neoplastic glands, suggesting loss of normal polar differentiation. Incubation with fetal calf serum modulated ECM RNA levels to a varying extent in all but one cell line (AsPC-1). The results suggest that human pancreatic ductal adenocarcinomas cells are capable of synthesising and producing extracellular matrix proteins in vitro and in vivo, but that the extent and pattern of ECM expression differs between the various tumours and conditions tested."}
+{"text": "Serum levels of TAG 72 were measured in 726 serum samples from patients with benign and malignant gynaecological conditions in order to evaluate the clinical usefulness of TAG 72 alone or in combination with other tumour markers. Sixty-six per cent of patients with ovarian cancer showed abnormal concentrations of TAG 72 antigen. A good correlation was also found between serial TAG 72 values and the clinical course of disease during chemotherapy and follow-up. In cervical and endometrial cancer abnormal TAG 72 values occurred in 23% and 14% of cases, while none of the patients with breast cancer had abnormal TAG 72 levels. Among patients with benign disease only one out of 12 patients (8%) with benign ovarian tumours and one of 15 patients with uterine fibromyomatosis (7%) showed high TAG 72 serum levels. However, the determination of TAG 72 did not increase the sensitivity of CA 125 and squamous cell carcinoma antigen (SCC), in ovarian and cervical cancer, respectively. The systemic administration of recombinant interferon alpha-2b to 15 patients with ovarian cancer and different basal levels of TAG 72 did not increase serum levels of the antigen."}
+{"text": "Serial image guided 31P magnetic resonance spectroscopy (MRS) studies were performed in eight patients with non-Hodgkin's lymphoma to determine the changes in phosphorus metabolites that occur in vivo in response to chemotherapy. Pre-treatment spectral characteristics were different in high and low grade lymphoma. A larger inorganic phosphate (Pi) peak was seen in high grade NHL relative to phosphomonoesters (PME) or beta adenosine triphosphate (beta ATP), producing significant differences in the PME/Pi and Pi/beta ATP metabolite ratios, and probably reflecting a larger hypoxic cell fraction within the high grade lymphomas. Consistent metabolite changes were seen with treatment, and before reductions in tumour bulk had occurred. Alterations in tumour energetics with changes in Pi and beta ATP, and increases in phospholipid turnover reflected as an increase in the phosphodiester (PDE) resonance were detected. Changes were seen between days 10 and 27 in low grade lymphoma treated with oral alkylating therapy and between days 1 and 5 in lymphoma treated with intensive combination chemotherapy. Increases in the PDE/beta ATP metabolite ratio may be an early indicator of response to chemotherapy in human tumours. These studies illustrate the feasibility and clinical potential of image guided 31P MRS as a means of assessing response to therapy."}
+{"text": "Sequential methotrexate (Mtx) absorption studies were undertaken in 127 children undergoing treatment for childhood non-T acute lymphoblastic leukaemia (ALL) to determine whether serum drug concentration, clearance and dosage affect event free survival (EFS). Higher serum concentration and area under the plasma concentration curve (AUC) were not associated with an improved EFS. Methotrexate clearance was not found to be of prognostic significance. Patients who tolerated only low 6-mercaptopurine (6-MP) doses because of neutropaenia and those who randomly were prescribed higher doses of Mtx had a lower rate of leukaemia relapse after the completion of therapy. This suggests that the use of maintenance therapy in maximally tolerated doses may be associated with an increased survival in childhood ALL."}
+{"text": "Prognostic information is essential for the evaluation, judgement and optimal treatment of patients with squamous cell cancers (SCCs) of the upper aerodigestive tract. Using immunohistochemical and flow cytometric techniques, we have studied the significance of cellular expression of the Ki-67 antigen, epidermal growth factor receptor (EGFR), the transferrin receptor (TFR) and DNA ploidy status in a prospective analysis of patients with SCCs of the head and neck region. All 42 fresh tumour samples  expressed both EGFR and TFR to varying degrees. Receptor expression was most marked on the peripheral invading margin of cancer cell islands although staining was also demonstrated in a random fashion within cellular islands and consistently along the basal cell layer of overlying stratified squamous epithelium. The percentage of cancer cells that reacted with the Ki-67 monoclonal antibody was assessed as low (less than 10%) in 15 samples (35.8%), intermediate (10-30%) in 19 samples (45.2%) and high (greater than 30%) in eight samples (19.0%). Eleven of 15 samples (73%) with a low percentage reactivity were DNA diploid, whereas seven of eight samples (87.5%) with a high percentage reactivity were DNA aneuploid. Poorly differentiated SCCs were significantly more often aneuploid than were either moderately or well differentiated tumours. Our results suggest that EGFR and TFR are widely distributed on SCCs, especially on proliferating cells at the invading tumour margin. In addition, there is a close spatial correlation between cells expressing EGFR, TFR and those expressing the Ki-67 antigen. Tumours in which the staining intensity for both EGFR and TFR was intense invariably expressed the Ki-67 antigen in a high proportion of cells. Further patient follow-up will be important in determining whether intense EGFR and TFR staining, combined with a high percentage reactivity with Ki-67 antibody and DNA aneuploidy, will ultimately define a subset of head and neck cancer patients with a poor clinical outcome."}
+{"text": "ABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs.Generalized progressive retinal atrophy (gPRA) is a hereditary ocular disorder with progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina  analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA4 (for 9 breeds), CX36 (for 12 breeds), MERTK  and RDH12 (for 9 breeds).Based on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes  Single strand conformation polymorphism (SSCP) analysis is a simple and cost-effective method with high reliability for the identification of base substitutions or other sequence variations like small deletions or insertions in large cohorts of individuals . We usedABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) for mutations leading to ar gPRA in 29 breeds of dogs. The ABCA4 gene encodes the ABCR or RIM protein (RmP), thought to act as a flippase for N-retinylidene phosphatidylethanolamine (N-retinylidene-PE), thereby facilitating the transport of all-trans-retinal from the disk lumen to the photoreceptor cytoplasm  dCTP (10 mCi/ml) was included. PCR products were digested depending on the lengths of the fragments with different restriction enzymes [see All PCRs were performed under standard PCR conditions -12 in a 2 see . For SSCymes see  in orderTL conceived the experimental outline, collected blood samples, conducted the experiments, analyzed the data and drafted the manuscript. SMP, BK and SED carried out parts of the experiments and were involved in analyzing the data. JTE and GD participated in design and coordination of the study and helped to draft the manuscript. All authors read and approved the final manuscript.ABCA4, CX36, MERTK and RDH12 genes in different dog breeds and indirect exclusion of the genes as causing gPRA, respectively. The data provided represent the results of the mutation screening of the candidate genes ABCA4, CX36, MERTK and RDH12.Sequence variations in the Click here for filePrimers, conditions for PCR amplification and restriction enzymes used before SSCP analyses. The data provided represent the information for PCR amplification and restriction of PCR products which were used in SSCP analyses.Click here for file"}
+{"text": "The testis is the third common site of relapse after primary treatment of childhood acute lymphoblastic leukaemia, but in adults relatively few testicular relapses of acute lymphoblastic leukaemia have been reported. In the present investigation the differences in the behaviour of leukaemia in immature and mature rat testis and the interactions of testicular and leukaemic cells were studied. Intraperitoneal injection of rat T-leukaemic cells to sexually immature animals induced testicular infiltrations in 100% of animals in 17 days. The infiltrations were small and located perivascularly in the interstitial tissue. Intraperitoneal injection of T-leukaemic cells to sexually mature animals induced testicular infiltrates in 42% of the animals. Leukaemic cells injected directly to the lymph sinusoids of sexually immature and mature testis proliferated rapidly causing testicular enlargement. The M(r) > 5 K fraction of extracts of 50 days old normal rat testes inhibited 3H-TdR incorporation of both normal and leukaemic ConA-stimulated rat lymphoblasts significantly. The same fraction of extracts of testes of 25 days old rats did not have any effect on 3H-TdR incorporation. The normally occurring pubertal increase in the lymphocyte inhibitory effect of the M(r) > 5 K fraction of testis extracts on 3H-TdR incorporation of PBL was prevented following either intraperitoneal or intratesticular injection of rat leukaemic lymphoblasts administered at the age of 25 days. The present observations suggest that physiological pubertal changes in the permeability of vascular endothelium and immunosuppressive effect of the testis may be important explanatory factors for the smaller number of testicular relapses in men compared to boys seen after treatment of ALL."}
+{"text": "In the Edinburgh Randomised Breast Screening Project (EBSP) to December 1988 there were 500 cancers in the study population invited to screening and 340 cancers identified in the control population. The size and negative lymph node status characteristics of invasive cancers from the two populations were significantly different (P less than 0.05). The cancers detected by screening were predominantly 'early stage', with 16% noninvasive (PTIS) and 42% invasive stage I (pT1 node negative), whereas cancers were frequently 'late stage' (more than pT2) and inoperable in nonattenders (44%) and controls (36%). Grouped according to customary size ranges of invasive cancers, the proportion of cases lymph node positive differed in those screen detected compared with controls, but the benefit in favour of screen detection was not constant. In comparisons of cancers detected at prevalence and incidence screens, as a test of conformity with screening theory, no significant differences were apparent according to size and lymph node status, yet the characteristics of histological type of cancer discriminated significantly (P less than 0.05). When these same histological characteristics were used to compare survival, the capacity to separate invasive cancers into two groups having good and poor survival probabilities was evident, with a significant improvement for the screen detected poor survival group compared with controls (P less than 0.05)."}
+{"text": "Immunoreactive inhibin-like material (ILM) was measured by radioimmunoassay (RIA) in serum and gastric juice samples of 23 fasting normal men, 27 men with chronic superficial gastritis (CSG), and 21 men with carcinoma of stomach . Serum ILM levels in carcinoma of stomach patients (367 +/- 55.5 ng ml-1) were significantly higher than in normal men  and in patients with CSG . Sixty two per cent and 86% of patients with carcinoma of stomach showed elevated ILM levels which were higher than the highest noted in patients with CSG and normal men respectively."}
+{"text": "Thyroid dysfunction is a well-recognised side-effect of treatment with interleukin-2 (IL2). We assessed the correlation between the development of abnormal thyroid function and tumour response in 13 patients receiving IL2 and interferon-2 alpha  for advanced malignancy. Seven patients had normal thyroid function during treatment, and all of these patients have since died of progressive disease. Of six patients who did develop thyroid dysfunction during treatment, one patient has died of progressive disease. However, statistically we were unable to confirm a definite correlation between the development of thyroid dysfunction and survival in this small group of patients."}
+{"text": "Widely disseminated neuroblastoma in children older than infancy remains a very poor prognosis disease. Even the introduction of marrow ablative chemotherapy with autologous rescue has not significantly improved the outlook for these children, presumably because of a failure to eradicate minimal residual disease. One additional approach which may hold promise is the use of immunomodulation with cytokines such as IL2 in the setting of minimal residual disease (MDR), for example after intensive chemotherapy and ABMT. However, considerable variability in the susceptibility of neuroblastoma cells to natural killer (NK) and lymphokine-activated (LAK) killing has been observed, and it is presently unclear how NK and LAK cells recognise neuroblastoma cells. In this paper we examine expression of cell adhesion molecules on neuroblastoma to determine which of these modify interaction with NK and LAK cells. We find that LFA-3 (CD58), the ligand for CD2 is of predominant importance in predicting susceptibility of neuroblastoma to the cytotoxic actions of NK and LAK cells, while expression of ICAM-1 (CD54) may also modify susceptibility. These findings were confirmed by blocking experiments in which co-culture of target cells with ICAM-1 and LFA-3 reduced LAK and NK cytotoxicity. Study of the immunophenotypic features of each patient's neuroblastoma cells before induction of MRD may be valuable in determining the likely effect of IL2 in predicting disease reactivation."}
+{"text": "Antipsychotic medications are widely prescribed for the treatment of psychotic disorders but carry a variable propensity to increase weight. Thus metabolic dysfunction is the primary cause of premature death in psychosis patients. A system-based approach to understanding the molecular mechanisms behind metabolic dysfunction can potentially provide scope for tailored interventions and alternative treatment pathways that avert such risks on an individual basis. The aim of this study is to identify transcriptomic predictors of high Body Mass Index (BMI) and blood glucose in first episode and chronic psychosis patients.100 first-episode and 100 chronic cases of psychosis meeting ICD-10 criteria (F20-29 and F30-33) were recruited as part of 2 independent studies from 3 NHS Trusts: South London and Maudsley (SLAM), Oxleas and Sussex. Cases were ethnically mixed and aged between 18\u201365. All participants gave informed consent for biological sampling and a range of physical health assessments. Blood glucose was measure using HbA1c while height and weight data were also taken and used to calculate BMI. For FEP subjects biological measures were taken at baseline, 3 months and 12 months post recruitment. RNA samples were collected at the baseline timepoint via PAXgene blood tubes and interrogates, using the Illumina HumanHT-12.v4 beadchip array. Samples were run at the National Institute for Health Research\u2019s (NIHR) Biomedical Research Centre for Mental Health (BRC-MH) at the Institute of Psychiatry, Psychology and Neuroscience. A total of 4756 probes passed a stringent quality control across the 200 samples.Quantitative data on BMI and hba1c levels were used to assess the predictive efficacy of variables grouped by source  in first episode psychosis patients. All the predictor categories were included in the initial model, although individual categories were then dropped one at a time. This leave-one-out strategy allowed the direction, impact and relative contribution of the different feature classes to be assessed. Gene-expression and clinical features were consistently associated with the lowest Mean Squared Error after 100 iterations of K-fold cross-validation and after 11 different values of the alpha parameter across 500 imputed datasets. Hba1c or BMI was used as the clinical predictor, depending on whether Hba1c or BMI was used as the target variable. Unattributed surrogate variables derived from surrogate variable analysis (n=6) were analysed within the technical feature set. Having established that gene expression has inherent value as a predictor of metabolic status the same analytical steps were repeated for the discretised versions of these traits (ie. diabetes and obesity). Top-ranking gene transcripts were compared between the quantitative and discretised models. Rank lists of transcripts were subsetted to allow the power distribution across ordered transcripts to be profiled.The top performing transcripts identified are undergoing validation analysis in the chronic sample. Results will be conveyed in terms of sensitivity and false positive rates (ie. the area under the Receiver Operating Characteristic curve). We will undertake further validation through trajectory analysis of gene-expression profiles in followed-up patients."}
+{"text": "PRJEB18926), and paired antibody heavy and light chain variable region-encoding transcripts of memory B cells of three subjects . The nucleotide compositions of the corresponding 5\u2032-ends of sequences encoding the CDR3 are presented for transcripts with an origin in 47 different IGHV alleles. These data have been used  The highly variable complementary determining region 3 (CDR3) of antibodies is generated through recombination of immunoglobulin heavy chain variable (IGHV), diversity, and joining genes. The codons encoding the first residues of CDR3 may be derived directly from the IGHV germline gene but they may also be generated as part of the rearrangement process. Data of the nucleotide composition of these codons of rearranged genes, an indicator of the degree of contribution of the IGHV gene to CDR3 diversity, are presented in this article. Analyzed data are presented for two unrelated sets of raw sequence data. The raw data sets consisted of sequences of antibody heavy chain-encoding transcripts of six allergic subjects (European Nucleotide Archive accession number  Specifications TableValue of the data\u2022These data are useful for further development of processes used to infer the immunoglobulin gene repertoire of an individual, and for interpretation of the results of such analyses.\u2022These data are useful for further development of processes used to infer new germline gene sequences.\u2022These data are useful to investigators of antibody repertoire as they suggest avenues to identify the existence of, to this date, unrecognized alleles of immunoglobulin germline genes.\u2022These data are useful for interpretation of sequence diversity in the ascending strand of CDR3 of na\u00efve and antigen-specific immune repertoires.1This article present data of nucleotide composition in antibody heavy transcripts originating in 47 different immunoglobulin heavy chain variable (IGHV) germline genes/alleles  [1]. The22.1Peripheral blood and bone marrow samples of six allergic subjects were collected , and used to construct libraries of antibody H chain V domains, as previously described 2.2PRJEB18926) generated in our laboratory, constituted the main data set. They were processed as previously described FASTQ raw data files  Another, unrelated set of raw sequence data was downloaded from the European Nucleotide Archive  may however also encode the first base of codon 108. Thereby, the nucleotide composition was analysed also at this position for transcripts originating in any of these four germline genes/alleles.Most of the studied IGHV genes may contribute to nucleotides of the first three codons that encode the CDR3 . The structures were visualized using MacPyMol 1.8.0.6 .Example structures of antibodies encoded by genes with a particular germline gene origin were identified using IMGT/3Dstructure-DB"}
+{"text": "Literature has confirmed the pathogenic role of cadmium (Cd) and its exposure in the induction of dyslipidemia implicated in the development and increasing incidence of cardiovascular diseases. The current study explored whether polyphenolics isolated from virgin coconut oil (VCO) prevent Cd-induced dyslipidemia and investigate the underlying mechanism of action, in rats.Rats were pretreated with VCO polyphenols  2 weeks prior to concurrent Cd administration (5 mg/kg) for 5 weeks. Subsequently, serum concentrations of lipid and lipoprotein cholesterol and cardiovascular risk ratios were determined. Hepatic activities of superoxide dismutase (SOD) and catalase (CAT) as well as reduced glutathione (GSH) and malondialdehyde (MDA) contents were analyzed.Sub-chronic Cd administration significantly increased the serum levels of total cholesterol, triglycerides, low density lipoprotein cholesterol and very low density lipoprotein cholesterol while markedly reduced high density lipoprotein cholesterol. Hepatic activities of SOD and CAT as well as GSH content were suppressed by Cd, whereas MDA level was obviously increased. The co-administration of VCO polyphenol with Cd remarkably restored lipid profile and cardiovascular risk ratios and stabilized antioxidant defense systems comparable to control group.This is the first study presenting that polyphenols isolated from VCO prevent Cd-induced lipid abnormalities and cardiovascular risk ratios by improving antioxidant defense systems.  Cadmium (Cd) is a widespread environmental and occupational pollutant that has emerged as a major cause of pathobiochemical events and damage in a number of organs. Cadmium concentration has increased in the biosphere through mining, smelting, agricultural and industrial activities , gallic acid, and 1, 1-diphenyl-2-picrylhydrazyl (DPPH) were obtained from Sigma-Aldrich Chemical Co. . Folin-Ciocalteu reagent was purchased from Merck Co. . Solvents such as n-hexane and methanol were purchased from Loba Chemie Pvt. Ltd. Mumbai, India. Reagents used for the assays were commercial test kits and products purchased from Randox, UK. All other chemicals used were obtained from local commercial suppliers.Cadmium . They were kept in cages with wood-chip bedding and allowed free access to standard pellet diet  and clean water, ad libitum. The rats were acclimatized one week prior to initiation of the treatment and were handled in a humane manner according to the approved animal experimental procedures of NIH Guidelines for the Care and Use of Laboratory Animals  were used as experimental animals in the present investigation. The rats were housed in animal facility of the Department of Biochemistry, Ebonyi State University, Nigeria, under standard conditions  according to the method of Nevin and Rajamohan (2004)oC) to remove moisture. The floating oil was gently scooped out and filtered into an air-tight container. This oil which was prepared without refining, bleaching and deodorizing, was used for the isolation of polyphenols administered to rats in the current study.The coconuts were purchased from the Central market, Abakaliki, Ebonyi State Nigeria, in November, 2016. The VCO was extracted from coconuts (Extraction of polyphenols from VCOin vitro antioxidant activity of the polyphenol fraction was determined.Polyphenols in VCO were extracted according to the method described by Nevin and Rajamohan (2004)In vitro antioxidant assay of polyphenol fractionDetermination of total phenolic contentTotal phenolic content of the VCO polyphenol fraction was estimated by Folin\u2013Ciocalteu colorimetric method  radical according to the method described by Blois (1958)Ferric reducing antioxidant power (FRAP) assay3+) to ferrous ion (Fe2+) complex. The reducing power was calculated using the following formula: The total antioxidant activity of the VCO polyphenol fraction was evaluated using the ferric reducing antioxidant power (FRAP) assay described by Oyaizu  = 100 \u00d7 (absorbance of the control - absorbance of the sample)/absorbance of the control.Experimental designAfter 1 week of acclimatization, rats were randomly divided into 6 groups (n=8) as follow:Group 1 : received clean water  for 7 weeks.Group 2 (polyphenols=PF control): received PF  for 7 weeks.Group 3 (Cd control): received Cd  for the last 5 weeks of experimental period : received PF  for 7 weeks + Cd  for the last 5 weeks.Group 5 (PF + Cd II): received PF  for 7 weeks + Cd  for the last 5 weeks.Group 6 (PF + Cd III): received PF  for 7 weeks + Cd  for the last 5 weeks.The rats were pretreated daily with polyphenols  2 weeks prior to concurrent administration of Cd (5 mg/kg) daily for 5 weeks. At the end of the treatment period (7 weeks), all animals (fasted) were slightly anaesthetized using diethyl ether and blood samples were collected from retro-orbital venous plexus by capillary tubes into plain sample bottles and allowed to clot. The clotted blood samples were centrifuged (3000g for 15 min) for separation of serum used for analysis of lipid profile, total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C) and high density lipoprotein cholesterol (HDL-C). The liver was dissected out after sacrifice by decapitation, washed in cold saline solution, dried using tissue paper, homogenized in 0.1M phosphate buffer  and centrifuged (4000 g for 20 min). The obtained supernatant was used for analyses of hepatic antioxidant enzyme activity (SOD and CAT), and GSH and MDA content.Biochemical analysesoC using RANDOX kits. The hepatic activity of SOD was assayed by the method of Arthur and Boyne (1985). The activity of catalase was assayed by the method of Sinha (1972)Determination of biochemical parameters was carried out using standard commercially available kits purchased from RANDOX, UK. Lipid profile parameters were analyzed in serum stored at 4Cardiovascular risk indicesThe coronary risk index (CRI), cardiovascular risk index (CVRI) and atherogenic index (AI) were calculated using the following formulae  = LDL cholesterol/HDL cholesterolCoronary Risk Index (CRI) = Total cholesterol/HDL cholesterolCardiovascular risk index (CVRI) = Triglyceride/HDL cholesterolStatistical analysispost-hoc test . A p<0.05 was considered significant. Results are expressed as mean \u00b1 SEM. Statistical evaluation was conducted by one-way ANOVA followed by Tukey\u2019s Effects of administration of VCO polyphenols and Cd on lipid profile parameters in treated ratsEffects of administration of VCO polyphenols and Cd on coronary and cardiovascular risk indices in treated ratsAntioxidant activity of polyphenol fractionEffect of administration of VCO polyphenols, and Cd as well as their co-administration on hepatic markers of oxidative stress in treated ratsThe hepatic markers of oxidative stress are depicted in Cadmium is a non-essential heavy metal known to induce a broad spectrum of toxicological effects and biochemical disruptions posing serious hazards to health. Published papers indicate that Cd toxicity triggers lipid and lipoprotein abnormalities which play undeniable roles in the pathogenesis of CVD and diabetes complications , while CAT decomposes H2O2 to water and molecular oxygen 0122 and Moreover, evidence shows that lipid ratios are important in predicting cardiovascular risk (Gasevic et al., 2014Conclusively, this is the first study to assess beneficial health effect of polyphenols extracted from VCO in Cd-induced dyslipidemia. This study confirmed previous findings that Cd can adversely affect lipid and lipoprotein profile. It has provided evidence that dyslipidemia induced by Cd exposure may be attenuated by antioxidant property of VCO polyphenols in rats. The authors declare no conflict of interest"}
+{"text": "This article presents the psychosocial risk factors identified in the cases of 20 children less than four years of age who were victims of fatal or near-fatal physical abuse during a 12 month period in the Commonwealth of Kentucky. These data are related to the article \u201cHistory, injury, and psychosocial risk factor commonalities among cases of fatal and near-fatal physical child abuse\u201d   Specifications TableValue of the data\u2022These data reveal commonalities among cases of fatal and near-fatal child abuse and highlight the high prevalence of psychosocial risk factors among caregivers.\u2022prior to each child\u05f3s fatal or near-fatal event, these data may assist medical providers, psychologists, social workers, and legal representatives in collaboratively assessing risk for maltreatment and intervening to prevent future injury.By identifying indicators of maltreatment that were present \u2022These data open doors for further exploration of risk factors for maltreatment, and may guide future research efforts to better inform strategies for child abuse prevention.1Psychosocial risk factors identified in 20 cases  of physical child abuse are presented in 2n=10) or near-fatal (n=10) child abuse in the Commonwealth of Kentucky The Institutional Review Boards at the University of Louisville and the Kentucky Cabinet for Health and Family Services (KY CHFS) approved this research. Our retrospective record review included 20 children younger than four years of age who had been victims of fatal ("}
+{"text": "Turdus merula) populations as 15.7% inside USUV-suitable areas but found no significant effect for the other 14 common bird species investigated. Our results show that the emergence of USUV is a further threat for birds in Europe and that the large-scale impact on population levels, at least for common blackbirds, must be considered.Usutu virus (USUV) is an emerging mosquitoborne flavivirus with an increasing number of reports from several countries in Europe, where USUV infection has caused high avian mortality rates. However, 20 years after the first observed outbreak of USUV in Europe, there is still no reliable assessment of the large-scale impact of USUV outbreaks on bird populations. In this study, we identified the areas suitable for USUV circulation in Germany and analyzed the effects of USUV on breeding bird populations. We calculated the USUV-associated additional decline of common blackbird ( In addition, we selected a new set of 10,000 random background points for each model. We weighted background points and occurrence points equally in each of the 300 BRT models, which we averaged for the final USUV distribution map. We converted the continuous distribution map for USUV to a binary map with areas that are suitable or unsuitable for USUV. Following Pigott et al. (We applied an ensemble boosted regression tree (BRT) approach using R software  and 10 subsets for test datasets (comprising 90% of the presence and background observations) each. We used the training datasets to assess the ability of the models to predict the test dataset with the area under the curve (AUC) statistic. We averaged the AUC values of the models across the 10 models of each split sampling dataset and finally across the 300 average AUC values. Furthermore, we applied a pairwise distance sampling procedure to avoid AUC inflation due to spatial sorting bias, which is considered to give a more realistic quantification of the model performance especially regarding its transferability (Cyanistes caeruleus), common chaffinch (Fringilla coelebs), Eurasian magpie (Pica pica), European greenfinch (Chloris chloris), black redstart (Phoenicurus ochruros), great tit (Parus major), common blackbird, house sparrow (Passer domesticus), Eurasian tree sparrow (Passer montanus), common swift (Apus apus), common house martin (Delichon urbicum), carrion crow (Corvus corone), common wood pigeon , European robin (Erithacus rubecula), and common starling (Sturnus vulgaris). The dataset consisted of 317,533 unique observation datasets with anonymized sampling locations at the level of postal code regions in Germany, each giving information on the number of specimens per bird species and sampling site. Bird abundance data were collected within the citizen science program Stunde der Gartenv\u00f6gel (Hour of the Garden Birds) in Germany. This program is organized by the German BirdLife partner Naturschutzbund Deutschland (Nature and Biodiversity Conservation Union) and its counterpart Landesbund f\u00fcr Vogelschutz in Bayern (Bavarian Society for the Protection of Birds). During the second weekend of May each year, German citizens were requested to count the maximum number of specimens per bird species observed in their gardens in a time frame of 1 hour. We used the data for the 15 most commonly detected bird species, with at least 247,000 observed specimens each during 2006\u20132016, for further analyses: Eurasian blue tit ; this year was the last time bird abundance data were collected before the first epizootic outbreak of USUV in Germany (2 of the country (2.7%). The EuroLST bioclimatic variable with the strongest influence on USUV risk was the annual mean temperature, contributing 71.4% to the variation in the ensemble of models. The next most influential variables were mean temperature of the coldest quarter of the year (8.9%), temperature seasonality (7.2%), and minimum temperature of the coldest month (5.2%). The other 5 variables had <5.0% effect each on USUV risk: mean temperature of the warmest quarter (2.8%), mean diurnal range (1.6%), temperature annual range (1.3%), maximum temperature of the warmest month (1.2%), and isothermality (0.4%)   Figure 2Eleven of 15 bird species analyzed did not show a statistically significant difference in the population development between the areas suitable and unsuitable for USUV since 2011. We determined overlapping 95% bootstrap CIs between USUV-suitable and USUV-unsuitable areas for 2016 Figure 3,During the past 2 decades, an ongoing spread of USUV and a continuous circulation of the virus after initial establishment have been observed in different countries in Europe  (2 (8 million breeding pairs each having approximately 3 fledglings per year [2), >167,119 birds died due to USUV since 2011; this estimate does not include other population effects like immigration compensating a part of the USUV-related population decline. The estimate is substantially higher than the one determined in the study by Bosch et al.  and a statistically significant lower population index in the USUV-suitable area compared with the USUV-unsuitable area (nonoverlapping CIs between both areas). We observed no significant effect for the other 14 bird species included in the study. Five years after the first detection of USUV in southwest Germany, the circulation of the virus resulted in an additional decline of \u224815.7% in the common blackbird populations compared with the development of populations not affected by USUV. Avian populations are under different threats, including changes of land use and climate change (Additional information regarding the analysis of Usutu virus in Germany."}
+{"text": "Combined effects of climate change and deforestation have altered precipitation patterns in the Amazon. This has led to changes in the frequency of extreme events of flood and drought in recent decades and in the magnitude of the annual flood pulse, a phenomenon that influences virtually all aspects of river-floodplain ecosystem dynamics. Analysis of long-term data revealed abrupt and synchronous changes in hydrology and fish assemblage structure of a floodplain lake near the confluence of Amazon and Negro rivers. After an intense drought in 2005, the assemblage assumed a different and fairly persistent taxonomic composition and functional structure. Declines in abundance after 2005 were more pronounced for species of all sizes having equilibrium life history strategy, large species with periodic life history strategy, and for all trophic levels except primary consumers. Our results suggest that the extreme drought triggered changes in the fish assemblage and subsequent anomalous hydrological conditions have hampered assemblage recovery. These findings stress the need to account for climatic-driven hydrological changes in conservation efforts addressing aquatic biodiversity and fishery resources in the central Amazon. Climate change is impacting biodiversity and ecosystem services on a global scale46789111213Hydrology in the middle reaches of the Amazon is regulated by precipitation in catchments that span a vast portion of the basin6616Consequences of hydrological changes on the Amazonian fish fauna are poorly understood. Only a few studies have examined impacts of recent climatic change on aquatic ecology in the Amazon, and these have analyzed responses to drought over relatively short time intervals18Here we investigate temporal changes in fish assemblage structure during the period of 1999\u20132014, when the central Amazon experienced abnormally large inter-annual hydrological variation. To evaluate trends in inter-annual and intra-annual hydrologic variation, we analyzed river discharge data from 1950 to 2014 using principal components analysis (PCA). Multivariate ordination methods also were used to assess taxonomic and functional assemblage structures, the latter according to two ecological aspects: life-history strategies and trophic positions. Fish abundance data were obtained from standardized fish surveys conducted in a floodplain lake  near the confluence of Negro and Amazon rivers . We applMultivariate ordination of hydrological data produced a dominant gradient in the first axis (PCA1) that contrasted annual flood pulses with lower amplitudes, dry seasons with higher water levels, and longer periods of rising water level with the opposite set of conditions . In the Taxonomic and functional composition of the fish assemblage differed markedly before and after 2005 ; the rel5,7\u2009=\u200913.54, P\u2009=\u20090.001; trophic levels: RM-ANOVA F 4,8\u2009=\u200914.527, P\u2009<\u20090.001; The 2005 drought significantly affected abundance (capture per unity effort CPUE) of most groups  and 2 (secondary consumers), all of which shifted to lower values after 2005 and then remained relatively stable . HoweverThe year of 2005 corresponded to the first extreme drought that occurred within our field study time frame and after which a set of changes occurred in the river hydrological regime26273031Significant changes in Amazon floodplain fish assemblages after the 2005 drought have now been reported by two different studies, this supports the hypothesis that recent extreme climatic events have altered key environmental factors affecting fish ecology. The Amazon has undergone unprecedented shifts in rainfall and hydrology over the last 10\u201312 years101186sensu ref. 35Hemiodus sp., Curimatella alburna, Triportheus angulatus), and would be especially affected by reduced habitat connectivity during longer dry seasonsBrycon spp., Colossoma macropomum, Prochilodus nigricans, Semaprochilodus spp.), and therefore should be particularly sensitive to changes in flood-pulse timing as well as lateral connectivity.The similarity of response functions obtained for hydrological and biological time series, together with concordance of their change points and the fundamental importance of seasonal flood pulsing for fish ecology, strongly implies that hydrology  was the main driver  and Brazil\u2019s National Agency for Water (http://hidroweb.ana.gov.br). Temporal components of the annual flood pulse were defined based on analysis of water level recorded over 100 yearsstats library and prcomp function4949Daily records of the water level in the Negro River in Manaus were obtained from the website of Porto de Manaus Company  as defined for the hydrological analysis (see previous paragraph).vegdist function in vegan library. PCoA analysis was performed using stats and BiodiversityR.Taxonomic structure - In total, 97 common species out of 196 total species were included in the data matrix for analysis ; Equilibrium-large ; Intermediate-small ; Periodic-large ; Periodic-small . Fishes with an opportunistic life history strategy  essentially were missing from our samples, because they were too small (<60\u2009mm SL) to be caught by the standardized sampling method (gillnets). Further details on criteria used to categorize species according to life-history traits can be found in Life history - For all 97 species, we obtained information on five life history traits that were considered likely to influence how populations respond to patterns of environmental variation and allow assignment of species into life history strategies3052Consumer trophic level 1- herbivorous and detritivorous species (n\u2009=\u200926); Consumer trophic level 1.5- omnivorous species (n\u2009=\u200921); Consumer trophic level 2- invertivorous and planktivorous species (n\u2009=\u200926); Consumer trophic level 3- piscivorous species (n\u2009=\u200924) (Trophic level - Each species was assigned one of the four trophic levels: (n\u2009=\u200924) . Furtherdecostand function in the vegan library to reduce influence of more abundant groups but keeping proportionality before performing PCATemporal variation in life history and trophic assemblage structures was assessed using PCA25The effect of 2005 and 2010 droughts on abundance (CPUE) of each functional group was tested by Repeated-measures analysis of variance (RM-ANOVA) using two analytical designs: i) years before 2005 compared to years after 2005; ii) years after 2005 drought  compared to after 2010 drought . Assumptions regarding data normality and homoscedasticity were met for this analysis.To evaluate temporal changes of fish assemblage (PCA and PCoA object scores) and temporal trends of abundance (CPUE) of each functional group, we applied a statistical procedure recently proposed to identify regime shifts in time series data254949nlme package and gnls functionAICcmodavg library and AICc function25Response functions and significance of shifts were tested using generalized nonlinear least-squares regression, a method that allows dealing with nonlinear relationships and non-normal errors25The possible driving factors of assemblage dynamics  were inferred by comparing the type of response function between environmental and assemblage structure changesHow to cite this article: R\u00f6pke, C. P. et al. Simultaneous abrupt shifts in hydrology and fish assemblage structure in a floodplain lake in the central Amazon. Sci. Rep.7, 40170; doi: 10.1038/srep40170 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "There is an error in the third sentence of the Abstract. The correct sentence is: This study aimed to describe features of Australian commercial chicken farms, with particular interest in free range farms, by conducting on-farm interviews of 25 free range layer farms, nine cage layer farms, nine barn layer farms, 15 free range meat chicken farms and 15 barn meat chicken farms in the Sydney basin bioregion and South East Queensland."}
+{"text": "Individuals with schizophrenia typically suffer a range of cognitive deficits, including in executive functioning (EF) and working memory (WM) . Such difficulties are strongly predictive of functional outcomes, but there is a lack of effective therapeutic interventions [3].Transcranial direct current stimulation (tDCS) is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive applications; however there has been a dearth of understanding of mechanistic effects of this intervention [4].The aim of this study was to evaluate the neurophysiological effects of tDCS during WM and EF assessment in individuals with schizophrenia.We utilized functional magnetic resonance imaging (fMRI) to evaluate the impact of tDCS on WM and EF in individuals with schizophrenia, randomized to receive either \u2018real\u2019 or \u2018sham\u2019 (placebo tDCS). Participants completed a WM (blocked 0\u20133 back) and an EF (color-word Stroop) during 30 min of 2mA tDCS applied to Broadman area 10/46 (anode 35cm2); with cathode placed on right supraorbita. Sham stimulation was applied for 30 sec. tDCS was applied during fMRI (online) [5].In addition to whole brain, we also conducted task relevant region of interest analysis (ROI) to compare mean frontal and prefrontal (Broadman are 10/46 mask) and anterior cingulate cortex (ACC) activity between the two groups during tDCS. All analyses were restricted a p-value of 0.05, following family wise-error correction (FWE).There were no between-group differences in socio-demographic or clinical characteristics (Tab 1.) Participants did not differ on WM task performance during online tDCS (Tab 2). However, there were significant between-group differences in manipulation of information with the real tDCS performing significantly better than sham, controlled for baseline  after consolidation [6].During WM the ROI analysis demonstrated increased activation underneath the site of the anode in the medial frontal gyrus in the real tDCS group, as compared to sham. There was a positive correlation between with consolidated performance and the activity in the medial frontal gyrus.Further, tDCS demonstrated significantly reduced activation in the left cerebellum.During EF task, increased performance was associated with decreased activity in the ACC [5].This is the first tDCS study to examine the brain activity during WM and EF assessment in individuals with schizophrenia using fMRIThis data suggests that biasing the membrane potential of neuronal populations in the frontal cortex seems to improve their response to other inputs i.e. decreased BOLD activation in the WM and EF network. Although the mechanism of action of tDCS is not clear yet [6], one may speculate that if the BOLD response represents synaptic activity [7], including input from other areas, then tDCS might increase the probability that a synaptic input will generate a response in an output neuron, without the need of any additional energy expended by the cell. tDCS offers a potential new therapeutic approach to the treatment of cognitive deficits."}
+{"text": "Progranulin deficiency in humans is associated with neurodegeneration. Its mechanisms are not yet fully understood. We performed a Yeast-2-Hybrid screen using human full-length progranulin as bait to assess the interactions of progranulin. Progranulin was screened against human fetal brain and human bone marrow libraries using the standard Matchmaker technology (Clontech). This article contains the full Y2H data table, including blast results and sequences, a sorted table according to selection criteria for likely positive, putatively positive, likely false and false preys, and tables showing the gene ontology terms associated with the likely and putative preys of the brain and bone marrow libraries. The interactions with autophagy proteins were confirmed and functionally analyzed in \"Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy\"   Specifications TableValue of the data\u2022Progranulin Y2H interactors are useful for comparison of interactors obtained with different methods or with different libraries.\u2022Progranulin interactors give insight into its putative functions.\u2022Progranulin Y2H results can be used to build protein networks and signaling paths.1The full Y2H table contains all of the information and data from the screen and the blast analysis, as well as the sequence of the inserts. If the blast analysis gave two identically scoring hits for a prey sequence, both hits can be found in the full table. A description of the columns is given in comments of the column headers (full table) and explained in the \"Info\" and in the \"The short table shows a summary of the results sorted according to the libraries (brain and bone marrow) and marked with different colors to indicate likely positive hits (green), putative hits (white), possibly wrong hits (yellow) and false hits (red), based on the selection criteria explained in the \"The tables \"GO terms\" and \"GO slim\" contain the results of the Gene Ontology over-representation analysis of likely positive and putative preys.22.1The Y2H screen was done for human fetal brain and bone marrow libraries with the Matchmaker GAL4 system (Clontech) by ImaGenes GmbH  using Gateway Invitrogen plasmids for human full length progranulin as bait as described in 2.2http://genetrail.bioinf.uni-sb.de/) https://david.ncifcrf.gov/home.jsp) and subsequently IDs were submitted to ORA using all genes in the database as background. ORA parameters were set to p-value threshold tp=0.05 and Bonferroni \u03b1 correction (Results in http://www.pantherdb.org/). The results are in The gene ontology terms associated with the Y2H progranulin-preys were obtained by means of over-representation analysis (ORA) using the web-based GeneTrail tool ("}
+{"text": "Upon publication of the original article  it was hAdditional file 1:Location of epigenetic clock CpGs in relation to the nearest glucocorticoid response element (as shown by within GR ChIP-Seq peaks in a lymphoblastoid cell line) and their methylation changes in response to the glucocorticoid receptor agonist dexamethasone. (XLSX 69 kb)"}
+{"text": "Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP).MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general."}
+{"text": "To the editor: We read with concern the reports of two human cases infected with swine influenza virus (SIV) that both occurred in October 2016 in Europe [Eurasian avian-like SIV A(H1N1)v were identified in both patients. In Europe, these viruses circulate widely in the pig population . The virThese two cases are the first severe human cases of SIV A(H1N1)v reported to the European Centre for Disease Prevention and Control (ECDC) or the World Health Organization Regional Office for Europe (WHO/Europe) since the 2009 influenza A(H1N1) pandemic, apart from a few sporadic detections in mild or asymptomatic persons during research projects . The detThe 2009 pandemic was the latest of several pandemics caused by a swine-origin influenza virus . The twoPeople who develop influenza-like symptoms after exposure to pigs should be promptly assessed for influenza infection. Specimens should be characterised virologically and isolates should be shared with the WHO Collaborating Centres. Early treatment with neuraminidase inhibitors should be considered and patients isolated to reduce risk of further transmission, in line with relevant national recommendations. Follow-up of other exposed individuals and contacts of the index cases should be considered to identify further cases and to detect any human-to-human transmission of the virus. A rapid sharing of such information nationally as well as internationally through the European Union\u2019s Early Warning and Response System (EWRS), the International Health Regulations  or direc"}
+{"text": "There is an error in the first sentence of the fifth paragraph in the \"Methods\" section. The correct sentence is: We compared baseline characteristics (at the time of first-line ART failure), rates of key adverse events, treatment discontinuation and virologic suppression among patients receiving second-line ART and concomitant tuberculosis therapy who received super-boosted lopinavir (with ritonavir 400 mg twice daily) and patients who received standard boosted lopinavir (with ritonavir 100 mg twice daily)."}
+{"text": "The objective of this study was to compare trajectories of antipsychotic response before and after relapse following response from a first episode of schizophrenia or schizoaffective disorder.The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse  in association with non-adherence; and (4) reintroduction of antipsychotic treatment. The following outcomes were used as an index of antipsychotic treatment response: change in the Brief Psychiatric Rating Scale (BPRS) total score and number of patients who achieved positive symptom remission, including 20% and 50% response improvement.A total of 130 patients were included in the analyses. All patients took the same antipsychotic in both episodes. Antipsychotic doses in the second episode were significantly higher than those in the first episode (P=0.03). There were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year  in favor of the first episode compared to the second episode. Results remained unchanged after adjusting for antipsychotic dose.The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia."}
+{"text": "Timing of pulmonic valve replacement (PVR) following repaired Tetralogy of Fallot (rTOF) is determined by the severity of right ventricular (RV) dilation. While it is known that cardiovascular magnetic resonance (CMR) can more accurately quantify RV size than 2D-echocardiography (2DE), many centers have not fully integrated serial CMR assessment into the management of these patients, despite guideline recommendations. The aim of this study is to determine the extent to which visual assessment of RV size using 2DE would wrongly classify individuals that should be considered for PVR.CMR and 2DE results were obtained from 61 patients with a history of rTOF. Patients were first classified into events and non-events , based on three cutoffs of RV volume determined by CMR . For each event and non-event group, patients were then reclassified based on presence of greater-than-moderate RV dilation determined qualitatively by 2DE. The net reclassification index (NRI), a measure of prediction improvement, was calculated for each of the three CMR cutoff values. Negative NRI values suggest poorer prediction with 2DE, while positive values suggest improved prediction. Hypothesis testing was conducted with McNemar's method.A cutoff of greater-than-moderate RV dilatation determined by 2DE yielded negative NRI for all three CMR event cutoffs . All three NRI were also negative for non-events (Table Regardless of the RV cutoff value used to trigger referral for PVR, visual assessment of RV size using 2DE results in significant misclassification of both individuals with rTOF who should be referred for PVR and those who should not be referred for PVR. Visual determination of RV size based on 2DE cannot substitute current guidelines recommendations for using CMR to determine timing of PVR. Solutions to increase CMR availability or the identification of appropriate surrogates are needed for the management of these patients."}
+{"text": "NUT midline carcinoma (NMC) is a very aggressive and lethal type of squamous epithelial cell cancer caused due to fusion of BRD4and NUT genes. The gene fusion results into a new fusion protein that promotes oncogenesis. The detailed molecular mechanismsunderlying the NMC are still not clear and new findings are urgently required to complement the current efforts. AbnormalmicroRNAs (miRNA) expression promotes tumour formation by modulating the functional expression of critical genes other than theparent genes involved in tumour cell proliferation or survival. Here, using Insilco methods, miRNA targeting the transcripts of parentgenes (BRD4 and NUT) and the BRD4-NUT fusion gene were predicted. We investigated a situation, wherein abnormal miRNAexpression in malignant cells could arise due to deletion and fusion of genomic regions encompassing the target site of miRNAgenes. A set of 48 dysregulated miRNAs targeting the critical genes other than the parent genes (BRD4 and NUT) was identified.Functional enrichment analysis of KEGG pathways of target genes of these Ex-miRNAs implicates their role in cancer pathways.Amplification in the expression level of these miRNAs can be used for NMC diagnosis and prognosis. NUT midline carcinoma (NMC) is a fatal form of undifferentiatedepithelial cancer affecting both children and adults .CommonlMicroRNAs (miRNAs) play a critical role in regulating targetgenes and are involved in the initiation and progression of cancer. miRNAs Here, we have idetified the miRNA targeting the transcripts ofparent genes (BRD4 and NUT) and the BRD4-NUT fusion gene.We hypothesize that some of the miRNAs regulating theirrespective BRD4 and NUT gene expression may not be requiredafter the BRD4-NUT gene fusion, as the regions targeted by thesemiRNAs are deleted. This may lead to an apparent amplificationin the miRNAs, which in turn may regulate the pathways leadingto cancer. A comparative study of miRNAs regulating fused geneand its parent gene was performed and their target genes werediscovered. A functional enrichment analysis of KEGG pathway of target genes of these Ex-miRNAs shows its role in cancerpathways.BRD4 gene (Refseq: NM_058243.2), NUT gene (GenBank:AF482429.1) and BRD4-NUT fusion gene (GenBank: AY166680.1)transcript sequences were retrieved from the NCBI Nucleotidedatabase. In order to locate the deleted regions in the fusion genetranscript, the mRNA sequences of parent (BRD4 and NUT) werecompared against the fusion gene (BRD4-NUT) using align twosequences option of NCBI- BlastN tool. Prediction of miRNAstargeting the BRD4, NUT and BRD4-NUT fusion gene transcriptswas performed using MIRDB (http://mirdb.org/miRDB) [It is generally accepted that fusion genes are translated intofusion proteins, which are drivers of cancer pathway activation.On the other hand, it is well established that alterations inmiRNA expression promote tumour formation. The dysregulatedmiRNAs modulate the functional expression of critical genesother than the parent genes involved in tumour cell proliferationor survival . Recent We predicted and compared the miRNA targeting the BRD4and NUT transcripts region before and after the gene fusionevents. Sequence alignment of parent BRD4, NUT and fusionBRD4-NUT mRNA sequences, using NCBI Blast tool, revealedthat 2818 bases (54%) from 3\u05f3 region of BRD4 and 170 bases from5\u05f3 region of NUT were deleted in the BRD4-NUT gene fusiontranscript . miRNAs In order to predict the Ex-miRNA, BRD4 (1-2830 region) andNUT (170-3795 region) of fused gene were subjected to miRNAprediction using miRDB. Out of 34 miRNAs of BRD4, 28 miRNAwere no more required to target the same gene, when comparedto its fused form. This situation arises because of the deletion of2818 bases from 3\u05f3end of BRD4 . SimilarA set of 18, 33, and 34 miRNAs were predicted to target theBRD4-NUT fusion gene transcript, BRD4 and NUT mRNArespectively. Comparative analysis of these miRNAs andfunctional enrichment of pathway revealed that a set of 48miRNA might be dysregulated to target the critical genes otherthan the parent genes (BRD4 and NUT), causing the cancer.Amplification in the expression level of these miRNAs can beused for NMC diagnosis and prognosis."}
+{"text": "This article contains the data on farmers' determinants of binary choices for manure use  and fertiliser use  at their fields in semi-arid northern Ethiopian Rift Valley. The data includes (i) a schematic diagram that represents local farmers' distinctions of the crop field types in terms of the distance from their houses and soil fertility and (ii) a table that describes a representative farmer's crop sequences and soil fertilisation methods in two consecutive years. Details about the literature review of the previous case studies on farmers' determinants of manure application technique adoption conducted in some parts of sub-Saharan Africa where cattle dung is used for manure are also summarized in a table. A table shows descriptive statistics of the independent variables used in the empirical analyses. Summary statistics of 4 binomial logit models and 4 multinomial logit models are indicated in a table, which represent model fit. Last two tables exhibited in this article show the logit analyses. Specifications TableValue of the data\u2022The data include the figure that describes local farmers' distinctions of the crop field types in terms of the distance from their houses and soil fertility in semi-arid northern Ethiopian Rift Valley.\u2022The data include the table that shows a representative farmer's crop sequences and soil fertilisation methods.\u2022These data are a benchmark for farmers' determinants of manure application and fertiliser use at their crop fields in Ethiopian lowlands including semi-arid Ethiopian Rift Valley.\u2022These data can be compared to the similar type of analyses conducted in other areas.1This article includes a schematic diagram representing local farmers' distinctions of the crop fields in terms of the distance from their houses and soil fertility , table t22.1Adama and Boset districts in Oromia region, Ethiopia, are classified into five agroecological sub-zones  2.2The following two-step procedures were used to select sample plots: in the first step, we set a goal to select 150 households from each maize growing sub-area. The target numbers of households were equally split by the number of sub-zones in each sub-area: four and two sub-zones in the MD and MM sub-areas, respectively, and were allocated to each sub-zone. Semi-structured questionnaires were prepared for interviewing randomly selected household heads in November and December 2012. After eliminating questionnaires with invalid data, we had data from 146 and 173 household heads living in the MD and MM sub-areas, respectively. It was found these 146 and 173 household heads had 313 continuous maize cropping fields  and 302 other than maize cropping fields . In the second step, we randomly selected 262 CMCFs (131 for MD and 131 for MM sub-areas) and 262 OCMFs (131 for MD and 131 for MM sub-areas) from these 313 CMCFs and 302 OCMFs to match the numbers of the plot data between CMCFs and OCMFs and between MD and MM sub-areas. The total number of the plot data became 524 (262 CMCFs+262 OCMFs).2.3n=262) had three fertilisation options: (i) no fertilisation (n=39), (ii) manure application (n=220), and (iii) fertiliser use (n=3), while the OCMFs (n=262) had three fertilisation options: (i) no fertilisation (n=4), (ii) fertiliser use (n=153), and (iii) both compost and fertiliser use (n=105). The following two empirical exercises were conducted by using different econometric models:(i)manure: 1=used, 0=not used), two binomial logit models were formulated for CMCF and OCMF subdatasets . Another two binomial logit models were created with and without variable crop  for the pooled dataset ; andTo analyse farmers' determining factors in binary manure use options fertilisation: 1=no fertilisation, 2=manure application, 3=fertiliser use, 4=both manure and fertiliser use), two multinomial logit models were built for the CMCF and OCMF subdatasets . Another two multinomial logit models were formulated with variable crop (model B3) and without variable crop (model B4) for the pooled dataset. Hausman test or Small-Hsiao test To assess the farmers' determinants of four fertilisation options , Bayesian information criterion (BIC), and the % correctly estimated values were examined. To test the validity of the subsampling method, the sum of squared residuals obtained from the pooled dataset and subdatasets to test the equality of coefficients were compared between the models Independent variables selected in this study were based upon the literature on technology adoption studies of manure/fertiliser use , Table 32.4Summary statistics  showed t"}
+{"text": "Severe bacterial infections can lead to both acute and chronic inflammatory conditions. Innate immunity is the first defense mechanism employed against invading bacterial pathogens through the recognition of conserved molecular patterns on bacteria by pattern recognition receptors (PRRs), especially the toll-like receptors (TLRs). TLRs recognize distinct pathogen-associated molecular patterns (PAMPs) that play a critical role in innate immune responses by inducing the expression of several inflammatory genes. Thus, activation of immune cells is regulated by cytokines that use the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway and microbial recognition by TLRs. This system is tightly controlled by various endogenous molecules to allow for an appropriately regulated and safe host immune response to infections. Suppressor of cytokine signaling (SOCS) family of proteins is one of the central regulators of microbial pathogen-induced signaling of cytokines, principally through the inhibition of the activation of JAK/STAT signaling cascades. This review provides recent knowledge regarding the role of SOCS proteins during bacterial infections, with an emphasis on the mechanisms involved in their induction and regulation of antibacterial immune responses. Furthermore, the implication of SOCS proteins in diverse processes of bacteria to escape host defenses and in the outcome of bacterial infections are discussed, as well as the possibilities offered by these proteins for future targeted antimicrobial therapies. Cytokines are signaling molecules secreted by cells to elicit a particular effect on the behavior and communication of surrounding cells  family of proteins apparently are modulators of a variety of diseases including those with autoimmune etiologies, inflammation, allergies, bacteria, and cancer. SOCS regulate signaling pathways on an intracellular level to potently and specifically inhibit cytokine and growth factor signaling      that have evaded detection by complement or antibody   and protein tyrosine phosphatases (PTPs) are negative regulators that activate the JAK/STAT pathway effectors of PRRs , led to the blockage of cytokine expression. In addition to IFN-\u03b2 signaling, which is involved in the GAS-induced SOCS1, the TLR4/MyD88 pathway was observed to play a crucial role in stimulating SOCS1 by forming a complex with JAK1/STAT1  and E. faecalis stimulated an increase in SOCS1 and SOCS3 mRNA transcripts in mouse macrophages by triggering NF-\u03baB and MAPK signaling pathways to regulate the production of pro-inflammatory cytokines   and arabinogalactan, and an external layer of hydrophobic mycolic acids   and NLRs  via TLR2/MyD88-activation of macrophages augment SOCS3 expression, and dislocation of the MyD88/TLR2 pathway modulated SOCS3 expression  T3SS and its encoded virulence factor SpiC trigger SOCS3 up-regulation via the ERK1/2 pathway for inhibition of the JAK/STAT inflammatory signaling cascades for its continued survival in macrophages. GAS, which causes various systemic diseases induced SOCS1 that participates in the GAS' evasion of host immune responses in murine macrophages by dampening cytokine expression leading to rapid bacterial infection , the spirochetal agent of Lyme disease, stimulates the expression of SOCS1 and SOCS3 in macrophages to possibly control its inflammatory disorders (Khor et al., B. burgdorferi via CD14 signaling induced SOCS1, SOCS3, and CIS as mediated by the p38 MAPK pathway to control the development of chronic inflammatory etiologies (Dennis et al., Results from studies by Uchiya and Nikai (Uchiya and Nikai, M. tuberculosis, M. avium, and M. bovis (Gao et al., M. bovis infection stimulated SOCS1 and SOCS3 in mouse macrophages, which mediated the inhibition of IFN-\u03b3-stimulated phosphorylation of STAT1 and thereby the subsequent inhibition of growth and activation of macrophages required for the control of this intracellular pathogen (Gao et al., M. tuberculosis (Sahay et al., Various mycobacteria manipulate IFN-\u03b3-driven immunity by inducing SOCS1 and SOCS3 to evade the immune response or hamper the disease control. Augmentation of SOCS1 and SOCS3 levels and their subsequent inhibition of IFN-\u03b3-induced STAT1 were found to alleviate the immune response for several mycobacterial species like in vitro and in vivo (Galm et al., SOCS proteins regulate cytokine signal transduction for maintaining immune functions but still contribute to the onset of immunological diseases and inflammation (Yoshimura et al., in vitro by interacting with the IFN-\u03b3 signaling complex and functionally reducing the phosphorylation of STAT1, which further resulted in inhibiting the production of pro-inflammatory cytokines and chemokines (Jo et al., The regulation of the levels of pro- and anti-inflammatory cytokines and chemokines by the immune system is critical in limiting or modulating the host defense against invading pathogens. SOCS proteins as negative regulators of JAK/STAT represent a promising target for anti-inflammatory therapies (Turkson and Jove, Staphylococcus aureus (Hennessy et al., The exploitation of host SOCS proteins and manipulation of their functions by bacterial pathogens make them particularly attractive therapeutic targets. Therapeutic approaches targeting host-directed immunomodulatory components against bacterial infections have already been described (Finlay and Hancock, A better understanding of the control mechanisms involved in SOCS modulation of immune responses and inflammation is key to developing effective targeted therapeutics and vaccines. Each SOCS protein contributes either to the negative regulation of cytokine signaling or the regulation of many biological processes. The expression of SOCS proteins can define host susceptibility to infection by facilitating accelerated bacterial growth or protecting the host from severe inflammation. However, the direct action of the SOCS-mediated inhibition in inflammatory response is yet to be fully elucidated, thus limiting the progress being made scientifically and clinically by microbiologist and immunologists. Additionally, factors such as increased virulence, mutations and antibiotic resistance over time pose recurring challenges in the control of epidemic bacterial diseases worldwide. Admittedly, SOCS-targeted therapy for bacterial-induced inflammation is provocative, but yet one that should be considered exploring. So far, inhibiting the action of JAKs by small composites or drugs show reparative potential (DiGiandomenico et al., SD did the literature search and exploration and wrote the manuscript. DB and RS helped with writing and reading the manuscript. SS read and edited the manuscript. VD edited the manuscript and coordinated the project. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The last confirmed wild poliovirus (WPV) case in Democratic Republic of the Congo (DRC) had paralysis onset in December 2011  (1\u20136). AVDPVs are classified as circulating (cVDPVs) when there is evidence of community transmission; immunodeficiency-associated VDPVs (iVDPVs) when isolated from persons with primary immunodeficiency ; or ambiguous (aVDPVs ) when the identity is uncertain    is held in a global stockpile for response to poliovirus type 2 outbreaks after the switch , 11 of DRC\u2019s 26 provinces reported 118 cases of acute flaccid paralysis (AFP) with VDPVs isolated in stool samples  (1\u20136). UHistorically, the routine immunization program in DRC has not met global standards . TheThe first cVDPV2 patient in Maniema province had paralysis onset on March 26, 2017, in Kindu health zone  (6). TheThe Advisory Group approved the release of mOPV2 for two SIAs targeting 276,076 children aged <5 years in eight health zones surrounding and including Kindu and Kunda in June and July  (6). ResThe first patient in the cVDPV2 outbreak in the Haut Lomami outbreak area had paralysis onset on February 20, 2017 in Malemba-Nkulu health zone  (6). TheThe Advisory Group recommended mOPV2 for two SIAs targeting 513,820 children aged <5 years in 12 health zones , including and surrounding the health zones where cases were reported (6). The SIAs were conducted in June and July  (6). ResJust after the Advisory Group\u2019s approval in October 2017, the first of 13 additional, genetically linked cVDPV2 cases were confirmed in Ankoro and Manono health zones in Tanganyika province, with paralysis onset from September 14 to December 22, 2017 . In-deptAfter the December 2017 SIAs, two new VDPV2 emergences were confirmed in Haut Lomami and Tanganyika provinces. The first was in an AFP case with paralysis onset 15 November 2017 in Lwamba health zone (Haut Lomami province); this case has been classified as an aVDPV2 and the occurrence a VDPV2 event  (8). TheThe emergence and circulation of VDPVs during many years and over a broad geographical area is evidence of widespread suboptimal poliovirus immunity in major portions of DRC  were of insufficient geographic scope to confine the outbreak  was established in late 2017 in Kindu (Maniema province) and in Lubumbashi (Haut Katanga province adjacent to Haut Lomami) and will continue. The risk for VDPV emergence in DRC will remain until population immunity is increased and maintained. The immediate goal is to interrupt VDPV transmission in the outbreak areas so that efforts can be turned toward improving polio vaccination and surveillance in other high risk areas in DRC.Democratic Republic of the Congo has had cases of polio caused by vaccine-derived polioviruses (VDPVs) documented since 2004. The emergence of these VDPVs, which cause paralysis similar to wild polioviruses, can occur where population immunity to poliovirus is suboptimal. After an outbreak of 30 circulating VDPV type 2 (cVDPV2) cases during 2011\u20132012, only five VDPV2 cases were reported during 2013\u20132016. In 2017 , 25 cases of VDPV were reported from three provinces, Haut Lomami, Maniema, and Tanganyika. Among the 25 VDPV cases, 22 were classified as cVDPV2, with 20 associated with an emergence that started in Haut Lomami province and spread to Tanganyika province and two associated with a separate emergence in Maniema province. Despite response efforts, transmission of these VDPVs has not yet been interrupted.Risk for VDPV emergence in DRC will remain unless population immunity to poliovirus is increased and maintained. Efforts are being made as part of the current VDPV outbreak response to overcome long-standing constraints to polio vaccination. Such efforts will be extended to other regions of the country once transmission in the current outbreak areas is interrupted."}
+{"text": "In 12 patients, this approach was not applied because of cardiac insufficiency. Videothoracoscopy and decortication after thoracotomy ensured the recovery of functions.Our study shows the different therapeutic procedures in 64 patients with pleural effusion due to MRSA pneumonia. The thoracostomy tube associated with pleural washing was decisive in 10 simple effusion patients. Video-assisted thoracic surgery allowed a complete resolution of the disease in 22 complex parapneumonic effusion patients. In 20 of 32 patients with frank pus in the pleural cavity, the videothoracoscopic insufflation of carbon dioxide (CO"}
+{"text": "The anatomical and functional information of a cardiac mass collected by cardiovascular magnetic resonance (CMR) imaging could be clinically important by affecting diagnosis, management and prognosis. Whether CMR impacts clinical care in those with known or suspected cardiac masses is not entirely clear.We identified consecutive patients referred to the University of Minnesota Medical Center (\"Minnesota\" cohort) between January 1, 2007 and December 31, 2013, and the University of Pittsburgh Medical Center between October1, 2009 and May 30, 2014 (\"Pittsburgh\" cohort) who were diagnosed with a potential cardiac mass before or after CMR. Final diagnoses were defined by clinician's opinion of histopathology or clinical evidence. Significant clinical impact was defined as CMR establishing a new diagnosis, affecting surgical procedures, or causing medication change as documented in the medical record.We identified 34 patients  with masses in the Minnesota cohort n = 1621) and 58 patients  in the Pittsburgh cohort (n = 3358). Overall, CMR resulted in significant impact in 71% (24/34) of the patients in the Minnesota cohort and 72% (42/58) in the Pittsburgh cohort (Table 621 and 5CMR of cardiac masses significantly impacts clinical management by facilitating accurate diagnosis and directing clinical management in a substantial percent of patients who had undergone prior evaluations with traditional imaging such as echocardiography. In addition, it also led to avoidance of surgical interventions in masses deemed to be benign or identified as thrombus. CMR is an essential step in the evaluation of majority of patients with cardiac masses or those suspected to be at high risk for developing cardiac masses."}
+{"text": "The development of novel targeted agents aimed at selective inhibition of dysregulated oncogenic pathways has been a major focus and advancing area in translational oncology research. In acute myeloid leukemia (AML) the first successes have been in targeting mutations in the receptor tyrosine kinase FLT3. Small molecule inhibitors targeting FLT3 have been in clinical use for the past two decades with many patients showing favorable initial responses; however, development of resistance occurs almost universally. Here we describe mechanisms of resistance to FLT3 inhibitors and ongoing studies aimed at overcoming it.Mutations in FLT3 (FMS-like tyrosine kinase 3) are the most common genetic alteration in patients with AML occurring in approximately 30% of adult and 15% of pediatric patients at the time of diagnosis ; howeverPreclinical studies demonstrating robust anti-leukemic effects of FLT3 inhibition lead to development of ATP-competitive tyrosine kinase inhibitors (TKIs) targeting mutated FLT3 for clinical use. First generation agents with activity against FLT3 such as sunitinib, sorafenib, and midostaurin were multi-kinase inhibitors that also targeted related receptors such as PDGFR and KIT. Given the multi-kinase nature of these compounds, their use was limited due to poor potency against FLT3 and increased toxicity due to off-target activity. To address these concerns, the second-generation TKI, quizartinib (AC220) was developed with increased potency against and selectivity for FLT3. Initial responses to treatment with single-agent quizartinib were promising with 44% of relapsed or refractory FLT3-ITD AML patients achieving a composite complete remission in a phase II study ; howeverFurther analysis of patient samples to better understand mechanisms of relapse revealed secondary point mutations in the FLT3 kinase domain in patients who relapsed during quizartinib monotherapy.The most common quizartinib-resistance conferring mutations occur at the D835 and F691 loci and confer cross-resistance to the first-generation inhibitor sorafenib \u201319. MutaDevelopment of secondary point mutations represent the best characterized mechanism of acquired resistance to FLT3 inhibition; however, resistant FLT3-ITD cells lacking secondary point mutations have been frequently identified  indicatiActivation of parallel signaling pathways independent of the FLT3 receptor also plays a role in resistance to FLT3 inhibition. For example, upregulation of the receptor tyrosine kinase AXL has been implicated in resistance to TKIs in a number of tumor types \u201331. SimiThe above findings highlight some of the challenges to successful translation of FLT3 inhibition to clinical application. A number of new inhibitors and dual inhibition strategies have been developed to overcome these barriers. Two of the newer generation FLT3 inhibitors that have advanced the furthest in clinical development are crenolanib and gilteritinib. Crenolanib is a type 1 TKI that is highly selective for FLT3 and PDGFR and retains a high level of activity against D835 mutant FLT3 and to a lesser degree against the F691 gatekeeper mutation . In clinThe ongoing struggles to translate the preclinical promise of FLT3 inhibition into successful clinical use underscore the importance of a deep understanding of the biology of target receptors when developing translational strategies. As it is unlikely that FLT3 inhibition alone will be sufficient to induce durable remissions, ongoing research should be aimed at devising rational combination strategies with other targeted agents based upon understanding of the molecular mechanisms at play. Other promising preclinical lines of investigation include combination with MEK inhibitors  or targe"}
+{"text": "In late August and early September of 2017, Hurricanes Harvey and Irma swept through the Caribbean and made landfall in the continental United States. As Texas and Florida readied for direct impacts of the storms, nearby states prepared for the arrival of internally displaced persons. During the weeks surrounding the storms, the Tennessee Department of Health (TDH) supported all-hazards situational awareness for public health partners by enhancing syndromic surveillance activities, i.e., the monitoring of symptom combinations or other indicators within a population to inform public health action  data from 70 hospitals across Tennessee using the Electronic Surveillance System for Early Notification of Community-Based Epidemics (ESSENCE)  patient visits by Texas residents and 1,041 (0.4%) visits by Florida residents. The number of ED visits by patients from Texas remained stable during the monitoring period (average 7.3 per day). In contrast, there was an increase in patients from Florida visiting Tennessee EDs beginning 3 days before Hurricane Irma made landfall in the continental United States. The increase peaked on the day of impact in Florida (September 10) at 116 ED visits, and returned to baseline levels (between 10\u201320 patients per day) within 1 week . The incSyndromic surveillance data are often used to identify clusters of illness based on geography or time (At TDH, ESSENCE is the only easily accessible information source capable of rapidly collecting health information on out-of-state patients. This initiative allowed TDH to observe where and when out-of-state patients were seeking ED care in Tennessee and to monitor the need for targeted messaging and resources to heavily affected areas. Additionally, close surveillance of chief complaints among out-of-state patients provided assurance that no unusual patterns in illness or injury were occurring.Enhancing syndromic surveillance during these storms was an important strategy for improving situational awareness among public health stakeholders and will be incorporated into future response activities by TDH."}
+{"text": "MMWR Recommendations and Reports, \u201cPrevention of Measles, Rubella, Congenital Rubella Syndrome, and Mumps, 2013: Summary of Recommendations of the Advisory Committee on Immunization Practices (ACIP),\u201d an error occurred in the third sentence of the first paragraph under the heading \u201cMeasles Component\u201d on page 8. That sentence should read:In the 1967), live attenuated vaccines containing the Edmonston B (available in the United States from 1963 through 1975), and Schwarz strain (available in the United States from 1965 through 1976).\u201cBecause of increased efficacy and fewer adverse reactions, the vaccine containing the Enders-Edmonston vaccine strain replaced previous vaccines: inactivated Edmonston vaccine (available in the United States from 1963 through"}
+{"text": "Odocoileus virginianus) in Illinois, USA, to investigate the potential effect of landscape on social network structure by weighting the edges of seasonal social networks with association rate (based on proximity inferred from GPS collar data). At the local level, we found that sociality among female deer in neighboring social groups (n = 36) was mainly explained by their home range overlap, with two exceptions: 1) during fawning in an area of mixed forest and grassland, deer whose home ranges had low forest connectivity were more social than expected; and 2) during the rut in an area of intensive agriculture, deer inhabiting home ranges with high amount and connectedness of agriculture were more social than expected. At the global scale, we found that deer populations (n = 7) in areas with highly connected forest-agriculture edge, a high proportion of agriculture, and a low proportion of forest tended to have higher weighted network closeness, although low sample size precluded statistical significance. This result implies that infectious disease could spread faster in deer populations inhabiting such landscapes. Our work advances the general understanding of animal social networks, demonstrating how landscape features can underlie differences in social behavior both within and among wildlife social networks.Intraspecific social behavior can be influenced by both intrinsic and extrinsic factors. While much research has focused on how characteristics of individuals influence their roles in social networks, we were interested in the role that landscape structure plays in animal sociality at both individual  and population  levels. We used female white-tailed deer ( Loxodonta africana) ) density ,20, pred density , and hun density ,23. The  was low , African drought , oribi . Female white-tailed deer represent an interesting model to explore social behavior because they form matrilineal social groups )S1 FigWe randomly selected an increasing number of locations for each dyad, calculated association rate, and repeated this 100 times. The solid line represents the seasonal association rate . The dashed lines represent the association rate that we would expect for a dyad with one more or one less association than what we observed for our focal dyad across the entire season; if the mean subsampled association rate was within these bounds, then the error associated with the number of locations should not interfere with our rank order of association rates. The value in the upper right corner is the number of locations at which the association rate was within the dashed lines.(DOCX)Click here for additional data file.S2 FigBoxes represent the median (centre line) and the first and third quartiles (the range that contains 50% of the data). Whiskers represent the highest (lowest) value that is within 1.5*interquartile range. Points represent outliers and vertical lines delineate seasons. Data were pooled over study area  and year (2004\u20132009).(DOCX)Click here for additional data file.S3 FigThe upper map is a conductance surface, where white represents forest  and black represents absence of forest . The lower map represents current density (white is high current and black is low current) across the forest conductance surface between pairs of sites . The white box outlines the study area; the map outside of the box was later clipped to remove current density that was likely biased high due to the arbitrary placement of the 50 sites.(DOCX)Click here for additional data file.S4 FigWhite represents high current density of forest, agriculture, or the edge between forest and agriculture, and black represents low current density. Current density is analogous to random walkers moving across the landscape between sites located around the perimeter of the buffered study areas .(DOCX)Click here for additional data file.S5 FigWe used a Box-Cox power transformation on the dependent variable  to redu(DOCX)Click here for additional data file.S6 FigWe estimated home range overlap as the volume of intersection (VI) of 95% kernel utilization distributions  for each(DOCX)Click here for additional data file.S7 FigAn example of a) the configuration of forest  and non-forest , and b) the corresponding current density of forest  in a portion of the Carbondale, IL study area. Areas of high current density (the probability of movement through a cell) tend to be where corridors of forest are surrounded by non-forest .(DOCX)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 TableCoefficients with 95% CI that did not overlap zero are in bold font.(DOCX)Click here for additional data file.S5 TableCoefficients with 95% CI that did not overlap zero are in bold font.(DOCX)Click here for additional data file."}
+{"text": "This article provides descriptive detailed (pre and post) values of physical capacity variables, NT-proBNP, physical activity levels and quality of life in patients with pulmonary arterial hypertension (PH)  by New York Heart Association (NYHA) class before and after an 8-month exercise intervention. The data are supplemental to our original Randomized Controlled Trial (RCT) entitled \u201cBenefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi+12 trial\u201d  [1]. Specifications TableValue of the data\u2022Data presented here provide the descriptive overview of the PH patients by NYHA class involved in an exercise RCT.\u2022We describe the changes in physical capacity-related primary outcomes (peak watts in leg and bench press) and the changes in physical capacity-related secondary outcomes  of the PAH patients by NYHA class involved in the RCT (control vs. intervention).\u2022We describe values of physical activity (PA) levels (min/day in inactivity and moderate-vigorous PA) of PH patients by NYHA class involved in the RCT (control vs. intervention).\u2022We show the values of health related quality of life  of PH patients by NYHA class involved in the RCT (control vs. intervention).\u2022This data could be useful to physicians to make comparisons with other cohort datasets and so to contribute to the knowledge of the PA effect in PH patients by NYHA class.1NCT02288442) conducted from January 2015 to June 2016 at the Hospital 12 de Octubre  following the Consolidated Standards of Reporting Trials (CONSORT) guidelines Descriptive values of physical capacity-related variables, NT-ProBNP, cardiopulmonary exercise capacity, PA levels and HRQoL of PAH patients involved in the RCT 220 PH patients were involved in the intervention group of the RCT and 20 PH patients in the control group. The RCT intervention lasted 8 weeks and included 3 main components: aerobic and muscle resistance, and specific inspiratory muscle training. All sessions were supervised by experienced fitness instructors. Data outcome (by order of aquisition) were: i) blood sampling for NT-proBNP determination, PImax, 6MWD, muscle power, 5-STS, and distribution of HRQoL questionnaire (1st day); ii) cardiopulmonary exercise testing ; and iii) seven days of accelerometry recording for objective PA determination. Please see Gonzalez-Saiz et al. (2017)"}
+{"text": "Human cytomegalovirus (CMV) remains the most common infection affecting organ transplant recipients. Despite advances in the prophylaxis and acute treatment of CMV, it remains an important pathogen affecting the short- and long-term clinical outcome of solid organ transplant recipient. The emergence of CMV resistance in a patient reduces the clinical efficacy of antiviral therapy, complicates therapeutic and clinical management decisions, and in some cases results in loss of the allograft and/or death of the patient. Common mechanisms of CMV resistance to ganciclovir have been described chiefly with the UL97 mutations. Here we evaluate Incidence of ganciclovir resistance in 144 CMV-positive renal transplant recipients and its association with UL97 gene mutations. Active CMV infection was monitored by viral DNA quantification in whole blood, and CMV resistance was assessed by UL97 gene sequencing. Six mutations in six patients were detected. Three patients (2.6%) of 112 patients with history of ganciclovir (GCV) treatment had clinical resistance with single UL97 mutations at loci known to be related to resistance . three patients who were anti-CMV drug na\u00efve had single UL97 mutations (D605E) without clinical resistance. Our results confirm and extend our earlier findings on the specific mutations in the UL97 phosphotransferase gene in loci that have established role in ganciclovir resistance and also indicate that clinical ganciclovir resistance due to UL97 gene mutations is an issue in subjects with history of with ganciclovir treatment. D605E mutations remains a controversial issue that needs further investigations.  Human cytomegalovirus (CMV) is a member of the Betaherpesviridae subfamily that belongs to Herpesviridae family, a significant human pathogen . The preIn immunocompetent individuals, primary infections are mostly subclinical and self-limited. In contrast, infections in immunocompromised persons including organ transplant recipients are accompanied by some important morbidity and mortality . CMV remIt was in the 1980s that Resistance of CMV to antiviral agents was first observed in the laboratory. OccurreAmong The 3 common antiviral drugs, ie, GCV, foscarnet, and cidofovir, ganciclovir targets both UL97 and the UL54 gene where foscarnet and cidofovir target just UL54 gene , 13. In Since GCV is the first-line treatment for CMV infections in immunocompromised patients , and ComPatients and methodsPatient population and CMV isolates0C until tested. In accordance with Shahid Beheshti University of Medical Sciences law, only patients who consented to the review of their medical records were included.The aim of this study was to investigate prevalence of GCV resistance in CMV-positive renal transplant recipients and its association with UL97 gene mutations. We utilized clinical specimens submitted to one of the private Virology Laboratory in Tehran for CMV quantitative measurement. A total of 144 post kidney transplant patients (from different transplant centers in Tehran), with quantitative PCR > 2000 copies/mL were included in the study for UL97 sequencing. After obtaining whole blood from patients\u2019 plasma viral DNA was extracted using QIAamp DNA Minikit (Qiagen), in accordance with the manufacturer\u2019s instructions. Viral DNA purification efficiency was analyzed by means of a dual-color detection system supplied with the kit and then they were stored at -20 UL97 gene analysisDrug resistance was evaluated for the UL97 region only by a readily available assay using detection methods previously reported , BrieflyPatients and virus isolates3 to 8\u00d7106 copies/mL serum) were studied. One hundred and forty-four CMV isolates , from 144 immunocompromised patients (post kidney transplantation) with viral load >2000 copies/mL . Clinical data and results of genotypic studies are summarized in Definition of drug resistance and UL97 gene mutation Definition of drug resistance: (no improvement (or with relapses) in CMV viremia or clinical disease during prolonged antiviral therapy especially in the presence of risk factors. Generally, prolonged therapy means 6 or more weeks of cumulative antiviral drug exposure, including more than 2 weeks of ongoing full dose therapy at the time of evaluation). Analysis of CMV DNA by sequencing revealed the presence of 6 single UL97 gene mutations in six patients who had received treatment with GCV .Three patients (2.6%) of 112 patients with history of GCV treatment had clinical resistance with single UL97 mutations at loci known to be related to resistance including an Ala-to-Val mutation at codon 594, MET-to-Thr mutation at codon 460 , and His-to-Gln mutation at codon 520. 3 patients had UL97 mutation without clinical resistance. No clinical resistance or UL97 mutation were observed among patients who were anti-CMV drug na\u00efve. The 6 patients with UL97 mutations were followed for 6 month to see the outcomes.Ganciclovir resistance and clinical outcomeDemographic and clinical characteristics and the outcomes of the 3 patients with UL97 confirmed mutations without clinical resistance and 3 patients with UL97 mutations and clinical drug-resistant are presented in In 3 patients with UL97 mutations without clinical resistance no relapses were seen.Our goal in this study was to determine incidence of ganciclovir resistance in CMV-positive renal transplant recipients and its association with UL97 gene mutations in Iranian post kidney transplant patients. In this study, we analyzed viral DNA in the blood of 144 post kidney transplantation patients (32 patients were anti-CMV drug na\u00efve) with CMV (> 2000 copies/mL) in order to determine incidence of GCV resistance and identify mutations in the CMV UL97 gene associated with clinical resistance to GCV. Clinical GCV resistance with UL97 conformed mutations were detected in 3 of 112 patients (2.6%) with history of GCV treatment. No clinical resistance or UL97 mutation were observed among patients who were anti-CMV drug na\u00efve. GCV has been the drug of choice for treatment of systemic CMV disease. However, long-term therapy, ongoing active viral replication due to factors such as the lack of prior CMV immunity (D+/R-), high levels of immunosuppressive therapy, and suboptimal drug concentrations increase the risk of development of GCV resistance. The UL97 gene is by far the most frequent site of mutations conferring GCV resistance, and extensive work by a number of groups established that nucleotide changes associated with GCV resistance are clustered at codons 460, 520, and 590 to 607. These mutations are A594V, M460T, and H520Q , 15. In The outcome of patients with CMV disease because of ganciclovir-resistant CMV is generally poor, manifested by a high rate of allograft loss as illustrated in our study and those of others -30. In oIn conclusion, CMV disease caused by drug resistant virus is not an uncommon consequence of widespread and increasing rate of GCV use and increase in the incidence of drug-resistant CMV could be subsequent issue. The observations in this study may therefore foreshadow the emergence of drug-resistant CMV as an entity that could threaten the outcome of transplantation. The morbidity of clinical disease because of drug-resistant CMV, the complexity of its treatment, and the poor outcome of patients should be taken into consideration in the determination of concise role of different mutations and their association with clinical resistance and afterword development of optimized strategies for prevention of drug-resistant CMV and also development of drugs with less toxicity."}
+{"text": "Bencao (materia medica) literature review is the very first step in the standard authentication procedure of Chinese medicinals. As an important part of China\u2019s cultural heritage, these various bencao (materia medica) texts represent centuries of accumulated wisdom in combating disease and preserving health. In this short review, bencao (materia medica) classics of China are broadly divided into three major categories in our routine practice: mainstream bencao (materia medica), thematic bencao (materia medica) and regional bencao (materia medica). The overall significance and current situation of exploration of bencao (materia medica) literature are summarized as well.Books that record the sources and applications of medicinal materials are commonly known as  The Chinese term \u201cbencao\u201d, which literally means \u201crooted in herbs\u201d, reflects the fact that most medicinal materials are derived from botanical sources. Bencao (materia medica) texts of past dynasties primarily describe three aspects of Chinese medicinals: medicinal materials, medicinal properties, and medicinal principles. As an important part of China\u2019s cultural heritage, these various bencao (materia medica) texts represent centuries of accumulated wisdom in combating disease and preserving health. The Complete Collection of Traditional Texts on Chinese Materia Medica, a 410-volume and 246,000-page collection complied by the Association of Chinese Culture Research, includes more than 800 bencao (materia medica) classics from 220 BC to 1911 AD. This collection highlights the value of traditional Chinese medicine (TCM) as a rich source for knowledge-based medical rediscovery due to its documentation of clinical experiences over thousands of years, and also illustrates the monumental challenge of selecting the best parts of TCM for modern innovation bencao (mbencao (materia medica) literature is uniquely developed in Chinese medicine, and represents a tremendous historical and cultural resource as well as an important reference point for clinicians, medical historians, and scientists in disciplines such as new drug discovery and Chinese medicinal authentication. Authentication is fundamental for Chinese medicinal standardization, and bencao (materia medica) literature review is the very first step in the standard authentication procedure of Chinese medicinals bencao (mbencao (materia medica) classics of China are broadly divided into three major categories: (a) mainstream bencao (materia medica): the most influential bencao (materia medica) classics from key historical periods, (b) thematic bencao (materia medica): specialized bencao (materia medica) texts dedicated to specific topics, and c) regional bencao (materia medica): bencao (materia medica) texts focused on medicinal materials from specific regions.In practice, bencao (materia medica) literature. They are the most influential classics from key historical periods.The Divine Husbandman\u2019s Classic of Materia Medica (Shen Nong Ben Cao Jing) This is the earliest extant bencao (materia medica) text, compiled in the Eastern Han Dynasty (25\u2013220 AD). This text records 365 medicinals and summarizes medicinal experiences up to the Han Dynasty. Medicinals are classified into three categories  based on their medicinal effects and toxicity. Entries for each medicinal substance include nomenclature, properties, compatibilities, and medical applications. Descriptions of production regions and the ecological environment of some medicinal plants are also recorded briefly.Collection of Commentaries on the Classic of the Materia Medica (Ben Cao Jing Ji Zhu) Tao Hongjing, a physician of the North and South Kingdoms period (420\u2013589 AD), compiled this text by preserving and annotating The Divine Husbandman\u2019s Classic of Materia Medica (Shen Nong Ben Cao Jing) and adding another 365 medicinals. It records 730 medicinals and established the framework of bencao (materia medica) compilations adopted by later generations. In this book, medicinal substances are further classified into seven categories based on their natural properties: jades/stones, herbs, trees, insects/beasts, fruits/vegetables, crops, and medicinals with names but without actual applications.Newly Revised Materia Medica (Xin Xiu Ben Cao) In 659 AD, commissioned by the government of the Tang Dynasty (618\u2013907 AD), this text records 850 medicinals and is considered to be the earliest national pharmacopoeia in China.Materia Medica Arranged According to Pattern (Zheng Lei Ben Cao) Compiled by a physician named Tang Shenwei and published in 1108 AD, this is the most praiseworthy bencao (materia medica) of the Song Dynasty (960\u20131279 AD) as it comprehensively summarizes herbal knowledge up to that time. There are three versions of this book  currently in circulation. It records 1746 medicinals and is the only bencao (materia medica) text from the Song and previous dynastic periods that survived intact. It features clearly preserved quotations from previous works and stands out as an important reference point for bencao (materia medica) knowledge leading up to the Song Dynasty.Compendium of Materia Medica (Ben Cao Gang Mu) Written by Li Shizhen, a physician of the Ming Dynasty (1368\u20131644 AD), this text was first published in 1596. It records 1892 medicinal substances. This massive and influential compilation represents the highest academic achievement among all the ancient Chinese bencao (materia medica). It not only comprehensively summarized medical knowledge up to the sixteenth century in China, but also contributed greatly to the development of natural sciences in the world.Over the past 2000\u00a0years, five monumental works stand out in the genre of bencao (materia medica) refer to specialized bencao (materia medica) texts dedicated to specific topics, such as medicinal processing, authentication, dietary therapy, and medicinal properties. Examples include Grandfather Lei\u2019s Treatise on Herbal Processing (Lei Gong Pao Zhi Lun) and Origins of the Materia Medica (Ben Cao Yuan Shi). The former is the first monograph on Chinese medicinal processing, written in about 500 AD in the North and South Kingdoms period; it summarizes the literature and experiences of the ancient practice of processing. The latter stands out in the history of bencao (materia medica) as an outstanding monograph on macroscopic identification, written by Li Zhongli in the Ming Dynasty (1368\u20131644 AD). It is characterized by detailed illustrations and descriptions of diagnostic features of raw medicinal materials. Other examples of thematic bencao texts include the Materia Medica of Dietary Therapy (Shi Liao Ben Cao) of the Tang Dynasty and the Materia Medica for Decoctions (Tang Ye Ben Cao) of the Yuan Dynasty (1279\u20131368 AD). The former was dedicated to the theory and practice of dietary therapy, and the latter to the theory of medicinal properties and clinical experience.Thematic bencao (materia medica) texts record knowledge related to medicinal substances derived from specific local regions. Examples include the Materia Medica from Steep Mountainsides (Lu Chan Yan Ben Cao) and the Essentials of Raw Herbs in Lingnan (Sheng Cao Yao Xing Bei Yao). The former was the first regional bencao (materia medica) with color illustrations dedicated to local medicinal plants; compiled in 1220 AD in the Song Dynasty, it focused on the area around modern-day Hangzhou. The latter was compiled in 1711 AD in the Qing Dynasty (1644\u20131911 AD); it records botanical medicinals used in the Lingnan region, a geographic area located in the southern part of China.Regional Bencao (materia medica) tradition provides a rich record of knowledge that has been gradually refined for centuries, opening a window into the cultural tradition of scholarship and textual research that defines TCM. Bencao (materia medica) literature such as the Compendium of Materia Medica (Ben Cao Gang Mu) illustrates important developments in the broader history of natural sciences in China, and this text has been translated into European languages since 1735 AD. In recent decades, exploration of bencao (materia medica) literature has facilitated dramatic medical discoveries, such as the anti-malarial drug artemisinin from sweet wormwood  [bencao (materia medica) literature remains underestimated outside of the TCM community. Therefore, in addition to other aspects of TCM, attention is needed to preserve the cultural resources that lie at the heart of bencao (materia medica).However, at present, the overall significance of daodi medicinal materials, medicinal authentication and Chinese medicinal processing are closely connected to bencao (materia medica) literature [bencao (materia medica) research depends upon a multidisciplinary approach that protects the past while embracing the future.Although our research efforts related to terature \u20139, the f"}
+{"text": "Oxytocin and vasopressin mediate a range of physiological functions that are important for osmoregulation, reproduction, social behaviour, memory and learning. The origin of this signalling system is thought to date back ~600\u2009million years. Oxytocin/vasopressin-like peptides have been identified in several invertebrate species and they appear to be functionally related across the entire animal kingdom. There is little information available about the biology of this peptide G protein-coupled receptor signalling system in insects. Recently over 200 insect genome/transcriptome datasets were released allowing investigation of the molecular structure and phylogenetic distribution of the insect oxytocin/vasopressin orthologue \u2013 inotocin peptides and their receptors. The signalling system is present in early arthropods and representatives of some early-diverging lineages. However, Trichoptera, Lepidoptera, Siphonaptera, Mecoptera and Diptera, lack the presence of inotocin genes, which suggests the peptide-receptor system was probably lost in their common ancestor ~280\u2009million-years-ago. In addition we detected several losses of the inotocin signalling system in Hemiptera , and the complete absence in spiders (Chelicerata). This unique insight into evolutionarily patterns and sequence diversity of neuroendocrine hormones will provide opportunities to elucidate the physiology of the inotocin signalling system in one of the largest group of animals. Insects  constitute the largest and most diverse group of organisms on earth, contributing to at least half of the global species diversity1a-, V1b- and V2-receptors. Oxytocin and vasopressin signalling is involved in a variety of vital functions both in the periphery and the central nervous system. Oxytocin plays crucial roles in reproduction including uterine contraction or milk ejection, and functions as neurotransmitter in complex social behaviour such as bonding, stress or anxiety66910Here we took advantage of this opportunity to investigate the repertoire of oxytocin/vasopressin-like peptides, namely inotocin peptide hormone precursors, and their cognate family of receptors. Although this peptide G protein-coupled receptor (GPCR) signalling system is thought to date back more than 600\u2009million yearsIn the present study we analysed over 260 invertebrate species of insects and other arthropods for the presence of the inotocin peptide GPCR signalling system. By sequence mining of publicly available genome and transcriptome datasets it was possible to identify and annotate peptide precursor and receptor coding sequences. Furthermore we carried out sequence analyses for conserved motifs on the sequences that were found and performed a phylogenetic analysis of the inotocin receptors. This revealed a unique insight into the phylogenetic distribution and aspects of the evolution of the oxytocin/vasopressin-like peptide GPCR signalling system in arthropods.in 12 out of these 23 species that contain partial sequences we found putative inotocin receptor sequences as well; in the 11 remaining species we cannot exclude the possibility that these inotocin precursor sequences may have been derived as artefacts or sequencing errors] that shared similarity to the neurophysin domain of oxytocin/vasopressin-like precursors (Scolopendra subspinipes (centipede), Atelura formicaria (silverfish) and Leptinotarsa decemlineata (beetle) and three different precursor genes/transcripts in Calanus finmarchicus (crustacean)  . The twoX4CPXG  contain an alanine or serine residue instead of glycine in position 9; in addition we identified three sequences of putative decapeptides that contain a 4-residue tail before the processing site, i.e. CYIINCIDND in Scolopendra subspinipes, CFITNCPVGG within Lepeophtheirus salmonus and CFITNCPVGS within Caligus rogercresseyi. One unusual sequence had neither an amidated glycine nor a typical amidation processing site (Speleonectes cf. tulumensis - CFILDCPLM-IRN) and hence it remains doubtful whether this precursor will actually be processed to a mature inotocin-like peptide.Sequence analysis of all putative inotocin precursors revealed that there is some degree of conservation within parts of the cysteine-rich C-terminal neurophysin domain . HoweverX4CPXG  whereof X4CPXG . NotablyLimulus polyphemus (3 subtypes), Ixodes scapularis (3 subtypes), Metaseiulus occidentalis (2 subtypes), Varroa destructor (2 subtypes), Achipteria coleoptrata (2 subtypes), Platynothrus peltifer (5 subtypes) and Strigamia maritima (2 subtypes). Additionally we found 4 different subtypes in crustaceans, e.g. Daphnia magna , appear to be conserved, which allows distinguishing them from CCAP receptors that contain alanine and valine/leucine/phenylalanine, respectively (AXNPV/L/F) in these two positions (To distinguish inotocin receptors from closely related crustacean cardioactive peptide (CCAP) receptors, which share a high degree of sequence similarity and evolved by gene duplication before Protostomia and Deutorostomia have separated, we aimed to identify sequence motifs exclusively present in the inotocin receptors. Firstly we prepared an alignment of 68 CCAP receptors of insects available at NCBI and 68 invertebrate and vertebrate oxytocin/vasopressin-like receptors that have been previously analysedositions . To confositions .in silico mining strongly relies on raw sequence data quality, completeness of genomes and sampling size, some orders (for instance Mantophasmatodea and Strepsiptera) only contained a few sampled species and hence the apparent absence of the inotocin signalling system in these orders should be treated carefully. Furthermore we identified inotocin precursor and receptor sequences in one species (Arachnocampa luminosa) of the order Diptera (flies), which most likely was due to a contamination of the dataset (FITNCPXG (with some exceptions) is distributed among Chelicerata, Myriapoda, Crustaceans and early-diverging lineages of Hexapoda; the putative peptide CLITNCPKG is almost exclusively present in the monophyletic insects group Polyneoptera (inclusive orders of Zoraptera to Isoptera), and the putative peptide CLITNCPRG is prevalent amongst the latest diverged lines of insects (orders Thysanoptera to Coleoptera).Having identified both inotocin peptides and receptors it was of interest to map their presence across all sampled arthropod species. In 105 species we were able to identify both an inotocin-like precursor as well as the cognate receptor, and in another 64 species we could establish evidence for the presence of the inotocin peptide GPCR signalling system by identification of either peptide or receptor. In addition there are 100 species that showed no evidence for the presence of inotocin precursor sequences or receptors . Bearing dataset . The tax dataset . For exaHalyomorha halys (both inotocin precursor and receptor) and the large milkweed bug Oncopelcus fasciatus (inotocin precursor only); in Auchenorrhyncha it was found in the plant/leaf/froghoppers, but not in cicadas. In a total of 62 analysed species of Hymenoptera, all sawflies, wasps (30 species) and ants (20 species) were identified to contain components of the inotocin signalling system. In agreement with the scientific literature10There are some heterogeneous groups of which some species do and others don\u2019t contain components of the inotocin signalling system; for instance in Hymenoptera and Hemiptera there appear to be losses of inotocin precursor and receptor genes . In Hemi1617Tribolium castaneum11Locusta migratoria22Oxytocin and vasopressin peptide ligands and their cognate receptors comprise one of the oldest and best-studied peptide GPCR signalling systems. Being present across a range of distantly-related animal species and dating back more than 600\u2009million years in evolution, it has been an intriguing model system for comparative endocrinology and neurophysiology199C. elegans, possess oxytocin/vasopressin-like precursor and receptorsIn this project, we analysed the presence or absence of ligands and receptors of the inotocin signalling system in Arthropoda and compared these data to the recently established phylogeny10Speleonectes cf. tulumensis we did not find the dibasic amidation signal between the peptide and neurophysin domain. There are a few exceptions, for instance the Colorado potato beetle (Leptinotarsa decemlineata) which has two copies of inotocin prepropeptides that encode two different inotocin-like peptides (CLITNCPKG and CLITNCPIG) while all other analysed beetle datasets showed evidence only for one copy of the prepropeptide encoding for the putative mature inotocin peptide CLITNCPRG. Interestingly, six of the identified multi-copy receptor species were found within the subphylum Chelicerata and one in Myriapoda, but not a single species within the Hexapoda. We also analysed four different Daphnia magna transcripts of inotocin receptors, which are probably the result of alternative splicing since these sequences are almost identical except for minor deletions/insertions in intracellular loop 3 as well transmembrane domains 3 and 5. The presence of multiple copies in some of the species could be explained by whole genome or large scale duplication events, which have been reported for Limulus polyphemus26Ixodes scapularisCalanus finmarchicusStrigamia maritima3133343534After defining a global map for the phylogenetic distribution of inotocin peptide GPCR signalling system in insects and other arthropods, we aimed to analyse the molecular structure of inotocin peptides and receptors. The vast majority of all sampled species contain one gene encoding for the inotocin receptor and one for the precursor (referred to as prepropeptide). All of the identified prepropeptides have a similar structure containing a signal peptide, a mature inotocin domain, an amidation/processing signal and a neurophysin domain . Only wiin silico mining approaches10Scolopendra subspinipes, Lepeophtheirus salmonis and Caligus rogercresseyi are decapeptides. Such unusual \u2018longer\u2019 oxytocin/vasopressin-like analogues have previously been identified in C. elegans39Ciona intestinalisStyela plicataXIXNC) and are similar to the ancestral vasotocin sequence  were used to perform off-line database searches using tblastn and blastp (version 2.2.31) with an E-value cut-off of 10\u2009e\u22124 and default parameters \u22124) were discarded and other hits were manually annotated and verified.Selected published oxytocin/vasopressin-like and inotocin precursor amino acid sequences (Accessions: \u22124) were assigned and confirmed based on two unique sequence criteria: (i) presence of a conserved motif at the end of transmembrane domain 2 and at the beginning of extracellular loop 1 (XPQX2WX5-6F), and (ii) presence of a CXNPW motif in transmembrane domain 7  was used to perform alignments analysis of peptides, precursor proteins and receptor sequences. Signal peptides, mature peptide domain, amidation signal and neurophysin domain were assigned based on homology to query sequences. For the preparation of sequence logos the free WebLogo tool (http://weblogo.berkeley.edu/) was used.ClustalO .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "Specifications TableValue of the data\u2022The data presents specific surface area and pore size distribution of vanadium oxides hollow microspheres.\u2022The SEM images of the solvothermal reaction products using different volume ratio of isopropanol/ethylene glycol was characterized by field emission scanning electron microscopy  and showed an appropriate amount of ethylene glycol is important for the formation of uniform microspheres structure.\u2022The FESEM images and TEM images of the microspheres prepared with different solvothermal reaction time were characterized by field emission scanning electron microscopy  and transmission electron microscopy  and showed the morphology of core-shell microspheres.12 adsorption-desorption isotherm and the corresponding pore size distribution curves (inset) data. The SEM image in The 22.1Brunauer\u2212Emmett\u2212Teller (BET) absorption and the pore size distribution were measured on an Xtended Pressure Sorption Analyzer  at 77\u202fK. The specific surface area and pore diameter distribution of the samples were analyzed by BET and Barrett-Joyner-Halenda (BJH) methods. The morphology of the sample was determined using field emission scanning electron microscopy  and transmission electron microscopy ."}
+{"text": "The data presented in this paper shows the spatiotemporal expansion of Dire Dawa City (eastern Ethiopia) and the ensuing land use land cover changes in its peri-urban areas between 1985 and 2015. The data were generated from satellite images of Thematic Mapper (TM), Enhanced Thematic Mapper-Plus (ETM+) and OLI  with path/raw value of 166/053 by using Arc GIS 10.1 software. The precision of the images was verified by geolocation data collected from ground control points by using Geographic Positioning System (GPS) receiver. Four LULC classes  with their respective spatiotemporal dimensions were clearly identified in the analysis. Built up area had shown an overall annual increment of 15.8% (82\u00a0ha per year) from 517\u00a0ha in 1985 to 2976\u00a0ha in 2015. Expansion took place in all directions but it was more pronounced along the main road towards other nearby towns, recently established business/service areas and the Industrial Park. Barren land, farmland and vegetation areas showed speedy decline over the years. Specifications TableValue of the data\u2022The data is helpful to Dire Dawa City administrators to speculate the extent of the spatiotemporal expansion of Dire Dawa and its potential impacts on the surround areas.\u2022The data provides information on the status of urban expansion towards rural peri-urban areas around Dire Dawa City.\u2022The data is vital to model urban expansion towards rural peri-urban areas surrounding Dire Dawa City to mitigate its adverse impacts on the livelihoods of the people inhabiting the area and the ecosystem.\u2022The data is useful to researchers, urban planners and experts working in the field.1The data in this article provides information on the spatiotemporal expansion of Dire Dawa City (eastern Ethiopia) and the ensuing LULC changes in its peri-urban areas between 1985 and 2015. 2landsat images of 30\u00a0m spatial resolution and path/row values of 166/053 as well as GPS-based ground survey records were vital data sources for this data article. The images were geo-referenced with World Geodetic System (WGS) 1984 datum and Universal Transverse Mercator (UTM) projection system zone 37 North. The analysis comprised of layer stacking, radiometric correction, image enhancement, haze reduction, band combination and false color combination. Google earth maps of each year were used for GPS-based ground verification with a minimum of 20 spatially distributed ground control points in the area. Reconnaissance survey and researchers\u05f3 experience of the study area were also vital. With this pre-assessment, four LULC classification schemes such as built up area, farmland, vegetation and barren land were identified considering the standard classes defined by the US Geological Survey as well as the study detail and objectives TM (1985), ETM+ (2005) and OLI (2015) dry season"}
+{"text": "Global efforts to eradicate polio began in 1988, and four of the six World Health Organization (WHO) regions currently have achieved poliofree certification. Within the remaining two regions with endemic poliomyelitis (African and Eastern Mediterranean), Afghanistan, Nigeria, and Pakistan have never interrupted transmission of wild poliovirus (WPV). The primary means of detecting poliovirus transmission is surveillance for acute flaccid paralysis (AFP) among children aged <15 years, combined with collection and testing of stool specimens for detection of WPV and vaccine-derived polioviruses (VDPVs)Two principal indicators measure the quality of AFP surveillance. The first is the nonpolio AFP (NPAFP) rate ; an NPAFP rate \u22652 is considered sufficiently sensitive to detect WPV or VDPV cases if poliovirus is circulating. The second indicator is the collection of adequate stool specimens from \u226580% of patients with AFP  cases were reported in AFR in 2017. The four WPV1 cases that occurred in AFR in 2016 were reported from Borno state in Nigeria . Among tAmong the 21 EMR countries, 15,951 AFP cases were reported in 2016, and 19,035 in 2017. Two EMR countries (Afghanistan and Pakistan) reported WPV1 cases in 2016 (33) and 2017 (22). The number of WPV1 cases reported by Afghanistan remained constant (13 in 2016 and 14 in 2017); the number reported from Pakistan declined from 20 (2016) to eight (2017). In 2016, one cVDPV2 case was reported in EMR, in Pakistan. In contrast, during 2017, 74 cVDPV cases were reported from EMR. All cases were type 2 and occurred in Syria; the most recent case occurred in September 2017 , resultiSewage sample testing supplements AFP surveillance by identifying poliovirus transmission that might occur in the absence of detected AFP cases  isolate and identify poliovirus, 2) conduct intratypic differentiation (ITD) to identify WPV or screen for Sabin (vaccine) poliovirus and VDPV  genotype was the only WPV1 genotype circulating globally and was detected in Afghanistan and Pakistan. West Africa B1 (WEAF-B1) genotype was last detected in Nigeria in 2016. Sequence analysis associated with the SOAS genotype indicates that WPV1 cases might have been missed by AFP surveillance in 2017; orphan WPV1 isolates (those with less genetic relatedness [\u226498.5% in VP1 gene] to other circulating viruses) were associated with three of 22 WPV1 cases reported from Afghanistan and Pakistan, indicating possible gaps in AFP surveillance. In 2017, cVDPV viruses with extended divergence from the parental Sabin strain were also isolated from stool specimens of AFP cases and from environmental samples in three countries.The number of reported WPV cases declined to the lowest point ever in 2017; however, reported cVDPV cases increased from 2016 to 2017 because of major cVDPV2 outbreaks in the Democratic Republic of the Congo and Syria. Although most national-level surveillance quality indicators improved in 2017, considerable variation exists at subnational levels, particularly in inaccessible areas, and timely detection of circulating polioviruses can be hampered if active surveillance efforts are not rigorous. Repeated detection of WPV and cVDPV from sewage samples in locations where poliovirus cases have not been detected or where sewage detections have preceded detection in persons can provide early evidence of viral circulation within a community  . Strong supervision and monitoring of surveillance performance, especially at subnational levels, is important to achieve high-quality surveillance that can detect poliovirus transmission. Environmental surveillance has been an important supplement to AFP surveillance and, when carefully conducted in populations covered by sewage networks, can improve detection of circulating virus, particularly in high-risk areas with suboptimal AFP surveillance , the fewest number ever reported globally. Polio cases caused by circulating vaccine-derived polioviruses increased from four in 2016 to 96 in 2017 because of large outbreaks in Syria and the Democratic Republic of the Congo. Although surveillance performance indicators are improving at the national level, gaps remain, including at subnational levels. As polio cases decline, sensitive and timely surveillance becomes even more important. As long as polioviruses circulate in any country, all countries remain at risk."}
+{"text": "Heredity: The gene family that cheats Mendel. Published 20, June 2017sp (spore killing) and rsp (resistant to sp) genes in Neurospora bread molds\" with the sentence: \"Example: sk (spore killer) and rsk (resistant to sk) genes in Neurospora bread molds\" on panel B of Figure 1. Please note that this correction does not affect the results and conclusions of the original paper.The gene names in the example of the two-gene model provided on panel B of Figure 1 were incorrectly spelled and abbreviated. We have corrected this error by replacing the sentence \"Example: The corrected Figure 1 is shown here:The originally published Figure 1 is also shown for reference:The article has been corrected accordingly."}
+{"text": "Introduction. Postoperative pancreatic fistula formation remains the major complication after distal pancreatectomy. At our institution, we have recently developed a novel bovine serum albumin-glutaraldehyde sealed hand sutured fish-mouth closure technique of the pancreatic remnant during distal pancreatectomy. The aim of this study was to analyze the impact of this approach with regard to technical feasibility and overall postoperative outcome. Patients and Methods. 32 patients who underwent a bovine serum albumin-glutaraldehyde sealed hand sutured fish-mouth closure of the pancreatic remnant during distal pancreatectomy between 2012 and 2014 at our institution were analyzed for clinically relevant postoperative pancreatic fistula formation (Grades B and C according to ISGPF definition) and overall postoperative morbidity. Results. Three out of 32 patients (9.4%) developed Grade B pancreatic fistula, which could be treated conservatively. No Grade C pancreatic fistulas were observed. Postpancreatectomy hemorrhage occurred in 1 patient (3.1%). Overall postoperative complications > Clavien II were observed in 5 patients (15.6%). There was no postoperative mortality. Conclusion. The performance of a bovine serum albumin-glutaraldehyde sealed hand sutured fish-mouth closure of the pancreatic remnant was shown to be technically feasible and may lead to a significant decrease of postoperative pancreatic fistula formation after distal pancreatectomy.  Distal Pancreatectomy (DP) is performed as the standard procedure in patients with malignant, cystic, or neuroendocrine tumors and/or chronic pancreatitis in the body and tail of the pancreas . ContinuWe retrospectively analyzed 33 consecutive patients who underwent a bovine serum albumin-glutaraldehyde (BioGlue) sealed fish-mouth closure of the pancreatic remnant during distal pancreatectomy for primary malignant or cystic tumors of the pancreas as well as for chronic pancreatitis at the Department of General, Visceral and Transplantation Surgery, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Campus Virchow, between January 1, 2012, and January 1, 2015. All operations were performed by five experienced visceral surgeons who were all educated about the technical steps of this novel procedure as part of the inclusion criteria of this study. This study was performed in accordance with the Declaration of Helsinki and its amendments and approved by the institutional ethic committee.DP was performed as open surgery in each patient. The extent of the pancreatic resection, as well as the need for additional lymphadenectomy and splenectomy, was determined based on the underlying disease and/or cancer stages. The pancreatic resection was performed in all cases using electrocautery in an incision line, which creates a fish-mouth shaped cutting surface of the pancreatic remnant . After aThe levels of amylase and/or lipase in the blood and in the intra-abdominal drains were routinely measured on the 2nd and 5th postoperative day or immediately in the presence of laboratory or clinical signs of infection. Oral food intake was usually begun on the second postoperative day depending on the patient condition and bowel function. The drains were usually removed within 6 postoperative days if the output was clear and if there were no signs or symptoms of infection. We did not perform a standardized Somatostatin analogue  prophylaxis for POPF prevention and pancreatic enzyme were only supplemented in the event of clinical signs of exocrine pancreatic insufficiency.We also did not use a standardized protocol for POPF treatment. The drains were left in situ or replaced interventionally and continuous rinsing of the drain was initiated until the drain secretion was clear and the amylase/lipase had declined back to normal values. A cessation of oral food intake and/or eventually octreotide administration during POPF treatment was decided on individual basis in each patient.The patients who had undergone an additional splenectomy received haemophilus, pneumococcal, and meningococcal vaccination according to current guidelines .All patients were observed in our outpatient department for a postoperative period of at least 30 days.Data collection in all patients included relevant information on their medical history, the pathological examination with regard to the underlying disease and resection margin status and the overall postoperative clinical outcome with documentation of any significant procedure related morbidity, the need for reintervention or reoperation, and the length of hospital stay. Postoperative morbidity was classified according to the Clavien-Dindo classification . POPF anBesides a general analysis of the technical feasibility of this novel approach the primary outcome of our study was to investigate the rate of clinically relevant POPF equivalent to POPF Grades B and C. All other complications within 30 days of the operation were also recorded.Statistical analysis was performed using PASW statistics 19 . Continuous variables were reported using mean or median values where appropriate with range, whereas categorical variables were described using frequencies and percent.Between January 1, 2012, and January 1, 2015, 32 consecutive patients underwent a bovine serum albumin-glutaraldehyde sealed fish-mouth closure of the pancreatic remnant during distal pancreatectomy.There were 15 males (47%) and 17 females (53%) with a median age of 62 years (32\u201377). The indication for distal pancreatectomy was pancreatic adenocarcinoma in 11 patients (34%), intraductal papillary mucinous neoplasm (IPMN) of the pancreas in 7 patients (22%), chronic pancreatitis in 3 patients (9%), neuroendocrine tumors (NET) of the pancreas in 2 patients (6%), mucinous cystic neoplasms (MCN) of the pancreas in 3 patients (9%), cyst adenoma in 4 patients (13%), cyst adenocarcinoma in 1 patient (3%), and leiomyosarcoma in 1 patient (3%). Two of the 32 patients (6%) underwent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic papillotomy (EPT) and endoscopic pancreas stent placement prior to the operation .A splenectomy was performed in 27 of the 32 patients (84%). Seven patients (22%) underwent an additional multivisceral resection with partial or total gastrectomy in 4 patients (13%), colon resection in 5 patients (16%), and/or partial adrenalectomy in 3 patients (9%). The mean operation time was 199 minutes (116\u2013282 minutes). No patient required intraoperative administration of packed red blood cells. The pancreas tissue texture was found to be soft in 13 patients (41%) and hard in 19 patients (59%) according to the intraoperative assessment of the operating surgeon. Major postoperative morbidity > Clavien II occurred in 5 of the 32 patients (16%). Three patients (9%) developed a clinically relevant POPF Grade B. Each of the three patients could be treated conservatively with a however prolonged hospital stay of 40, 71, and 93 days. No Grade C pancreatic fistulas were observed. Postpancreatectomy hemorrhage Grade A occurred in one patient (3%) as an intraluminal bleeding, which did not require therapeutic consequences. Two patients underwent reoperations, due to an insufficiency of a colon anastomosis in one patient and an abdominal fascial dehiscence in another patient. There was no postoperative mortality. The median length of hospital stay was 12 days (7\u201393) .Postoperative pancreatic fistula formation remains the most relevant complication after distal pancreatectomy with a major impact on postoperative quality of life as well as on health care costs. In patients with an underlying malignant disease POPF may in addition lead to a delayed onset of further essential adjuvant treatment which has been identified as an independent risk factor for early peritoneal recurrence and decreased overall survival .Numerous surgical techniques have therefore been described in an attempt to possibly decrease the incidence and impact of POPF. However, even two recent prospective randomized trials failed to identify an ideal technique for the procedure with the pancreatic remnant. The DISPACT trial compared a stapler versus hand-sewn closure of the pancreatic remnant and the incidence of clinically relevant POPF Grades B and C was reported with 20% and 21% in each group . AnalogoThe creation of a fish-mouth shaped cutting margin of the pancreatic remnant may of course be challenging especially in a rather thin gland and may also be associated with an increased bleeding tendency . Also thThe use of bovine serum albumin-glutaraldehyde (BioGlue) as a sealant is of course rather expensive especially in comparison to widely used fibrin glue. However, several studies showed that the use of fibrin for sealing the cutting surface after PD or DP as well as for occlusion of the main pancreatic duct was not associated with a reduction of POPF , 35. In Complications of bovine serum albumin-glutaraldehyde (BioGlue) application reported in cardiovascular and pulmonary surgery include nerve damage, local or embolic vascular obstruction, and foreign body reactions , 37. L\u00e4mIt should of course be noted that any kind of additional physical barrier may lead to a delayed onset or at least clinical presentation of POPF . As partA reduction in the incidence of POPF may of course not just be achieved by restricting on surgical technical factors alone. Several studies have reported an improved postoperative outcome if EPT or pancreatic stent placement were performed prior to DP . This po"}
+{"text": "We report the results of pathologic examinations of 2 fetuses from women in Colombia with Zika virus infection during pregnancy that revealed severe central nervous system defects and potential associated abnormalities of the eye, spleen, and placenta. Amniotic fluid and tissues from multiple fetal organs tested positive for Zika virus. In October 2015, Colombia confirmed its first case of autochthonous Zika virus infection  with brain tissue loss, including absence of cerebral hemispheres . Amniotic fluid sampled at 17 weeks was positive for Zika virus by real-time reverse transcription PCR (rRT-PCR). The fetus was at 20 weeks of gestation when evaluated.Case 2 involved a 15-year-old pregnant resident of Bogot\u00e1 who reported symptoms compatible with Zika virus disease, including generalized rash for 2 days and myalgia, after travel to a municipality with prevalent Zika virus infections, with onset occurring at 16\u201320 weeks of gestation. She had an uncomplicated obstetric history with 1 prior live birth. Prenatal care started in week 26; an ultrasound at that time showed a fetus with abnormal clefts in the cerebral hemispheres of the brain , with cleft walls separated and filled with cerebrospinal fluid (open lip). Follow-up ultrasound indicated large regions of parietal and temporal brain parenchymal loss. The fetus was evaluated and Zika virus diagnosis confirmed at 27 weeks of gestation.Autopsies of fetal organs and placenta with anatomic pathology and microscopic evaluation were performed for both fetuses. Tissue samples were fixed in 10% neutral-buffered formalin and fixed in paraffin; 4-\u03bcm-thick cuts were stained with hematoxylin and eosin for morphologic analysis with light microscopy. RNA was extracted from fresh tissue by using a TRIzol plus RNA purification kit . We used rRT-PCR for the detection of Zika virus (NS5) and 1-step RT-PCR for the detection of the envelope protein\u2013coding region (360 bp) were performed as previously described , which highlights the potentially long window of vulnerability to adverse outcomes among pregnant women with Zika virus infection.\u2013Persistent viremia in maternal serum has been previously reported (Given the epidemic levels of Zika virus disease being reported in Colombia and the severe outcomes associated with congenital infection, we call attention to the importance of healthcare providers reporting cases of Zika virus disease for adequate public health surveillance. Recommendations might include enhanced surveillance of acute cases among pregnant women and stillbirths and abortions related to Zika virus disease during pregnancy, as well as adverse outcomes among live births. Collecting information on congenital Zika virus infection is important to helping public health authorities effectively address this new health threat and make evidence-based decisions, which will benefit Colombia and other countries throughout the world."}
+{"text": "Energy Information Administration\u05f3s International Energy Statistics (http://www.eia.gov/cfapps/ipdbproject/IEDIndex3.cfm?tid=44&pid=44&aid=2) and the Barro-Lee Educational Attainment Dataset (http://www.barrolee.com). These data can be used to examine the relationships between economic growth and different forms of energy consumption.The data presented in this article are related to the research article entitled \u2018Economic Growth, Fossil Fuel and Non-Fossil Consumption: A Pooled Mean Group Analysis using Proxies for Capital\u2019  The dataset is made publicly available to promote further analyses. Specifications TableValue of the data\u2022The data are useful for analysing the relationship between economic growth and different forms of energy consumption.\u2022The data are publicly available, but are dispersed within several different sources.\u2022The data are collected for 53 countries with varying levels of economic development.\u2022Other researchers may find the data useful for different types of analysis in areas such as environmental and development economics.1The data comprises real gross domestic product (GDP) and physical capital from the World Bank, fossil fuel and non-fossil fuel consumption from the U.S. Energy Information Administration and human capital from the Barro-Lee Educational Attainment Dataset for 53 countries over the period 1990\u20132012. Real GDP and physical capital stock are in millions of 2005 US dollars, fossil and non-fossil fuel consumption are both measured in trillions of British thermal units and human capital is in millions.2The data on real GDP were obtained from the World Bank\u05f3s World Development Indicators (WDI) The data on physical capital were constructed by accumulating real gross fixed capital formation (obtained from the WDI) assuming a constant depreciation rate using the perpetual inventory method Hit) were constructed as follows:Lit=total labour force sit=average years of schooling (obtained from r=return to education, set at 10% following The data on human capital (All the data were converted into logarithms for the purposes of the analysis"}
+{"text": "Maintaining genome stability is essential for preventing various human diseases including cancer. Previous studies have elucidated multiple cellular mechanisms for genome maintenance, which can be classified into two major groups: one that deals with replication-associated abnormalities, and the other that repairs various DNA lesions. The replication fidelity maintenance mechanisms involve DNA polymerases and the DNA mismatch repair pathway. While replicative DNA polymerases and the mismatch repair system are responsible for correcting mispairs generated during DNA replication , 2, tranCell and Bioscience presents a series of reviews attempting to provide an overview of the latest breakthroughs and developments in the field. Specifically, this series focuses on (1) novel regulation of DNA damage response by ubiquitinating and deubiquitinating enzymes ; (2) the impact of bulky DNA lesions on error-prone or error-free transcription ; (3) the genome maintenance function of Fanconi anemia proteins ; (4) new factors and mechanisms of DNA break end joining (Wang and Xu); (5) mutagenic and tumorigenic activities of APOBEC3B ; and (6) nonsense RNA-mediated cellular surveillance pathway .Building on the previous discoveries, recent investigations in the field have revealed new insights into the mechanisms of the genome maintenance systems. In this thematic series, It is our sincere hope that this thematic series brings our readers enlightenment and offers sufficient introductory information to help them appreciate the new breakthroughs and developments in the field."}
+{"text": "Arabidopsis thaliana. The first analysis was of two gene families with key roles in regulation of oil quality and in particular the accumulation of oleic acid, namely stearoyl ACP desaturases (SAD) and acyl-acyl carrier protein (ACP) thioesterases (FAT). In both cases, these were found to be large gene families with complex expression profiles across a wide range of tissue types and developmental stages. The detailed classification of the oil palm SAD and FAT genes has enabled the updating of the latest version of the oil palm gene model. The second analysis focused on disease resistance (R) genes in order to elucidate possible candidates for breeding of pathogen tolerance/resistance. Ortholog analysis showed that 141 out of the 210 putative oil palm R genes had homologs in banana and rice. These genes formed 37 clusters with 634 orthologous genes. Classification of the 141 oil palm R genes showed that the genes belong to the Kinase (7), CNL (95), MLO-like (8), RLK (3) and Others (28) categories. The CNL R genes formed eight clusters. Expression data for selected R genes also identified potential candidates for breeding of disease resistance traits. Furthermore, these findings can provide information about the species evolution as well as the identification of agronomically important genes in oil palm and other major crops.Comparative genomics and transcriptomic analyses were performed on two agronomically important groups of genes from oil palm versus other major crop species and the model organism,  Elaeis guineensis, is a major global crop that can benefit considerably from the application of modern genomic advances. According to recent industry statistics, the annual global production of palm oil increased by almost 600% over the period 1990\u20132017, from 10.5 to 62.9 million tonnes  Alignment of two oil palm FATBs with orthologs from A. thaliana and Z. mays. [C] Protein sequence alignment of the orthologous cluster OG1.5_1281 of stearoyl-acyl carrier protein desaturases (SAD) aligned using MUSCLE to produce more than 70% identity between oil palm and A. thaliana and maize proteins.[A] Alignment of two oil palm FATAs with orthologs from (PDF)Click here for additional data file."}
+{"text": "The role of the diet as well as the impact of the dietary habits on human health and disease is well established. Apart from its sleep regulatory effect, the indoleamine melatonin is a well-established antioxidant molecule with multiple health benefits. Convincing evidence supports the presence of melatonin in plants and foods with the intake of such foods affecting circulating melatonin levels in humans. While numerous actions of both endogenous melatonin and melatonin supplementation are well described, little is known about the influence of the dietary melatonin intake on human health. In the present review, evidence for the cardiovascular health benefits of melatonin supplementation and dietary melatonin is discussed. Current knowledge on the biological significance as well as the underlying physiological mechanism of action of the dietary melatonin is also summarized. Whether dietary melatonin constitutes an alternative preventive treatment for cardiovascular disease is addressed. The role of the diet as well as the impact of the dietary habits on human health and disease has been described since the antiquity , A strong inverse relationship exists between endogenous melatonin levels and cardiovascular disease  reduces BP values of hypertensive men , intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelin-1 (ET-1) while it increases endothelial nitric oxide synthase (eNOS), nuclear erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO-1), catalytic glutamate cysteine ligase (GCLC) and heme oxygenase-1 (HO-1) in a rat model of a smoke-induced vascular injury  play an important role in the pathological process of pulmonary hypertension and subsequent heart failure   which, in turn, activates tumor necrosis factor-\u03b1 (TNF\u03b1)/STAT3 pathway  hypertrophy and cardiac fibrosis with the hallmarks of the heart failure  administration or other forms of preparations  ; FN: conception, literature choice, figures and tables, revised the final draft manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Japanese encephalitis (JE) virus is the most important vaccine-preventable cause of encephalitis in the Asia-Pacific region. The World Health Organization (WHO) recommends integration of JE vaccination into national immunization schedules in all areas where the disease is a public health priority . TInformation on JE surveillance and immunization programs was obtained from several sources. Health officials from 18 WHO countries with endemic JE who attended the 7th Biregional Meeting on Prevention and Control of JE in 2016 were surveyed; abbreviated surveysRepresentatives from all 24 countries with JE virus transmission risk completed the surveys.During 2015, WHO received reports of 4,087 JE cases from 20 (83%) of 24 countries; 3,549 (87%) of these cases were reported from four countries . No other country reported more than 115 cases.Twelve (50%) of the 24 countries had a JE immunization program in 2016 ; 10  virus is a leading cause of encephalitis in Asia. The World Health Organization recommends integration of JE vaccination into national immunization schedules in all areas where the disease is a public health priority.A review of surveillance and immunization program data in the 24 countries with JE virus transmission risk found that in 2016, 22 countries conducted at least some surveillance for JE, and 12 had implemented a JE immunization program. This represents substantial progress in JE prevention and control measures, but challenges remain, including incomplete case reporting, misclassification of cases, lack of immunization program monitoring data, and inadequate monitoring of JE vaccination coverage following vaccine introduction.Strengthened surveillance, continued commitment, and adequate resources for JE vaccination should help maintain progress toward prevention and control of JE."}
+{"text": "The correct sentence should read: Left ventricular mass index (LVMi) was calculated using the Devereux-modified cube formula based on linear measurements of interventricular septum thickness, left ventricular cavity diameter and posterior wall thickness as assessed by the American Society of Echocardiography (ASE) method and indexed to body surface area (in m"}
+{"text": "In 2015, birth testing for certain asymptomatic HIV-exposed infants was included in the South African National Consolidated Guidelines for the first time.in utero and intrapartum HIV-infected infants failed to recognise:The notion that a single HIV polymerase chain reaction (PCR) test performed at 6 weeks of age would detect virtually all 4the HIV-related mortality that occurs prior to testing at 6 weeks of agethe reduced sensitivity of HIV PCR tests as a consequence of the increase in the number and duration of drugs used for prevention of mother-to-child transmission of HIV (PMTCT) prophylaxis.There is increasing evidence that both fixed dose combination (FDC) maternal PMTCT prophylaxis and daily dose nevirapine (NVP) infant prophylaxis (Option B or B+) contribute towards reduced detection of perinatal HIV infection at 6 weeks of age. The literature demonstrates that:in utero infected infants at 5 days and 2 weeks of age respectively.6 No HIV PCR sensitivity data for 6-week-old HIV-exposed infants, tested at discontinuation of 6 weeks of daily dose NVP, are available.a single perinatal dose of NVP reduced viral load to below the limit of detection in 38% and 17% of 7the probability of a positive HIV PCR at age 6 weeks in perinatally HIV-infected infants is decreased with multi-drug maternal and/or infant PMTCT prophylaxis8in non-breastfed infants, HIV DNA and RNA PCR sensitivity at 1 month of age for perinatally infected infants was 89%9in formula-fed infants who received 6 weeks of postpartum zidovudine (AZT), with or without other antiretrovirals, 32% of intrapartum-infected infants tested HIV DNA PCR negative at 6 weeks of age but tested positive at 3 months of age10prophylaxis reduces HIV DNA concentrations at birth complicating early identification of infected infants for initiation of early treatment12there are case studies illustrating the challenges of \u2018false negative\u2019 and \u2018indeterminate\u2019 HIV PCR results in early infant diagnosis in the context of current PMTCT prophylaxis and calling for revised diagnostic guidelines.in utero and intrapartum HIV infections in the context of current PMTCT interventions. It is too late to diagnose infants who die prior to 6 weeks of age and to achieve early combination antiretroviral therapy (cART) initiation by 7.4 weeks of age as was done on the Children with HIV Early Antiretroviral Therapy (CHER) trial to reduce early morbidity and mortality.13 It is too early to diagnose in utero and intrapartum infections suppressed by daily dose NVP and/or maternal prophylaxis via the placenta and/or breastmilk.The 6-week test, conveniently scheduled at the same time as the 6-week expanded programme for immunisation (EPI) visit, is therefore too late and too early to detect all in utero and intrapartum HIV infections) can never approach 100% because it detects in utero infection only and cannot detect intrapartum infection, namely an infection transmitted at the time of labour and delivery and essentially in the window period at birth. Prior to the implementation of PMTCT and the use of standardised HIV assays, Dunn et al.\u2019s meta-analysis demonstrated that 38% of all perinatal infections were detectable at birth.14 With World Health Organization (WHO) Option A prophylaxis and a single dose of NVP at birth for infants, Lilian et al. demonstrated that 76% of all early HIV infections were detectable at birth.15 This increase was attributed to more sensitive viral detection assays and a proportional increase in in utero to intrapartum infections as a result of PMTCT prophylaxis targeting intrapartum infections during late pregnancy and delivery. As the majority of women deliver in health facilities in South Africa, identifying all HIV-infected women at delivery coupled with birth HIV PCR testing would yield three-quarters of all perinatal HIV infections with close to 90% coverage.The HIV PCR sensitivity at birth for detecting perinatal HIV infections , low birth weight (LBW < 2500 g) or symptomatic HIV-exposed neonates and those born to women who were unbooked or received a late diagnosis of HIV (e.g. at delivery) or received < 4 weeks of antiretroviral PMTCT prophylaxis or had viral loads > 1000 copies per millilitre or were co-infected with tuberculosis during pregnancy. The Western Cape PMTCT guidelines also recommend targeted birth testing that include additional and slightly modified high-risk factors.17 These high-risk factors predict vertical transmission but not necessarily in utero transmission, and therefore the birth HIV PCR test may be negative.The 2014 South African National Consolidated Guidelines recommend targeted birth testing, namely HIV PCR testing of only those HIV-exposed neonates identified as being at high risk of HIV transmission.in utero and intrapartum infections, on every HIV-exposed infant can be offset by following 2010 WHO guidelines to use HIV rapid tests (HRT) from 9 months of age.18 As the majority of HIV-exposed, uninfected infants demonstrate seroreversion by 9 months of age by testing HRT negative, only those with positive HRT would require HIV PCR tests.19 This approach reduces the number of HIV PCR tests required for symptomatic infants or those requiring testing post-cessation of breastfeeding.Universal birth testing of all HIV-exposed infants may be simpler to implement than targeted birth testing. The cost of performing two early HIV PCR tests, to detect To avoid morbidity and mortality, all positive HIV PCR results require urgent action to (1) confirm the HIV-infected status on a second blood sample and (2) initiate cART. Healthcare facilities require good communication with the laboratory to access positive results within 2\u20137 days and systems for patient follow-up to see all HIV PCR-positive patients as soon as possible. As neonates usually return to their primary healthcare clinic and not the maternity unit for follow-up after birth, ensuring that birth HIV PCR test results reach patients will be pivotal to successful implementation of birth testing. Point of care (POC) HIV diagnosis would facilitate same-day identification of HIV-infected neonates.The results of the second, confirmatory viral detection assay should not delay cART initiation but should be obtained as early as possible because, once cART is initiated, it becomes progressively more difficult to detect HIV either by HIV PCR or viral load testing. The availability of two different POC assays for detection of HIV would facilitate same-day identification and confirmation of HIV infection in neonates.1 fewer cases of intrapartum infection may be identified owing to the viral load lowering effect of the daily dose NVP infant prophylaxis. The 2014 National Consolidated Guidelines cater for this in high-risk infants only by recommending a third HIV PCR at 16 weeks of age where prolonged infant prophylaxis (e.g. daily dose NVP for 12 weeks) has been used.1 The probability that the sensitivity of diagnostic virological assays is affected by antiretroviral prophylaxis has prompted American guidelines to recommend an additional HIV PCR test be performed 2\u20134 weeks after combination antiretroviral infant prophylaxis has been discontinued if negative HIV PCR results were obtained during prophylaxis.20 As for all HIV-exposed and uninfected infants, HIV PCR testing is recommended whenever clinical features suggestive of HIV infection are present and 6 weeks after cessation of breastfeeding (if < 18 months old). If, at 6\u00a0weeks after weaning, the child is \u2265 18 months old, a HRT or HIV enzyme-linked immunosorbent assay (ELISA) test should be performed instead of an HIV PCR test.If the birth HIV PCR test is negative, an HIV PCR test at 10 weeks of age is recommended to detect as many cases of intrapartum infection as possible. If the HIV PCR test is repeated at 6 weeks of age, as per national guidelines,In an evolving PMTCT environment, ongoing monitoring is necessary to assess the impact of early diagnosis of HIV infection in neonates and to ensure that an evidence-based, effective diagnostic algorithm is deployed."}
+{"text": "Escherichia coli O103 strains shed in the feces of cattle. We report here the genome sequences of 43 strains of enterohemorrhagic E.\u00a0coli (EHEC) O103:H2 isolated from feedlot cattle feces. The genomic analysis will provide information on the genetic diversity and virulence potential of bovine EHEC O103.The enterohemorrhagic pathotype represents a minor proportion of the  Escherichia coli (EHEC). The organism is shed in the feces of cattle, which can contaminate the hide and then carcass at slaughter, creating the potential for foodborne illness in humans  and intimin (eae) genes, the combination of these and presence of other major virulence genes, including enterohemolysin (ehxA), vary among EHEC O103 strains isolated from bovine feces , genome size, and number of contigs per genome are summarized in We report here the draft whole-genome sequences of 43 strains of EHEC O103:H2 isolated from feces of feedlot cattle in the United States . BacteriThe 43 strains deposited here will add to the limited publicly available genetic information on EHEC O103. These genomes will be a valuable resource for investigations into the genetic features of this major foodborne pathogen, including research into the genome evolution of EHEC O103 compared to other EHEC serogroups, and insights into specific factors allowing for adaptation to a bovine host. This work will also provide an opportunity to study the potential virulence risk of these EHEC O103 strains to humans.The whole-genome shotgun sequence has been deposited at DDBJ/ENA/GenBank under the accession numbers listed in"}
+{"text": "Androgen deprivation therapy (ADT) has been the standard of care for advanced prostate cancer (PCa) for decades, yet men with this condition inexorably develop resistance to ADT and progress to metastatic castration-resistant PCa (mCRPC) . Second It was shown previously that AR transcriptionally upregulates multiple DNA damage response (DDR) genes -5, and tin vitro [in vitro. We used multiple subcutaneous and orthotopic in vivo CRPC models, including an ENZ-responsive PDX model to validate the superiority of lead-in combination ENZ+OLA treatment compared to concomitant administration [We initially identified a subset of 10 HR genes which were upregulated in CRPC in 2 independent public data sets, and showed that 7 of these upregulated genes were contained within a 15 HR gene subset which was downregulated by ENZ in microarray analysis [The causative mechanisms for susceptibility of cancers with BRCA mutations to PARP inhibitor \u2014 mediated synthetic lethality are complex, and recent studies have pointed to the need to expand the concept of BRCAness in tumors beyond germline BRCA1 or BRCA2 mutations to include mutations in genes that modulate HR and confer PARP sensitivity . Our rec"}
+{"text": "Persons who experience symptoms of psychosis following a brain injury live with a complex dual diagnosis that is often accompanied by substantial distress and disability. However, a comprehensive examination of the clinical presentation of PFTBI using standardised clinical measures has not been reported in the literature. This information is vital for accurate diagnosis and effective treatment.Patients with PFTBI (n =10) and schizophrenia (n =98) participated in a comprehensive clinical assessment that included the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I/P), the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), and the Thought Language and Communication Index (TLC).The clinical profiles of the PFTBI group met symptom/course criteria for: schizophrenia (n = 6), schizoaffective (n = 2), schizophreniform (n = 1), and paranoid psychosis (n = 1). PFTBI patients had a significantly reduced PANSS negative score relative to schizophrenia patients. No other significant differences between PFTBI and schizophrenia clinical profiles were found.The clinical profile of PFTBI appears to be comparable to schizophrenia/ schizoaffective disorder except with respect to negative psychotic symptoms. Reduced negative symptoms in PFTBI have previously been reported in a small number of case studies, and thus warrant further investigation as a diagnostic distinction in this patient group."}
+{"text": "The carotid surgical experience of Cheltenham General Hospital over a 13 year period (1968-81) is presented. This includes 42 operations for stenosis, and 12 further operations for carotid body tumour, carotid aneurysm, subclavian steal syndrome and trauma to the internal carotid artery. The operative techniques and complications are briefly discussed and reasons advanced for a more agressive approach to the problems of extra-cerebral carotid disease in this country."}
+{"text": "The early differentiation of Alzheimer\u2019s disease (AD) from frontotemporal dementia (FTD) may be difficult. The Tower of London (ToL), thought to assess executive functions such as planning and visuo-spatial working memory, could help in this purpose.Twentytwo Dementia Centers consecutively recruited patients with early FTD or AD. ToL performances of these groups were analyzed using both the conventional statistical approaches and the Artificial Neural Networks (ANNs) modelling.p < 0.05) The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients. However, the discriminant validity of AS checked by ROC curve analysis, yielded no significant results in terms of sensitivity and specificity (AUC 0.63). The performances of the 12 Success Subscores (SS) together with age, gender and schooling years were entered into advanced ANNs developed by Semeion Institute. The best ANNs were selected and submitted to ROC curves. The nonlinear model was able to discriminate FTD from AD with an average AUC for 7 independent trials of 0.82.Ninety-four non aphasic FTD and 160 AD patients were recruited. ToL Accuracy Score (AS) significantly (The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients."}
+{"text": "It  Specifications TableValue of the data\u2022ilr transformation for other food compositions and interested researchers.The data include the sequential binary partition of fatty acid profiles in CoDa and could be useful for calculating balances and the \u2022The correlation among fatty acids expressed in percentages may help other researchers for finding spurious relationships.\u2022The information may facilitate the comparison of conventional multivariate techniques and compositional, regardless of the field, and promote international collaborations in data analysis.\u2022Presentation in the Simplex can be an appropriated way of graphing compositional data and treatments\u2019 effects.1ilr transformations based on it  Fatty acid profiles were obtained through analysis of their FAMEs by GC according to the procedures recommended in the Commission Regulation (EU) No 2015/1833 ilr transformed values (or coordinates)  were subjected to similar multivariate Cluster Analysis (based on the Euclidean distance and the Ward method) (The data matrix consisted of 10 rows (five treatments in duplicate) and 19 columns (fatty acids). Values were first tested for outliers and normality. The data were plotted in the Simplex , analysedinates)  [10], [1 method)  [12].TabCoDaPack v. 2.01.14 , XLSTAT 2014  were used for data processing and graph drawing."}
+{"text": "Objective: To characterize various dysgraphic symptoms in parietal agraphia. Method: We examined the writing impairments of four dysgraphia patients from parietal lobe lesions using a special writing test with 100 character kanji (Japanese morphograms) and their kana (Japanese phonetic writing) transcriptions, and related the test performance to a lesion site.Results: Patients 1 and 2 had postcentral gyrus lesions and showed character distortion and tactile agnosia, with patient 1 also having limb apraxia. Patients 3 and 4 had superior parietal lobule lesions and features characteristic of apraxic agraphia (grapheme deformity and a writing stroke sequence disorder) and character imagery deficits . Agraphia with impaired character recall and abnormal grapheme formation were more pronounced in patient 4, in whom the lesion extended to the inferior parietal, superior occipital and precuneus gyri.Conclusion: The present findings and a review of the literature suggest that: (i) a postcentral gyrus lesion can yield graphemic distortion (somesthetic dysgraphia), (ii) abnormal grapheme formation and impaired character recall are associated with lesions surrounding the intraparietal sulcus, the symptom being more severe with the involvement of the inferior parietal, superior occipital and precuneus gyri, (iii) disordered writing stroke sequences are caused by a damaged anterior intraparietal area."}
+{"text": "Intermittent catheterisation is the preferred method of managing the neurogenic bladder in patients with spinal cord injury. However, spinal cord physicians experienced problems when trying to implement an intermittent catheterisation regime in some spinal cord injury patients in the northwest of England. We present illustrative cases to describe practical difficulties encountered by patients while trying to adopt an intermittent catheterisation regime. Barriers to intermittent catheterisation are (1) caregivers or nurses are not available to carry out five or six catheterisations a day; (2) lack of time to perform intermittent catheterisations; (3) unavailability of suitable toilet facilities in public places, including restaurants and offices; (4) redundant prepuce in a male patient, which prevents ready access to urethral meatus; (5) urethral false passage; (6) urethral sphincter spasm requiring the use of flexible-tip catheters and \u03b1-drenoceptor\u2013blocking drugs; (7) reluctance to perform intermittent catheterisation in patients >60 years by some health professionals; and (8) difficulty in accessing the urethral meatus for catheterisation while the patient is sitting up, especially in female patients. These cases demonstrate the urgent need for provision of trained caregivers who can perform intermittent catheterisation, and improvement in public facilities that are suitable for performing catheterisation in spinal cord injury patients. Further, vigilance should be exercised during each catheterisation in order to prevent complications, such as urethral trauma and consequent false passages. Health professionals should make additional efforts to implement intermittent catheterisation in female spinal cord injury patients and in those >60 years."}
+{"text": "In the associated research article in vitro. We provide data demonstrating the use of nanoscale secondary ion mass spectroscopy (NanoSIMS) to identify specific ions in bulk dried NP. NanoSIMS is also used to visualize 40Ca microdomains in the z dimension of optic nerve that has been subjected to a partial optic nerve transection. The associated article 40Ca microdomains in optic nerve from animals treated with various nanoparticle preparations and provides further interpretation and discussion of the findings.Before using nanoparticles for therapeutic applications, it is necessary to comprehensively investigate nanoparticle effects, both  A sample raw NanoSIMS spectra of bulk dried NP and associated spatial resolution data demonstrate the ability to detect 56Fe within NP. NanoSIMS can be used to detect 40Ca microdomains in the z dimension of optic nerve following partial optic nerve transection.The oxidative stress indicator carboxymethyl lysine was assessed in an astrocyte-like immortalized M\u00fcller cell line (rMC1 cells). Cells were stressed with H2in vitro, assessed using ImageJ image analysis software  software .Fig. 1CeRaw NanoSIMS spectra  and specz-dimension of an optic nerve field of view (FOV) following partial optic nerve transection, collected using NanoSIMS. All procedures involving animals conformed to the National Health and Medical Research Council of Australia Guidelines on the Use of Animals in Research and were approved by the Animal Ethics Committee of The University of Western Australia   .Fig. 3Pa"}
+{"text": "Improving quality of maternal care as well as patients' safety are two important issues in health-care service. Therefore, this study aimed to assess the culture of patient safety at maternity units.This cross-sectional study was conducted among staffs working at maternity units in seven hospitals of Ilam city, Iran. The staffs included in this study were gynecologists and midwifes working in different positions including matron, supervisors, head of departments and staffs. Data were collected using the Hospital Survey on Patient Safety Culture (HSOPSC).This study indicated that 59.1% of participants reported fair level of overall perceptions of safety and 67.1% declared that no event was reported during the past 12 months. The most positively perceived dimension of safety culture was teamwork within departments in view of managers (79.41) and personnel (81.10). However, the least positively perceived dimensions of safety culture was staffing levels.The current study revealed areas of strength (teamwork within departments) and weakness  among managers and personnel. In addition, we found that staffs in Ilam's hospitals accept the patient safety culture in maternity units, but, still are far away from excellent culture of patient safety. Therefore, it is necessary to promote culture of patient's safety among professions working in the maternity units of Ilam's hospitals. Decreasing maternal mortality rate is recognized as an essential priority in health-care systems , 2. ImprThis cross-sectional study was conducted among staffs working at maternity units  in seven hospitals of Ilam University of Medical Sciences during year 2016. The staffs included in this study were gynecologists and midwifes working in several positions including managers, supervisors, head of departments and staffs. The total number of 350 staffs was invited to take part in the current study and 299 agreed to participate in the survey. Participants were informed about the aim, benefits and importance of the survey as well as their voluntary participation rights. Written informed consent was obtained prior to actual data collection. Data were collected using series of self-administrated questionnaires including socio-demographic characteristics and the Hospital Survey on Patient Safety Culture (HSOPSC). The socio-demographic and individual characteristics include age, gender, education, working hours per week, ward, organizational position, organizational tenure, work experiences in the current ward and type of employment. The Hospital Survey on Patient Safety Culture (HSOPSC) released by the Agency for Healthcare Research and Quality (AHRQ) to help hospitals assess the safety culture within their organization. The HSOPSC contains 42 items with 5 point Likert responses scale ranging from strongly disagree (1) to strongly agree (5). HSOPSC questionnaire contains both positively and negatively worded items. The average percent-positive score for each dimension was calculated and negative items were reverse scored prior to computing percent positive response. This questionnaire is designed to measure 12 dimensions of patient safety culture and these dimensions are: Supervisor/manager expectations and actions promoting safety (4 items), Organizational learning-continuous improvement (3 items), Teamwork within units (4 items), Communication openness (3 items), Feedback and communication about error (3 items), Non-punitive response to error (3 items), Staffing (4 items), Hospital management support for patient safety (3 items), Teamwork across hospital units (4 items), Hospital handoffs and transitions (4 items), Overall perceptions of safety (4 items), Frequency of event reporting (3 items) and Two outcome variables. The two outcome variables compose of \u201cOverall perceptions of safety\u201d and \u201cFrequency of event reporting\u201d. The HSOPSC questionnaire was validated in Persian language and shown a good validity and reliability to be used in Iran's hospitals . HoweverMean age of participants in this study was 33.52 (SD= 6.37) years old  and 84.1This study assessed culture of patient's safety in hospitals of Ilam University of Medical Sciences. Creating culture of patient safety requires assessment of safety culture using appropriate tool. This study measured culture of patient safety using HSOPSC questionnaire which is one of the best tools in this area . The curThe results of this study showed acceptable levels of overall perception of safety culture among both managers and personnel with higher perception among managers. This finding implies that health-care workers in Ilam's hospitals accept the patient safety culture in maternity units, but still are far away from excellent culture of patient safety. Maternal wards are among very important units in each hospital, which require special attentions. Therefore, it is necessary to promote culture of patient's safety among professions working in the maternity units of Ilam's hospital. There are several limitations in this study, which need to be addressed. One of the limitations in this study was lack of evidences in maternity units to compare the results. Therefore, future studies are recommended to assess the culture of patient safety in maternal care units using HSOPSC questionnaire. Another limitation in this study is use of self-reported data.International reports on maternal mortality rate has shown constant decreasing pattern during the last 15 years;Programs aimed at decreasing maternal mortality rate has always been a priority in the Iranian health system and some of these programs are promoting mother and child-friendly hospitals that offer maternal care using professional midwifery staffs;Promoting patients' safety and risk management are of great importance in maternity care units due to the fact that every procedure in this field will affect two individuals (both mother and baby).This study assessed culture of patient's safety in hospitals of Ilam University of Medical Sciences for the very first time and revealed areas of strength and weakness among managers and personnel;The most positively perceived dimension of safety culture was attributed to \u201cteamwork within department\u201d among both managers and personnel. While, the least positively perceived dimension was \u201cstaffing\u201d and \u201cnon-punitive response error\u201d, respectively;Positive perception toward \u201cstaffing\u201d was higher among managers compared to personnel and \u201cnon-punitive response error\u201d was almost equal between two groups.The authors declare no competing interests."}
+{"text": "This article evaluated the autosomal dominant polycystic kidney disease (ADPKD) modifiers to chronic kidney disease (CKD) such as allelic and nonallelic agents. Also, our study evaluated the role of the endotelin-1 which considered in some studies as the predictor of the ADPKD.Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life threatening inherited kidney disease which its prevalence is approximately 0.5 to 1 in 1000 subjects of general population ,3. FurthThe heterozygous mutations in PKD 1 (approximately 78%) and PKD 2 (approximately 13%) genes are responsible for the vast majority of the ADPKD incidence and no mutation detected (NMD) ADPKD exists in the other patients (9%)  and increase in kidney size are as modifiers. Furthermore some laboratory factors such overt hematuria, macroalbominuria, high level of serum copeptin concerned as predicting factor for chronic kidney disease (CKD) in ADPKD . The vasEndotelin-1 (ET-1) is another agent that has been reported to exert multiple effects on renal function . Some stIn summary, the progression of ADPKD to CKD depends on multiple factors include allelic and non-allelic factors that can be use in prevention of the CKD in these patients and need further researches for achieve to this issue.The authors contributed equally to the manuscript.The authors declared no competing interests.Ethical issues  have been completely observed by the authors.None."}
+{"text": "Nature Communications 10.1038/s41467-017-00717-y, published online 18 September 2017Correction to: The original version of this Article omitted the Acknowledgements section:\u201cThis work was sponsored by the Australian Research Council (ARC) Laureate Fellowship (FL120100029) and the Centre of Excellence program (CUDOS CE110001010). We acknowledge the support of the ANFF ACT.\u201dThis has now been corrected in both the PDF and HTML versions of the Article."}
+{"text": "Studies have shown that physiologic factors such as decreased LAA velocity and increased stasis are associated with thrombus formation in the LAA and may be better predictors for stroke. Currently available diagnostic tools such as TEE, however, are limited as they do not completely assess the complex 3D LAA blood flow and are invasive. As a result, the impact of AF on global and regional atrial 3D flow dynamics is poorly understood. In addition, it is unclear if the stimulus for LAA thrombus formation is driven by hemodynamic changes in the LAA alone or more broadly associated with AF induced flow alterations affecting the entire left atrium (LA). It was the aim of this study to test the potential of novel 4D flow MRI tools  for the characterization of LA and LAA flow dynamics.Atrial fibrillation (AF) is associated with increased risk of stroke due to development of left atrial appendage (LAA) thrombus. Clinical risk scores (CHA4D flow MRI was employed to measure in-vivo time-resolved 3D blood flow velocities in 75 subjects: 30 AF patients in sinus rhythm (AF-sinus), 30 AF patients in AF (AF-afib) and 15 normal controls. Data analysis included 3D segmentation of the LA and LAA to isolate the velocity data in the LA and LAA figure . Peak veLA and LAA mean velocity, stasis, and peak velocity were significantly different between controls, AF-afib patients, and AF-sinus patients  not just in the LAA but in the in the entire left atrium. An individual assessment of LAA and LA flow may thus help to better identify patients at risk for thromboembolism beyond current clinical risk scores."}
+{"text": "Phaseolus vulgaris L.). In this study, 41 rhizobia isolates were obtained from the root nodules of MAC 13 and MAC 64 climbing beans grown in upper and lower midland agro-ecological zones of Eastern Kenya. Eastern Kenya was chosen because of its high production potential of diverse common bean cultivars. The rhizobia isolates were characterized phenotypically on the basis of colony morphology, growth and biochemical features. Rhizobia diversity from the different regions of Eastern Kenya was determined based on the amplified ribosomal DNA restriction analysis (ARDRA) of PCR amplified 16S rRNA genes using Msp I, EcoR I, and Hae III restriction enzymes. Notably, native rhizobia isolates were morphologically diverse and grouped into nine different morphotypes. Correspondingly, the analysis of molecular variance based on restriction digestion of 16S rRNA genes showed that the largest proportion of significant (p < 0.05) genetic variation was distributed within the rhizobia population (97.5%) than among rhizobia populations (1.5%) in the four agro-ecological zones. The high degree of morphological and genotypic diversity of rhizobia within Eastern Kenya shows that the region harbors novel rhizobia strains worth exploiting to obtain strains efficient in biological nitrogen fixation with P. vulgaris L. Genetic sequence analysis of the isolates and testing for their symbiotic properties should be carried out to ascertain their identity and functionality in diverse environments.The increasing interest in the use of rhizobia as biofertilizers in smallholder agricultural farming systems of the Sub-Saharan Africa has prompted the identification of a large number of tropical rhizobia strains and led to studies on their diversity. Inoculants containing diverse strains of rhizobia have been developed for use as biofertilizers to promote soil fertility and symbiotic nitrogen fixation in legumes. In spite of this success, there is paucity of data on rhizobia diversity and genetic variation associated with the newly released and improved mid-altitude climbing (MAC) bean lines ( Rhizobia bacteria play a significant role in provision of agricultural ecosystem services due to their ability to form symbiotic association with a wide range of leguminous plants that results in biological nitrogen fixation . Some ofMimosa genus  and chickpeas (Cicer arietinum L.), while Bradyrhizobium strains are often found to nodulate soybeans (Glycine max L. Merrill), cowpeas (Vigna unguiculata L.) and green grams (Vigna radiata L.). However, in some cases, cross inoculation by both genera has been documented in some legumes such as mungbeans (V. radiata L.) and this is considered advantageous and economical to farmers growing different types of legumes (Rhizobia-legume symbiosis is a host-specific association and hence the need to determine the strains and the diversity of rhizobia associated with specific type of legume for better exploitation of the benefits associated with the rhizobia biofertilizers . Rhizobisa genus . Until racterium . However legumes .P. vulgaris L.), the MAC beans establish a mutual and a beneficial symbiotic partnership with Rhizobium leading to the formation of root nodules that catalyze nitrogen fixation from the atmospheric air , restriction fragment length polymorphism (RFLP) and amplified fragment length polymorphism (AFLP) have been used to evaluate the diversity of rhizobia . In addiIn this study, we hypothesized that there exists a large heterogeneity among the rhizobia isolates nodulating MAC beans grown in different AEZ with contrasting environmental conditions in Eastern Kenya. The aim of this study was to isolate, characterize morphologically and genetically and determine the diversity of the rhizobia populations associated with MAC 13 and MAC 64 climbing beans grown in different AEZ of Eastern Kenya.Field trapping of rhizobia was carried out during the first rainy season between March and August 2015 in four different sites of Eastern Kenya with contrasting agro-climatic conditions using MAC 13 and MAC 64 climbing beans as the host plants. Eastern Kenya was chosen because of its high production potential of diverse common bean cultivars . The fouTen healthy and undamaged root nodules of MAC 13 and MAC 64 climbing beans from each site were selected and used in the isolation of rhizobia following the standard protocols described by Rhizobium. Based on the differences in the observed morpho-cultural, Gram stain and growth features, the isolates were placed into different morphotype groups.Using the standard microbiological techniques described by Hae III, EcoR I and Msp I . Three reference strains; Rhizobium tropici CIAT 899, Rhizobium etli USDA 2667 strain and Rhizobium leguminosarum strain 446 were used. The three reference Rhizobium strains were obtained from the Microbiological Resource Centre (MIRCEN), University of Nairobi, Kenya.The molecular study involved 41 rhizobia isolates and was carried out at the Department of Microbiology, Kenyatta University. The analysis of genetic relatedness of the native isolates from Eastern Kenya was carried out using amplified rDNA restriction analysis (ARDRA) of the 16s rRNA genes using three restriction enzymes The extraction of total genomic DNA of rhizobia isolates was carried out following modification of a method outlined by Escherichia coli , 0.6 \u03bcl dNTP (10 mM), 0.3 \u03bcl of each Y1 and Y3 primers (10 \u03bcM), 0.6 \u03bcl 5% Tween 20, 0.15 \u03bcl Taq DNA polymerase (Biolabs) and 1.5 \u03bcl of DNA template. The sequences of the primers used for PCR amplification of the 16S rRNA gene were: Y1 forward primer (5\u2032-TGGCTCAGAACGAACGCTGGCGGC-3\u2032) that corresponds to positions 20\u201343 and Y3 reverse primer (5\u2032-TACCTTGTTACGACTTCACCCCAGTC-3\u2032) corresponding to positions 1482\u20131507 for 16S rDNA sequence of hia coli . A negatHae III, EcoR I, and Msp I restriction enzymes (Biolabs) (Polymerase chain reaction products of the isolates and reference strains were digested using Biolabs) . A masteH) was also used to determine the rhizobia diversity in different AEZ of Eastern Kenya.The data on rhizobia genetic diversity based on the different band patterns formed after PCR restriction were coded in binary form and analyzed as described by Table 1). Morphotype III was the most abundant (29%) and morphotype II accounted for a partly 2% of the total number of isolates. All isolates were Gram negative rods and did not absorb Congo red dye when incubated in the dark on YEMA-CR medium . Notably, all isolates turned BTB indicator from deep green to yellow when grown on YEMA-BTB indicating that the isolates were acid producers and fast growers . The colony color varied with milky white, cream white, cream yellow and watery colonies being observed which were either opaque or translucent with either firm gummy or smooth mucoid texture . Most of the isolates had a mucoid texture due to the production of excess EPSs. As expected, all isolates had an entire colony margin but the colony elevation varied consistently with convex and raised colonies being observed on YEMA media . The morphological characteristics of the reference strains Rhizobium tropici CIAT 899 and Rhizobium etli USDA 2667 were closely similar to those of morphotype III while Rhizobium leguminosarum strain 446 closely resembled morphotype V (Table 1).From the field trapping experiment using MAC 13 and MAC 64 climbing beans, 41 pure rhizobia isolates were obtained, which were placed in to nine distinct morphotype groups based on their morpho-cultural and biochemical features . Restriction of the 16S rRNA amplicons of the climbing bean rhizobia isolates using enzymes EcoR I , Hae III  and Msp I  produced multiple band patterns. Restriction enzyme Msp I produced the most diverse polymorphic patterns.The PCR amplification of the 16S rDNA region produced a single band of approximately 1500 bp (Na = 1.92 \u00b1 0.08) and effective alleles (Ne = 1.55 \u00b1 0.10) compared to other populations (Table 2). Rhizobia isolates from ELM had the highest percentage polymorphic loci (92.31% P) while isolates from EUM and TLM recorded the lowest at 61.54% P. The mean Shannon\u2013Wiener diversity (H) estimate showed that the four rhizobia populations from Eastern Kenya were genetically diverse with rhizobia population from ELM having the highest genetic diversity estimate of H = 0.47 (Table 2). The rhizobia population from zone TLM recorded the lowest genetic diversity estimate of H = 0.31. The average expected heterozygosity (He) varied among the four populations and ranged from 0.21 for rhizobia population from TLM to 0.32 for ELM population (Table 2).Based on ARDRA analysis of 16S rRNA amplicons, rhizobia population from ELM had the highest average number of different alleles  within populations . The variation among the rhizobia populations from the four AEZ (2.5%) and two Counties (0.5%) were, however, not significant (Table 3).Analysis of molecular variance (AMOVA) for the four rhizobia populations in Eastern Kenya showed a significantly high genetic variation . Isolates from TUM zone were the most distributed and appeared in all the four quadrants, while isolates from ELM zone were the least distributed .The principal coordinate analysis (PCA) of 41 native isolates from the four zones of Eastern Kenya and three rhizobia reference strains showed considerable differentiation . Rhizobia populations from ELM and TUM clustered together with a bootstrap value of 85% while rhizobia populations from EUM and TLM clustered with a bootstrap value of 82%.Based on the pairwise population matrix of Nei unbiased genetic distance and Euclidian similarity index, the neighbor joining dendrogram clustered rhizobia populations from Eastern Kenya into two main groups . Cluster I comprised of majority of the isolates while cluster III had only one isolate ELM5. The reference strain Rhizobium tropici CIAT 899 which was placed in cluster I, clustered together with native rhizobia isolates ELM33 and TLM32, indicating their close genetic relationship. Native isolates TUM26, TLM28, and EUM23 clustered together despite originating from different AEZ of Eastern Kenya. Rhizobium etli USDA 2667 strain was also placed in cluster I and was grouped together with TLM27 and TUM 41 isolates . The native isolate EUM7 clustered closely to Rhizobium leguminosarum strain 446 in cluster II but in a separate sub-branch.Based on the genetic distance after amplified rDNA restriction analyses and Euclidian similarity index, the phylogenetic tree clustered the native rhizobia isolates into three main clusters I, II, and III  estimate of rhizobia populations from Eastern Kenya based on genetic distance of ARDRA pattern analysis showed that the isolates were genetically diverse with rhizobia population from ELM zone having the highest genetic diversity estimate compared to TLM zone, which recorded the lowest diversity. This variation in rhizobia diversity could be due to the differences in agroclimatic and soil conditions of the four sites studied in Eastern Kenya. These results reinforce the promiscuous nature of P. vulgaris L. to nodulate with diverse strains of Rhizobium  genetic variation distributed within regions (89%) than among regions (11%) in S. meliloti and S. medicae obtained from drought and salt affected regions of Morocco. Moreover, The analyses of molecular variance (AMOVA) based on amplified 16S rDNA restriction profiles showed a highly significant genetic variation of native rhizobia isolates within rhizobia populations and not among the four populations nor across the two regions (Counties) of Eastern Kenya. Based on ARDRA fingerprints, the low level of genetic differentiation of MAC bean rhizobia could suggest that the rhizobia population within the region is weakly structured. This could be due to the absence of physical barriers to limit gene flow . Human aAgrobacterium, Bradyrhizobium, Rhizobium, and Ensifer). Based on the evolutionary relationship of 41 isolates inferred using Neighbor-Joining method, some of the native isolates clustered closely with the three reference rhizobia strains used in this study. The phylogenetic tree showed a diverse genetic variation among the native rhizobia isolates as evident by the different clusters and sub-clusters.The principal coordinate analysis (PCA) also showed low level of genetic differentiation of native rhizobia isolates from Eastern Kenya and thus showing congruent results with the dendrogram. However, the grouping and distribution patterns of the native isolates did not correspond to the AEZ, and this is an indicative of the likelihood of a common evolutionary origin of the isolates. Similarly, Rhizobium tropici CIAT 899 and R. etli USDA 2667 in cluster I. For instance, native isolates TLM 27 and TUM 41 clustered together with R. etli USDA 2667 while isolate TLM 32 clustered with R. tropici CIAT 899. These indicate the close genetic relationship between some of the native rhizobia isolates to R. tropici CIAT 899, R. etli USDA 2667 and R. leguminosarum strain 446  genetic variation distributed within populations (97%) than among populations (2.5%) in four AEZ of Eastern Kenya. Despite the high diversity shown within the rhizobia population, the Pairwise Population Matrix of Nei unbiased genetic distance of rhizobia populations in the study region showed a narrow range, which is an indication of a weakly structured genetic population and a highly conserved genetic structure of rhizobia within the study area. Further molecular studies using either full or partial gene sequences of bacterial genome, which is more sensitive and has a higher resolution power, needs to be carried out to establish the true diversity of native rhizobia isolates up to the species and strain levels.In this study, 41 rhizobia isolates were obtained from the root nodules of mid-altitude climbing (MAC) beans and based on morpho-cultural and biochemical characteristics, the isolates grouped into nine morphotypes indicating the diverse nature of rhizobia nodulating with MAC beans. Cluster analysis based on genetic characteristics obtained after PCR-ARDRA profiling, showed a larger proportion of significant (JK, OO, JM, and EN conceived and designed the research and data collection tools and participated in drafting the manuscript. GK and SM collected the data, participated in data analyses, and wrote the manuscript. EN performed the data analyses. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sertoli cells (Sc) are unique somatic cells of testis that are the target of both FSH and testosterone (T) and regulate spermatogenesis. Although Sc of neonatal rat testes are exposed to high levels of FSH and T, robust differentiation of spermatogonial cells becomes conspicuous only after 11-days of postnatal age. We have demonstrated earlier that a developmental switch in terms of hormonal responsiveness occurs in rat Sc at around 12 days of postnatal age during the rapid transition of spermatogonia A to B. Therefore, such \u201cfunctional maturation\u201d of Sc, during pubertal development becomes prerequisite for the onset of spermatogenesis. However, a conspicuous difference in robust hormone (both T and FSH) induced gene expression during the different phases of Sc maturation restricts our understanding about molecular events necessary for the spermatogenic onset and maintenance. Here, using microarray technology, we for the first time have compared the differential transcriptional profile of Sc isolated and cultured from immature (5 days old), maturing (12 days old) and mature (60 days old) rat testes. Our data revealed that immature Sc express genes involved in cellular growth, metabolism, chemokines, cell division, MAPK and Wnt pathways, while mature Sc are more specialized expressing genes involved in glucose metabolism, phagocytosis, insulin signaling and cytoskeleton structuring. Taken together, this differential transcriptome data provide an important resource to reveal the molecular network of Sc maturation which is necessary to govern male germ cell differentiation, hence, will improve our current understanding of the etiology of some forms of idiopathic male infertility. Spermatogenesis is a complex process where every step of male Germ cell (Gc) development are essentially supported by somatic Sertoli cells (Sc) . In respIn rodents, upto 3\u20135 days after birth, Sc keep proliferating and attract the gonocytes towards the basement membrane for establishing the spermatogonial stem cell (SSC) niche . NeonataTo understand the regulatory mechanism of spermatogenesis, it is imperative to explore the changing landscape of gene expression during various phases of Sc maturation. Microarray is a powerful technique to study differentially expressed genes in large numbers . DiffereRattus norvegicus) were procured from colony maintained by Small Animal Facility, National Institute of Immunology, New Delhi, India. Animals were maintained in a standard day night cycle with stable temperature and humidity and provided food and water ad libitum. All the animal experimentations were approved by Institutional Animal Ethics Committee (IAEC) and performed following standard guidelines of \u2018\u2018Committee for the Purpose of Control and Supervision of Experiment on Animals (CPCSEA),\u201d Government of India.Wistar outbred rats (In vitro hormone treatment was performed on day 4.Sc cultures were prepared from 5 days and 12 days old rat testes as described earlier . BrieflySc from mature rat testes (60 days old) were isolated and cultured as described earlier . BrieflyOn day 4, Gc contamination were found to be less than 5% in Sc cultures of all age groups. Purity of Sc in culture were identified by vimentin staining  whereas Peritubular Cell (PTc) or Leydig Cell (Lc) contaminations were determined by the alkaline phosphatase or the 3\u03b2-HSD activity respectively, as described by us before .\u22127M T in combination = FT media) in pulsatile manner (30min of FT pulse/3hr)The doses of both o-FSH and T were previously found bioactive in cultured Sc obtained from all three age groups studied ; 2) genes downregulated in 12d but upregulated in 60d , and 3) genes upregulated in both 12d and 60d . For each sample, the calculated quantity of each gene was normalized with the endogenous control Ppia (Cyclophilin A). The relative quantities of mRNAs for all target genes were determined by 2-\u0394\u0394Ct method as reported by us before [In order to authenticate the array data the expression patterns of some of the genes were validated by quantitative reverse transcription PCR (q-RT-PCR) with additional sets of Sc culture obtained from all three age groups with consistent hormonal treatments (pulsatile FSH and T in combination for 11hr) and were compared with that of the array data. The genes considered were divided in five groups: 1) FSH responsive genes like SCF, GDNF, ABP, Transferrin and Dmrt1 in both 5d and 12d as reported earlier either by us or others . T respos before ,19. It iPostnatal maturation of testicular Sc is critical in regulating male fertility. Therefore, it becomes essential to investigate the genes expressed by Sc during this phase of development. Our microarray results have indicated differential expression of genes associated with cyto-architecture, metabolism, cytokines, chemokines, growth factors, MAPK signaling and Wnt signaling among others. Taken together, this differential transcriptome data provide an important resource database to reveal the molecular network of Sc maturation which is necessary to govern male germ cell differentiation. This information will improve our current understanding of the etiology of some forms of idiopathic male infertility with persistent immature Sc even in adulthood.S1 FigThere are 96 genes common between our data and Zimmerman\u2019s data and these genes are mainly involved in signal transduction, cell-cell communication, energy and metabolism and cell growth.(TIF)Click here for additional data file.S2 FigA) Entity based clustering analysis of co-expressed genes identified four clusters of co-expressed genes. (B) Gene Ontology (GO) based functional analysis of genes grouped under four clusters. Functional analysis was performed for molecular function (MF), cellular components (CC) and biological processes (BP).((TIF)Click here for additional data file.S1 Table(XLS)Click here for additional data file.S2 Table(XLS)Click here for additional data file.S3 Table(XLS)Click here for additional data file.S4 Table(XLS)Click here for additional data file."}
+{"text": "Introduction: For many years, amblyopia was regarded as a disorder of the visual system in which an organic cause could not be identified. Optical Coherence Tomography opens new horizons in understanding the etiopathology of amblyopia and seems to highlight morphologic anomalies in the retina of the amblyopic eye. Purpose: The objective of this paper is to analyze the macular thickness, optic nerve changes, and choroidal thickness found in patients diagnosed with amblyopia based on trials reported in the literature.Material and methods: This study analyzes 30 clinical trials regarding amblyopia evaluation with Optical Coherence Tomography. The research articles analyzed were published between 2006 - 2016 and were identified on PubMed database.Results: 19 research studies focused on macular and nerve optic changes, 7 on choroidal changes and 6 on retinal changes after occlusion. The results were discussed according to the type of amblyopia, alteration of macular thickness, optic nerve changes, ganglion cell layer changes, and alteration of choroidal thickness. Conclusions: The results are of great variability, and it seems that macula and choroid involvement is more frequently suggested compared with optic nerve involvement.Abbreviations: OCT = Optical Coherence Tomography, RNFL = Retinal Nerve Fiber Layer, GCC = Ganglion Cell Complex, ACD = Anterior Chamber Depth, BCVA = Best Corrected Visual Acuity  The results are often contradictory because, as Kim says, when conducting an OCT in patients with anisometropia it is important to correct the magnification of the device according to refraction and axial length of the eye. Also, results differ depending on the device used [3].Another limitation regarding correct interpretation of OCT in children emerges from the inexistence of international established normative values of macular and retinal nerve fiber layer (RNFL) parameters in children ;- Wang (2012) stated that the average thickness of the foveola is thicker than in normal eyes, but other regions have no significant difference [5];- Wu (2013) showed in his study that hyperopic anisometropic amblyopic eyes have a thicker foveola than the contralateral eyes [6];- Araki (2014) concluded that there are significant differences between amblyopic and fellow eyes that are independent of abnormalities in the visual cortex. He showed that the macular outer retinal thickness (1 and 3 mm regions) is significantly thicker in \u201elazy eyes\u201d [7].- Demircan (2015) discovered that in patients age 5-42 years the mean central macular thickness in the amblyopic eyes was thicker patients under 12 years [After studying anisometropic and strabic ambliopic patients:9];- The Sydney Childhood Eye Study (2009) affirmed that in children aged 6 to 12 years, central macular thickness may be increased in \u201elazy eyes\u201d, although it is uncertain if this precedes or follows the development of amblyopia [10]; - Al-Haddad (2011) showed in his study that the mean macular thickness was significantly increased in amblyopic eyes compared with fellow eyes. This difference remained significant in the anisometropic group but not in the strabic group. The mean RNFL thickness was similar in amblyopic and fellow eyes [11];- In 2013 Tugcu claimed that in patients with combined (anisometropic and strabismic) amblyopia and in patients with anisometropic amblyopia the thickness of ganglion cell complex (GCC) was significantly increased in both amblyopic and nonamblyopic eyes compared to healthy patients. The strabismic amblyopia group presented with significant reduction in GCC thickness and increased foveal thickness compared to nonamblyopic eyes. He did not found significant differences in morphological and functional measures among amblyopic groups but he detected significant differences in the retinal morphology of both amblyopic and nonamblyopic eyes compared with healthy control subjects [12];- Rajavi (2014) showed that the average foveal thickness of children with moderate and severe amblyopia was 10 microns thicker compared with the congener eye or the control group. Also, male patients had a mean macular thickness thicker than female patients and there was no correlation between the types of amblyopia and macular morphology changes [13]. - Szigeti (2014) revealed that there are subtle changes that affect the outer nuclear layer of the fovea suggesting the possible involvement of the photoreceptors [Concerning deprivational amblyopia:2]; - Kim (2013) investigated OCT changes in deprivational amblyopia due to congenital cataract and concluded that the mean macular thickness in amblyopic eyes was not different from the contralateral eye or control group, but noticed a thickening of the nasal RNFL compared with the fellow eye or control group [14]. - Long (2016) stated that 3 months after surgery, unilateral pediatric cataract patients show no significant interocular anatomical parameters differences except for anterior chamber depht (ACD) and that the parameters evaluated by OCT were not significantly correlated with the final BCVA [15-18].Also, there are scientists like Kee (2006) Repka (2009), Firat (2013) and Yakar (2015) who claim the inexistence of differences between amblyopic patients and the control group in their studies regarding macula morphology .Wu (2013) affirmed in his study that hyperopic anisometropic amblyopic eyes have thicker peripapillary RNFL than the contralateral eyes .Some scientist such as Kee (2006), Repka (2009), Huynh (2009), Firat (2013), Yalcin (2014), Demircan (2015) and Yakar (2015) claimed that there are no differences in RNFL and optic nerve disc morphology between amblyopic patients and control groups [\u2022 Choroidal thickness20-25]. However, Celik (2016) stated that, in young Turkish adults with hyperopic anisometropic amblyopia, the subfoveal choroidal, ganglion cell complex, macular and RNFL thickness measurements were not statistically significant between hyperopic anisometropic amblyopic eyes and normal fellow eyes [25].Morphological changes of the choroid evidenced with the help of OCT were studied by some researchers who certified that in amblyopic patients the subfoveolar area is significantly higher than in the congener eye or control group [\u2022 Are there morphologic changes after occlusion?26-30]. 6 studies were identified regarding the effect of optical correction and occlusion on the retina, optic nerve and choroid morphology. Oner (2016) analyzed central choroidal thickness before and after 6 months of occlusive treatment and reported no thickness reduction of the central choroid after amblyopia treatment. While Miki (2010), Tugcu (2013), and Yassin (2015) did not found differences between macular thickness and RNFL thickness before and after occlusion therapy, Pang (2011) stated that the central macular thickness was reduced after treatment compared with peripheric macular thickness in which changes were not noticed [31].Also, Liu (2010) stated that some children with various types of amblyopia who failed to achieve normal visual acuity after treatment show macular abnormality on OCT examination [Today, with the help of OCT, a new controversy regarding the presence of morphologic retinal changes in patients diagnosed with amblyopia arises. This opens new horizons in better defining amblyopia and can confirm if ocular structure are affected or not. In the last years, scientists have been trying to determine if morphologic changes in the macula, optic nerve, or choroid of amblyopic patients exist. The results are of great variability and, it seems that macula and choroid involvement is more frequently suggested compared with optic nerve involvement.DisclosureNone."}
+{"text": "Transthoracic echocardiography (TTE) and focused cardiac ultrasound (FCU) are now considered essential skills and a requirement of training for physicians working in the intensive care unit (ICU) . TTE is Out of 114 ICUs, 69 (61 %) completed the survey, including 23 (33 %) that admitted cardiothoracic surgical patients and 44 (67 %) that did not. The proportion of ICUs performing TTE (94 %) and LU was high (83 %) but the use of TOE was low (33 %). The proportion of ICU consultants performing TTE, LU, and TOE was lower , respectively. The level of expertise (diagnostic versus focused) was highest in TTE (32 %) compared with TOE (22 %) and LU (12 %).The proportions of intensivists untrained in TTE and LU was 41 % and 30 %, respectively. Perceived barriers included lack of organized training (38 %) and time for training (25 %). Other barriers included a perceived lack of need for training (18 %), insufficient equipment (14 %), and resistance from other ultrasound providers (4 %). The most commonly reported training programs were tertiary courses, such as provided by the Australasian Society of Ultrasound in Medicine (68 %) and University of Melbourne (59 %), rather than board examinations or hands-on workshops.We conclude that although TTE and LU are used frequently in Australasian teaching ICUs, many ICU physicians are yet to be trained due to lack of ICU training programs and time for training. Although tertiary courses are popular and provide training to diagnostic level, they are lengthy and depend on trainers and patient caseload and are not, therefore, scalable. An attractive alternative is to begin training in medical school and to train more physicians in basic ultrasound with shorter, more efficient, and hands-on courses utilizing the internet and ultrasound simulators , advanci"}
+{"text": "Objective: The study aims to assess the spectrum of cognitive and behavioural disorders in patients affected by Amyotrophic Lateral Sclerosis (ALS) according to the recent consensus criteria [9]. The study also intends to assess the impact of physical disability on cognitive and behavioural abnormalities.Methods: Detailed neurological, neuropsychological and neurobehavioral evaluations were administered to 23 ALS patients, 11 Lower Motor Neuron Disease (LMND) patients and 39 healthy controls. Strong et al.\u2019s criteria [9] were applied to diagnose the presence of cognitive/behavioural impairment. Clinical and neuropsychological scores were used for group comparisons and correlation analyses.Results: In comparison with LMND and controls, a subgroup of ALS patients (\u223c30%) manifested executive dysfunction, which was severe enough to classify them as cognitively impaired. Action naming difficulties and short-term memory deficits were also observed. Aspontaneity, disorganization and mental rigidity reached clinical relevance in 20% of ALS patients. A small percentage of ALS patients (13%) also had comorbid dementia. The cognitive or behavioural status was not related to the clinical features of ALS.Conclusion: The use of consensus criteria for cognitive and behavioural impairment and the comparison with the LMND group proved useful in defining the spectrum of non-motor manifestations of ALS."}
+{"text": "Although multiple serum antiretinal autoantibodies (ARAs) have been reported in patients with paraneoplastic and non-paraneoplastic autoimmune retinopathy ((n)pAIR), not all retinal antigens involved in (n)pAIR are specified. This study aims to serologically identify patients with presumed (n)pAIR through determination of both known and unknown ARAs by autoantibody profiling.An antigen suspension bead array using 188 different antigens representing 97 ocular proteins was performed to detect ARAs in serum samples of patients with presumed (n)pAIR (n = 24), uveitis (n = 151) and cataract (n = 21). Logistic regressions were used to estimate the associations between ocular antigens and diagnosis. Validation of interphotoreceptor matrix proteoglycan 2 (IMPG2) and recoverin antigens was performed by immunohistochemistry and immunoblot, respectively.Samples of patients with presumed (n)pAIR exhibited a broad spectrum of ARAs. We identified retinal antigens that have already been described previously (e.g. recoverin), but also identified novel ARA targets. Most ARAs were not specific for (n)pAIR since their presence was also observed in patients with cataract or uveitis. High titers of autoantibodies directed against photoreceptor-specific nuclear receptor and retinol-binding protein 3 were more common in patients with presumed (n)pAIR compared to uveitis . The presence of all other ARAs did not significantly differ between groups. In patients with presumed (n)pAIR, anti-recoverin autoantibodies were the most prevalent ARAs. Validation of bead array results by immunohistochemistry (anti-IMPG2) and immunoblot (anti-recoverin) showed concordant results in (n)pAIR patients.Patients with (n)pAIR are characterized by the presence of a broad spectrum of ARAs. The diagnosis of (n)pAIR cannot be based on the mere presence of serum ARAs, as these are also commonly present in uveitis as well as in age-related cataract patients. Paraneoplastic and non-paraneoplastic autoimmune retinopathy ((n)pAIR) is a rare blinding retinal disorder of unknown pathogenesis. It is presumed that antiretinal autoantibodies (ARAs) are involved in the pathogenesis of (n)pAIR and damage ocular tissue causing poor visual outcome. Symptoms associated with (n)pAIR are progressive visual loss , visual field loss frequently associated with a ring scotoma or loss of the peripheral field, and decreased amplitudes on electroretinogram (ERG). \u20134Paraneoplastic autoimmune retinopathy (pAIR) includes two subgroups: cancer associated retinopathy (CAR) and melanoma associated retinopathy (MAR). In pAIR the presence of the same auto-antigens in both retinal tissue and malignant tissue has previously been described (e.g. recoverin). \u20137 The prMultiple serum ARAs have regularly been reported in affected patients , althougCurrently, antigen bead arrays are being used to profile autoantibody reactivity in body fluids. With thiOur study aimed to serologically identify patients with presumed (n)pAIR through determination of ARAs. For this purpose, we used a bead array-based multiplex assay for autoantibody profiling using 188 ocular antigens representing 97 different retinal proteins.Serum samples were either collected during routine diagnostic analysis for the presence of anti-recoverin autoantibodies in the Laboratory of Medical Immunology of the Erasmus University Medical Center between April 2013 and August 2015 or were obtained from biobank of our department. The study was approved by the local ethical committee from the Erasmus University Medical Center  and adhered to the tenets of the Declaration of Helsinki. The ethical committee decided that no informed consent of patients was required for the use of the remainder of the diagnostic material, as the samples were anonymized and the patients were not subjected to additional risk or procedures. Samples which were obtained from the biobank  included signed informed consent from all participants. All whole blood samples were centrifuged after at least 30\u2019 clotting time at 3,000 rpm for 10 minutes, and serum was stored at -80\u00b0C.According to the recently published report on the nomenclature of (n)pAIR, the general term autoimmune retinopathy (AIR) is recommended to indicate the non-paraneoplastic autoimmune retinopathy (npAIR) subtype. In our present series we indicate the specific subtype(s) of AIR pAIR) to prevent any misunderstanding regarding nomenclature. The diagAn additional group of presumed pAIR (CAR or MAR) patients (N = 7) in whom ERG or visual field tests were not performed , but who fulfilled all other inclusion criteria, was included separately. An additional required criterion for these patients comprised the development of a malignancy before or within 3 months after presentation with ocular problems.We collected various clinical data of the patients with presumed (n)pAIR, including patient demographics (age and gender) and ocular characteristics such as complaints of photopsia, complaints of nyctalopia, subjective or objective problems with colour-vision, unilateral or bilateral visual problems and the presence of a malignancy in the medical history or during follow-up.Controls consisted of two groups: 21 serum samples from cataract patients without retinal damage and 151 samples from patients with uveitis of different causes. Patients with age related cataract were included as controls rather than healthy people, as this disorders does not involve retina nor exhibits retinal damage, and represents a clinical setting in which the tests might be employed. Samples of control patients were collected at the department of Ophthalmology of the Erasmus University Medical Center between February 2009 and April 2015. Patient demographics (age and gender) and known malignancies of these patients were registered.Escherichia coli, with an affinity tag consisting of six histidines and an albumin binding domain from streptococcal protein G (His6ABP)  and one bead identity went through the coupling process without addition of antigen . After incubation, the coupled beads were washed and stored in a blocking reagent before combining all bead identities to create a bead array in suspension. Samples were distributed across 96-well microtiter plates, together with triplicate aliquots of a sample pool and a buffer blank in each plate for determination of the intra- and inter-reproducibility. Serum samples were diluted 1:250 in assay buffer before being mixed with the bead array. Incubation was performed at room temperature for 2 hours followed by detection of the IgG reactivity by a fluorophore conjugated anti-human IgG Fab fragment and measured in a FlexMap3D instrument (Luminex Corp.).Autoantibody profiling was performed in all serum samples from patients with presumed (n)pAIR (n = 24), uveitis (n = 151) and cataract (n = 21). Antigens used for the autoantibody profiling were selected based on potential relevance to ocular diseases according to literature and previous positive retinal immunohistochemistry staining, resulting in 188 antigens (human protein fragments) representing 97 unique proteins. The protein fragments were produced within the Human Protein Atlas and designed to represent unique parts of each target protein., 43 ProtHis6ABP) . ImmobilFor validation purposes, samples that tested positive for anti-recoverin autoantibodies on the antigen bead array, and all samples from patients with presumed (n)pAIR, were analysed on a recoverin specific immunoblot . Membrane strips coated with recombinant human recoverin were incubated with a sample buffer for 5 minutes. After aspiration of the sample buffer, the membrane strips were incubated with diluted serum samples for 30 minutes on a shaking platform. Subsequently membrane strips were washed three times, incubated with secondary antibodies (enzyme conjugated anti-human IgG), washed again for three times and stained with a substrate solution which was capable of promoting an enzymatic colour reaction. To identify positive reactions, assessment of visible bands was performed relative to the included control. Results from the antigen suspension bead array and the recoverin specific immunoblot were compared.\u00ae , followed by hydration in graded alcohols and blocking for endogenous peroxidase in 0.3% hydrogen peroxide. For antigen retrieval, slides were immersed and boiled in Citrate buffer\u00ae, pH6  for 4 min at 125\u00b0C and then allowed to cool to 90\u00b0C. Automated immunohistochemistry was performed essentially as previously described, using an Autostainer 480 instrument\u00ae (Lab Vision). Ant Ant46] AOur study shows that patients with (n)pAIR are characterized by the presence of a broad spectrum of various ARAs. We identified ARAs that have already been described in previous studies, such as anti-recoverin autoantibodies, but also identified new retinal targets. Our findings illustrate that serum ARAs are not only present in patients with (n)pAIR, but also in patients with cataract and uveitis. Though some ARAs appeared to be specific for (n)pAIR, their prevalence and consequently their sensitivity as markers for (n)pAIR were low. This autoantibody screening using 188 antigen provides insight into the autoimmune repertoire of patients with (n)pAIR and a base for further validation with independent methods for protein analysis and independent sample cohorts.A gold standard for the determination of ARAs is currently lacking. DifferenIn addition, information on clinical relevance of the specific ARAs and their pathological titres are lacking. A combination of different ARAs was observed in some cases and therefore their individual effects on retinal tissue could not be distinguished.In our study, we performed statistical analyses using different cut-off levels. By using a high cut-off value, a ratio > 25, false positive results were minimized and retinal targets with a high specificity for (n)pAIR were found. The low cut-off value, a ratio of >2 (indicating ARAs with at least twice the reactivity of the negative control), was used for a more sensitive approach, limiting the exclusion of possibly relevant ARA targets with a lower titre. However, with both cut-off values, no ARAs were found eligible for diagnostic purposes. Some ARAs were specific for (n)pAIR, but had low prevalence while others were more frequently identified but lacked specificity.In concordance with previous findings, positive results of serum anti-recoverin autoantibodies were not only observed in patients with presumed (n)pAIR, but also in patients with uveitis and cataract. Furthermore, no association between the presence of autoantibodies directed against recoverin and the presence of a malignancy was found. A discrepancy between the antigen suspension bead array results for anti-recoverin and the anti-recoverin immunoblot was found in three control patients (one with cataract and two with uveitis). The difference in results could be explained by the different techniques used for determination of ARAs imposing differences in analytical performance. Possibly, the number and/or availability of recoverin antigenic epitopes differed between the antigen suspension bead array and the immunoblot technique. The protein fragments we used in this study to screen for autoantibody reactivity in serum were designed to represent unique parts of each target protein. The binding of the autoantibodies towards their target may be influenced by the protein folding of antigens and may differ in comparison to full-length protein arrays or peptide arrays. Both linear and conformational epitopes, recognized by some ARAs, might be missed for some proteins, preventing recognition by certain autoantibodies.The identification of new ARAs in (n)pAIR is in line with findings from previous studies using Western blot analysis for the determination of ARAs., 48 AlthOur present study focused on the autoantibodies prevalent in serum, which reflects systemic production and is probably not influenced by potential  production or accumulation of specific autoantibodies within the eye. Analysis of local, intraocular retinal autoantibodies might show an entirely different pattern and may differ in clinical importance compared to retinal autoantibodies found in the peripheral circulation. The importance of locally produced autoantibodies has already been shown in cerebrospinal fluid for the central nervous system. In addition, it is unknown which autoantibodies penetrate from the circulation, through the blood retina barrier, into the retina and cause a local inflammation. Further research addressing the intraocular presence of specific retinal autoantibodies might elucidate the clinically relevant autoimmune processes directed against the retinal tissue in (n)pAIR.A gold standard for the definitive diagnosis of (n)pAIR is currently lacking. Also in this study, the diagnosis of presumed (n)pAIR was based on clinical symptoms. To compensate for this inaccuracy, we used strict inclusion criteria and selected a uniform cohort of patients with unexplained visual loss, visual field defects and decreased or absent ERG while other diagnostic possibilities leading to this configuration of clinical characteristics were (so far as possible) excluded. The presence of ARAs was found in all our patients with presumed (n)pAIR and therefore all fulfilled the criteria for the diagnosis of (n)pAIR.Although the mere presence of ARAs supports the diagnosis of (n)pAIR, it has been stated that there are no specific ARAs which would be exclusive for (n)pAIR and none of the ARAs were identified to be of higher diagnostic value than other ARAs., 9, 14 OIn conclusion, our study identified a heterogenous reactivity pattern of ARAs in serum of patients with (n)pAIR, although the presence of ARAs was not discriminatory between (n)pAIR, cataract and uveitis and exhibited a low sensitivity. Therefore, the diagnosis of (n)pAIR cannot be based on the mere presence of serum ARAs and such presence thus warrants careful interpretation. The determination of ARAs in intraocular fluid might provide more insight into the pathogenesis of (n)pAIR and might indicate more sensitive and specific diagnostic tools. Therefore, future research on the prevalence of ARAs in ocular fluid represents an important next step.S1 Table(DOCX)Click here for additional data file.S1 FigARAs not prevalent in patients suspected of paraneoplastic and non-paraneoplastic autoimmune retinopathy are not shown.* GNAS;GNAZ;GNA11-15;GNAL;GNAQ;GNAI1-I3;GNAO1;GNAT1-T3.(EPS)Click here for additional data file."}
+{"text": "Gadus morhua) and turbot  in Denmark. Phylogenomic analyses revealed that these two ranaviruses are nearly identical and form a distinct clade at the base of the ranavirus tree branching off near other fish ranaviruses.Ranaviruses have been isolated from Atlantic cod ( Cod iridovirus (CoIV) is the earliest isolation of a ranavirus in fish. It was isolated from wild Atlantic cod in Danish coastal waters in 1979 during an investigation of ulcers in cod . Ranavirg for 20\u00a0min, and total nucleic acids were purified using a DNeasy blood and tissue kit (Qiagen). The DNA libraries were prepared using the Nextera XT DNA kit (Illumina), and sequencing was performed using a V3 chemistry 600-cycle kit on a MiSeq platform (Illumina). De novo assembly of the paired-end reads in SPAdes (The Rmax and CoIV isolates were propagated in bluegill fry (BF-2) cells as previously described  and harvn SPAdes  producedIridoviridae core genes (The genomes of Rmax and CoIV were annotated using GATU  with epire genes  revealedThe isolation of nearly identical ranavirus strains from two different marine species, hundreds of kilometers and 20\u00a0years apart, indicates the persistence of a ranavirus strain of unknown virulence in the marine environment. With the exception of the grouper iridoviruses in Asia , the impKX574343 and KX574342, respectively.The complete genome sequences of Rmax and CoIV have been deposited in GenBank under the accession numbers"}
+{"text": "This article provides original data on median dietary intake of 18 amino acids from amino acid medical foods, glycomacropeptide medical foods, and natural foods based on 3-day food records obtained from subjects with phenylketonuria who consumed low-phenylalanine diets in combination with amino acid medical foods and glycomacropeptide medical foods for 3 weeks each in a crossover design. The sample size of 30 subjects included 20 subjects with classical phenylketonuria and 10 with a milder or variant form of phenylketonuria. Results are presented for the Delis-Kaplan Executive Function System and the Cambridge Neuropsychological Test Automated Battery; the tests were administered at the end of each 3-week dietary treatment with amino acid medical foods and glycomacropeptide medical foods. The data are supplemental to our clinical trial, entitled \u201cGlycomacropetide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial, 2016 (1) and \u201cMetabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria, 2017 (2). This data has been made public and has utility to clinicians and researchers due to the following: 1) This provides the first comprehensive report of typical intakes of 18 amino acids from natural foods, as well as amino acid and glycomacropeptide medical foods in adolescents and adults with phenylketonuria; and 2) This is the first evidence of similar standardized neuropsychological testing data in adolescents and adults with early-treated phenylketonuria who consumed amino acid and glycomacropeptide medical foods. Specifications TableValue of the data\u2022The data presented are the first comparison of how ingestion of medical foods comprised primarily of single amino acids or intact protein from glycomacropeptide (a 64-amino acid glycophosphopeptide isolated from cheese whey) affect the dietary intake profile of amino acids.\u2022The dietary intake of 18 amino acids provides useful information to clinicians and researchers related to typical amino acid intake of individuals with phenylketonuria.\u2022The data from the standardized neuropsychological tests can be compared with pharmacological studies using these same tests to contrast the effectiveness of dietary management with pharmacological treatment in subjects with phenylketonuria \u2022These data are useful to clinicians and researchers evaluating the safety and efficacy of glycomacropeptide medical foods in the nutritional management of phenylketonuria.1Summary data for dietary intake of amino acids and assessment of neuropsychological and executive function are presented for subjects with phenylketonuria enrolled in a randomized, controlled, crossover trial conducted from November 2010 to July 2015 2Thirty subjects with early-treated phenylketonuria, 20 with classical and 10 with a milder or variant form of phenylketonuria, completed the clinical trial 3Daily amino acid intake from the whole diet, medical foods, and natural food was calculated from consecutive 3-day food records at the end of the 3-week amino acid medical foods and glycomacropeptide medical foods treatments . Amino aNeuropsychological testing to assess executive function, the Delis-Kaplan Executive Function System\u2122 , and the Cambridge Neuropsychological Test Automated Battery  was conducted by research staff trained in the administration of standard psychological assessments under the supervision of a licensed psychologist after following the amino acid medical foods and glycomacropeptide medical foods treatments for 3 weeks , Table 3Department of Health and Human Services Grants R01 FD003711 from the FDA Office of Orphan Products Development to Ney, P30-HD-03352, T32 DK007665 to Ney, and by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000427. Cambrooke Therapeutics, Inc. donated the glycomacropeptide medical foods used in this study.This work was supported by"}
+{"text": "The physical examination showed violaceous petechial purpuric patches, coalescing by area, ulcerated nodular lesions extended to both lower limbs, with presence of necrosis in center of lesions (Vasculitis is an inflammatory disease of blood vessels characterized by the alteration or destruction of the vessel wall. A 55 year\u2019s old woman, followed for diabetes and hypertension, presented to our consultation complaining of generalized pruritic lesions, without fever arthritis or any other systemic manifestations. The patient reported the concept of taking Oxicam; Brexin lesions Figure 1A lesions Figure 1B"}
+{"text": "Resistance to intravenous immunoglobulin (IVIG) occurs in 10\u201320% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels.We explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis.ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders.Thirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of Gene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics. Kawasaki disease (KD) is an acute systemic vasculitis of infants and children, that occurs world-wide , but theIn this study, we explored the association of GGT level and IVIG resistance in KD patients to try to understand the biological mechanism of action underlying these two clinical findings. With our systematic analyses of gene regulation and associated clinical findings and outcomes, we hypothesize: (1) neutrophil apoptosis induced by IVIG plays a pivotal role in IVIG responsiveness; (2) changes in sialylation and GGT levels in acute KD patients may contribute together to IVIG resistance by blocking IVIG-induced neutrophil apoptosis.The normal ranges of GGT and alanine aminotransferase (ALT) are shown in Table A in A cohort with 686 subjects with KD (Cohort I) was used to explore the associations between GGT levels and IVIG resistance. All subjects in this cohort were enrolled at Rady Children\u2019s Hospital in San Diego after obtaining written parental informed consent and patient assent as appropriate. All subjects were treated with 2 g/kg of IVIG (Gammagard\u00ae) over a 10\u201312 hour period as per the pharmacy\u2019s standard protocol. The study protocol was conducted in accordance with the Declaration of Helsinki and was approved by Institutional Review Boards of UCSD and Stanford University. KD subjects in this study were: a) patients with fever  for no more than 10 days, plus at least four of the five principal clinical criteria, b) patients meeting fewer criteria but with coronary artery abnormalities (CAA) (Z-score \u22652.5 for left anterior descending [LAD] and/or right coronary arteries [RCA]) documented by echocardiogram, and c) patients with fewer than 4 clinical criteria but meeting the American Heart Association (AHA) criteria for incomplete KD by laboratory criteria [We performed gene expression profiles of whole blood obtained from a sub-cohort of 146 KD subjects (Cohort II) as previously described . Of thesFor each of the 31,000 genes in the 130 subjects, the explained variations in GGT levels or IVIG responsiveness were estimated using R square of linear regression or the McFadden's pseudo- R square , 19 of lCorrection for multiple hypothesis testing on the explained variations was performed using the permutation-based false discovery rate (FDR) analytical method . FDRs ofThe study population was divided into two sub-cohorts, one with normal and the other with elevated GGT levels, using age-specific reference ranges established in our clinical laboratory  with 587 KD subjects. Approved by the institutional review board of Korean University Medical Center, the medical records of KD patients from January 2008 to December 2013 were reviewed. The diagnosis and treatment of KD was based on AHA criteria . CAA werThe absolute neutrophil count (ANC) (mature and immature (band) forms) were calculated for both the UCSD and Korean cohorts.All statistical analyses and plots were performed using R 3.2.2  and ggplThe 575 IVIG responders and 111 IVIG non-responders in Cohort I had similar demographic and clinical characteristics . SubjectIVIG resistance was examined according to GGT levels quintiles . IVIG reOf the 130 KD subjects with gene expression data in Cohort II, 100 were IVIG responders and 30 were IVIG non-responders. At the time of diagnosis, 45 subjects had normal serum GGT levels, and 85 had elevated GGT levels  with IVIG resistance persisted for 12 out of the 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels  or elevated GGT levels (85 subjects including 62 IVIG responders and 23 non-responders). After applying the Bonferroni correction, significant associations  percentage reduction in neutrophil count than responders. A similar pattern was observed in Cohort IV, which included 222 IVIG non-responders and 365 IVIG responders . We further delineated changes in ANC by stratifying patients into quintiles according to the ANC at presentation ..ST6GALNAactoside , 35. Neuin vitro , suggestin vitro . These oin vitro . Circulain vitro , 39.Despite the fact there have been reports of KD occurring in the presence of Autoimmune neutropenia (AIN), 41, forST6GALNAC3 leads to increased enzymatic activity of ST6GALNAC3, producing more GD1\u03b1, which in turn binds to siglec-9 and prevents its recognition by Nabs-siglec-9 in IVIG; (2) elevation of GGT levels will increase the degradation of extracellular glutathione (GSH) to provide cysteine for de novo synthesis of intracellular GSH, reducing the intracellular reactive oxygen species (ROS) in neutrophils. Reduction of ROS in neutrophils decreases neutrophil apoptosis induced by IVIG in the presence of GM-CSF and IFN- \u03b3 [Naturally occurring antibodies (Nabs) against siglec-9 (Nabs-siglec-9) are found in IVIG and can induce apoptosis in neutrophils \u201344. MoreTo the best of our knowledge, we are the first to integrate multifaceted data sets of expression profiles, clinical parameters and outcomes to explore KD pathophysiology. We demonstrated that KD subjects with elevated GGT levels have a unique gene expression pattern that overlaps with the gene expression pattern associated with IVIG resistance. Our study suggests that reduction of circulating neutrophils is one of the hallmarks of the therapeutic effects of IVIG.ST6GALNAC3 and elevated GGT levels may lead to reduced neutrophil apoptosis, and consequently IVIG resistance  Nabs against siglec-9 (Nabs-siglec-9) in IVIG can induce apoptosis in neutrophils and contribute to the efficacy of IVIG in the treatment of KD. (2) Increased sialylation of gangliosides block IVIG-mediated neutrophil apoptosis and lead to persistent inflammation and IVIG resistance.If confirmed, our findings may account for the variable effectiveness of different IVIG lot preparations , 49, potS1 FigNumbers below the x axis are numbers of subjects whose ANC increased after IVIG treatment. Of the 13 IVIG responders with ANC increased after IVIG, 12 fell into the lowest quintile of acute phase neutrophils, and none in the last three quintiles.(TIF)Click here for additional data file.S2 FigLoess curve analyses of neutrophil reduction or the percentage reduction in neutrophil count as a function of the pretreatment ANC .(TIFF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S1 FileTable A in S1 File. The standard range for normal GGT (IU/L); Table B in S1 File. The standard range for normal ALT (IU/L); Table C in S1 File. The clinical characteristics and laboratory values for subjects selected for gene expression analysis; Table D in S1 File. Association of 12 genes with IVIG response in subgroup with normal and elevated CRP levels; Table E in S1 File. Association of 12 genes with IVIG response in subgroup with normal and elevated CRP levels.(PPTX)Click here for additional data file."}
+{"text": "HSPD1 gene that encodes the HSP60 subunit of the HSP60/HSP10 chaperonin complex. Investigations of the molecular mechanisms underlying these disorders have revealed that different degrees of reduced HSP60 function produce distinct neurological phenotypes. While mutations with deleterious or strong dominant negative effects are not compatible with life, HSPD1 gene variations found in the human population impair HSP60 function and depending on the mechanism and degree of HSP60 dys- and mal-function cause different phenotypes. We here summarize the knowledge on the effects of disturbances of the function of the HSP60/HSP10 chaperonin complex by disease-associated mutations.Heat shock protein 60 (HSP60) forms together with heat shock protein 10 (HSP10) double-barrel chaperonin complexes that are essential for folding to the native state of proteins in the mitochondrial matrix space. Two extremely rare monogenic disorders have been described that are caused by missense mutations in the  E. coli bacteria  stacked back to back  ) lists 95 missense variations for the protein product of the canonical HSPD1 transcript. This website provides high quality exome sequencing data from more than 60,000 unrelated adults without severe pediatric disease. Of the 95 HSPD1 missense variations 60 have only been seen in one single allele and only 9 have been observed in more than 10 of the ~120,000 alleles recorded , this variation may be disease-associated with reduced penetrance. The most frequently observed amino acid variation in HSP60, HSP60-p.Gly563Ala, has been found in homozygous form in one sporadic Danish spastic paraplegia patient  has been reported (Hansen et al., Effects of expressing the SPG13- and MitCHap60-associated mutant proteins on mitochondrial morphology have been assessed in Cos-7 cells transfected with cDNAs encoding the disease-associated mutant proteins (Miyamoto et al., ShRNA-mediated knock-down of HSP60 in human HEK293 cells decreased the steady state levels of the mitochondrial medium-chain acyl-CoA dehydrogenase (Corydon et al., Knock-out of both HSP60-encoding alleles in mice is not compatible with life. Such embryos died early during development (Christensen et al., E. coli 85 proteins that display obligate dependence on folding assistance by the bacterial chaperonin complex have been characterized (Kerner et al., Proteins like UQCRC1 or SOD2 thus appear to depend more than others proteins on folding assistance by the HSP60/HSP10 complex. For de novo mutations in the HSPD1 and HSPE1 genes in sporadic diseases. Clinical geneticists should therefore be aware of this and it will be important to collect the knowledge of these rare cases to be able study genotype/phenotype relationships and to assess the disease-causing nature of variations.Different mutations in HSP60 or its partner protein HSP10 lead to distinct phenotypes of neurological disorders with a clear mitochondrial dysfunction pattern. These diseases are very rare as deleterious effects of mutations in these essential genes are not compatible with normal embryonal development (Christensen et al., Besides being affected by mutations, the activity and function of the HSP60/HSP10 complex can also be regulated by its expression levels. The regulation of the transcription levels of both proteins occurs via different elements in the bidirectional promoter. SP1 elements provide robust house-keeping levels of expression and on top of that heat-shock elements, mitochondrial unfolding protein response elements, and STAT3 elements further modulate expression adapting it to specific situations (Zhao et al., Indeed, dysregulation of HSP60 expression in hypothalamus has been implicated with type 2 diabetes mellitus (Kleinridders et al., Finally, posttranslational modifications of the HSP60/HSP10 complex may regulate the activity of the complex. Like other molecular chaperones HSP60 is a highly modified protein with a long list of PTMs recorded in the UniProt database (Consortium, PF and PB have both contributed to writing the draft and producing the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Non-traumatic out of hospital cardiac arrest (OHCA) is the leading cause of death worldwide, acute coronary syndromes accounting for up to 2/3 of cases. Urgent angiography with a view to primary percutaneous coronary intervention (PPCI) is a class IB recommendation according to international guidelines. Diagnosis and management of patients with unobstructed coronaries or unidentified culprit lesion on angiogram is challenging. Cardiac magnetic resonance (CMR) with its superior tissue characterization is a well-established diagnostic technique. We sought to assess the additive role of CMR in diagnosis and management of patients with an inconclusive coronary angiogram and to determine which findings on CMR best predict clinical impact.We retrospectively analysed our database to collect data on consecutive patients surviving non-traumatic OHCA, undergoing urgent coronary angiogram and CMR. We focused the analysis on patients with an inconclusive angiogram, defined as the evidence of unobstructed coronaries or of coronary artery disease (CAD) without a clear culprit lesion. Clinical impact of CMR was defined as a change in diagnosis, as compared to that made on a multi-parametric pre-CMR basis , or a change in management, which could be a change in medication or the performance/avoidance of invasive procedures .Out of 157 patients surviving OHCA referred for CMR after urgent angiogram, we identified 104 patients  with inconclusive angiogram (66%): 67 patients (64%) had unobstructed coronaries and 37 (36%) had CAD with no clear culprit. Diagnosis based on CMR findings was ischemic heart disease in 42 patients (40%), non-ischemic heart disease in 30 (29%), a structurally normal heart was found in 25 patients (24%) and non-specific findings in 7 (7%). Overall, CMR had a clinical impact in 68/104 patients (65%), determining a change in diagnosis in 17% of patients, a change in management in 31% and both a change in diagnosis and management in 17%. CMR led to myocardial revascularization in 18% of patients and to ICD implantation in 16%; based on CMR findings, an invasive procedure was avoided in 17% of patients. In a multivariate model that included clinical and imaging parameters, LGE  and segmental regional wall motion abnormality  were the strongest independent predictors of CMR clinical impact (Table CMR had an additive clinical impact on diagnosis and management in 65% of patients surviving OHCA with an inconclusive coronary angiogram. LGE and segmental regional wall motion abnormality were the best independent predictors of clinical impact following CMR. CMR should be enclosed in the clinical-diagnostic work-up of this subgroup of OHCA survivors."}
+{"text": "Scientific Reports 10.1038/s41598-017-14674-5, published online 06 November 2017Correction to: The original version of this Article contained an error in the Abstract.\u201cChanges in miRNA expression glomerular of capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes.\u201dnow reads:\u201cChanges in miRNA expression of glomerular capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes.\u201dThis error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Ovis orientalis), 22 wild goat (Capra aegagrus), nine Indian gazelle (Gazella bennettii) and eight Goitered gazelle (Gazella subgutturosa) during the national survey for wildlife diseases in Iran. Serum samples were evaluated using serologic antibody tests for Peste de petits ruminants virus (PPRV), Pestiviruses [Border Disease virus (BVD) and Bovine Viral Diarrhoea virus (BVDV)], Bluetongue virus (BTV), Bovine herpesvirus type 1 (BHV-1), and Parainfluenza type 3 (PI3). Sera were also ELISA tested for Pestivirus antigen. Tissue samples including spleen, liver, lung, tonsils, mesenteric and mediastinal lymph nodes and white blood cells (WBCs) were tested using polymerase chain reaction (PCR) for PPRV, Foot and Mouth Disease virus (FMDV), Pestivirus, BTV, Ovine herpesvirus type 2 (OvHV-2) and BHV-1. Serologic tests were positive for antibodies against PPRV (17%), Pestiviruses (2%) and BTV (2%). No antibodies were detected for BHV-1 or PI3, and no Pestivirus antigen was detected. PCR results were positive for PPRV (7.8%), FMDV (11%), BTV (3%), OvHV-2 (31%) and BHV-1 (1.5%). None of the samples were positive for Pestiviruses.A molecular and serological survey of selected viruses in free-ranging wild ruminants was conducted in 13 different districts in Iran. Samples were collected from 64 small wild ruminants belonging to four different species including 25 Mouflon ( Habitat fragmentation, hunting, and infectious diseases often threaten biodiversity and may contribute to significant declines in wildlife populations , 2. ThesWide climatic variations and untouched landscapes in Iran support a diverse mammalian fauna including 191 species from 93 genera and ten orders , 11. WilMost of the wild ruminants in Iran are on the International Union for the Conservation of Nature (IUCN) Red List as a direct result of infectious diseases, illegal hunting and drought .Goitered gazelle, listed by the International Union for Conservation of Nature (IUCN) red list as vulnerable, are found in the Zargros region of Iran. Indian gazelle, protected in Iran but a considerable population of Indian gazelle are found in the Kavir National Park . Both WiMorbillivirus (family Paramyxoviridae) closely related to the eradicated rinderpest virus, causes the disease Peste des petits ruminants (PPR) which is considered to be one of the most significant livestock diseases in the Middle East, Africa and Asia [The majority of pathogens that cause disease outbreaks in wild ruminants worldwide are viral . Peste dand Asia , 17. PPRand Asia . Multipland Asia , 20. PPRand Asia , 22.Foot and Mouth Disease (FMD) is caused by a single-stranded negative sense RNA virus that belongs to the genus Aphthovirus from the Picornaviridae family. The FMD virus (FMDV) contains seven different serotypes, O, A, C, Asia 1, Southern African Territories (SAT) 1, SAT 2 and SAT 3 . MoleculPestivirus infections in animals are caused by a group of viruses from the Flaviviridae family, genus pestivirus. Three different pestiviruses have been described, namely, bovine viral diarrhoea virus (BVDV), Border disease virus (BDV) and Classical Swine Fever Virus (CSFV) . BVDV anOrbivirus from the family Reoviridae. There are 24 antigenically distinct serotypes in the genus and differing levels of cross reactivity have been observed between different serotypes[Culicoides midges [Another important infection seen in domestic and wild ruminants is Bluetongue virus (BTV) an serotypes. Epidemiserotypes. Sero-epserotypes\u201344. Howeserotypes. BTV cirs midges , 46 withs midges .Malignant Catarrhal Fever (MCF) is caused by members of subfamily Gammaherpesvirinae, genus Macavirus . AlcelapInfectious bovine rhinotracheitis virus (IBRV) and parainfluenza type 3 virus (PI3V) are the main viral respiratory diseases in livestock worldwide , 57.Paramyxovirus family, is one of the most common viral respiratory infections in cattle. Although PI3V can cause primary respiratory disease in cattle, it usually leads to the development of secondary bacterial infections in the respiratory tract of large ruminants [Infectious bovine rhinotracheitis (IBRV), caused by Bovine herpesvirus 1 (BHV-1), is associated with several clinical features in cattle. BHV-1 can produce a lifelong latent infection with occasional reactivation of the virus followed by viral shedding for several days. A serological positive response in animals is evidence of a latent infection . Parainfuminants . Both seuminants .The exteuminants .The aim of this study was to investigate if there is evidence of these commonly seen livestock viruses in wild ruminants in the national parks and protected regions of Iran using serological and molecular techniques.Ovis orientalis), 22 wild goat (Capra aegagrus), nine Indian gazelle (Gazella bennettii) and eight Goitered gazelle (Gazella subgutturosa).The study animals comprised wild ruminants from four different species including 25 Mouflon   each indWhole blood was collected from the jugular vein, by cardiac aspiration or from the thoracic or abdominal cavities during fresh field necropsies by an authorized veterinarian from the Iran DOE. The collected blood was divided into two tubes, with and without anti-coagulant (EDTA) and labelled. Samples were transported, refrigerated, to the Virology laboratory at the Faculty of Veterinary Medicine at the University of Tehran within 24 hours.The names of the regions and their geographic information system coordinates for all sampled animals and the age and sex of wildlife species tested in this study are shown in Tables At the laboratory, serum was separated by centrifugation at 2000 RPM for 10 min. White blood cells from each blood sample was separated for antigen detection and RNA/ DNA isolation for molecular detection.WBCs were isolated using Ficoll-Hypaque density gradient separation method. In brief, five mL of blood was diluted two-fold in sterile phosphate buffered saline (PBS) then added into the 10 mL of Ficoll-Hypaque (Sigma Aldrich), centrifuged for 400 \u00d7 g at room temperature for 30 min. The cells were isolated and washed twice with PBS . AliquotThe study was approved by the Research and Ethics Committee of Iran Department of Environment. Animals were shot by authorized hunters and autopsied by veterinarians who specialized in wildlife studies during the national programme for survey of wildlife diseases. The hunting licences were issued by the Iran Department of Environment for the DOE qualified hunters.Serological tests used to detect antibodies included the following: a) PPR cELISA kit , b) pestivirus blocking ELISA kit (BVDV) and (BDV) , c) Bluetongue competitive ELISA  and d) Bovine Herpesvirus 1 (BHV-1) ELISA kit and e) virus neutralization test (VNT) for parainfluenza type 3 . PestiviIn all serological ELISA tests positive and negative control sera were included in each plate. In addition to the control samples (provided within the ELISA kits), two more known positive and negative samples were included in each round of ELISA or VNT tests. The positive and negative-control serum samples were serum from animals who had been tested at the diagnostic virology unit at the Razi Vaccine and Serum Research Institute or Virology laboratory at the Faculty of Veterinary Medicine at the University of Tehran, Iran and kept as standard control samples. Each of these serum samples were previously evaluated in different assays. For virus neutralization test, each serum sample was tested in two independent assay runs and serum samples with a titre of 1/64 or higher were considered positive . All of White blood cells and the fresh/frozen tissues from all animals were subject to DNA and RNA isolation. RNA extraction was performed using QIAamp Viral RNA Mini kit  according to the manufacturer's instructions. The cDNA was synthesized from extracted RNA using Moloney Murine Leukemia Virus-Reverse Transcriptase (MMLV-RT) and random primers . Total DNA was isolated from the above mentioned samples using QIAamp DNA Mini Kit  according to the manufacturer's instructions. The synthesized cDNA and isolated DNA were saved as aliquots and stored at \u221280\u00b0C for further analysis.Previously published PCR protocols were used to detect; a) PPR , b) FMD Serological exposure of the 64 wild ruminants to PPR, BVD and BD, BTV, BHV-1, PI3 and pestivirus antigen is shown in The PCR results for PPRV, FMDV, Pestivirus, BTV, OvHV-2 and BHV-1 are shown in Four mouflon, two wild goats and one Indian gazelle were positive for FMDV by PCR on tonsil samples. The only positive Indian gazelle for FMDV was from Tooran and the positive Mouflon were from Tooran (n = 1), Khojir (n = 2) and Angooran (n = 1). Two FMDV positive wild goats were from Khojir National park and Mujen protected region. All positive PCR tests for PPRV, FMDV, BHV-1 and four of the OvHV-2 samples were confirmed by sequencing. Edited nucleotide sequences were compared to the nucleotide sequence database for similarity using BLASTn search tool and was shown to have significant homology to the available sequences for the listed viruses. \u2013S5 FilesThis is the first survey of viral diseases in wild ruminants in Iran. It will provide valuable information for future research in disease ecology and risks associated with transmission of these viruses between wildlife and livestock.Studies have shown that PPRV is endemic in Iran and the other neighbouring countries with multiple devastating outbreaks occurring in domestic and wild ruminants , 22. MorBorder disease is considered as an endemic disease in domestic sheep and goats in Iran  and so MFoot and mouth disease has been reported in Mouflon, wild goats and Indian gazelles in several countries , 35. As Previous work in southeast Iran identified the serological existence of Bluetongue virus in domestic sheep with no reports of clinical signs , 44, 78.In this survey all of the seropositive and PCR positive BT samples were seen in Mouflon from Bamo National Park. The locality of this survey overlaps geographically with the district where a high prevalence of BTV is seen in livestock .There was no serological evidence for PI3 and IBR, the main viral infections of Iranian livestock, and there was just one Indian gazelle positive for BHV 1 using PCR. These viruses mainly cause disease in intensively managed livestock populations, so the lack of seroprevalence was expected in wildlife. In addition, BHV 1 infection is rarely seen in small ruminants and the clinical form is mainly associated with intensive feedlot or dairy production industries .PCR tests showed a high prevalence of OvHV-2 in Mouflon. The virus does not produce clinical signs in small ruminants and there have been no reports of clinical disease in wild and domestic sheep and goats , 81. In In conclusion, while there is clear evidence that transboundary disease viruses particularly FMDV, BTV and PPRV are circulating in wild ruminants. Further studies are required to investigate the transmission pathways and disease ecology between wildlife and livestock.S1 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file.S2 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file.S3 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file.S4 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file.S5 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file."}
+{"text": "SH2 domain-containing tyrosine phosphatase-2 (PTPN11 or Shp2) is a ubiquitously expressed protein that plays a key regulatory role in cell proliferation, differentiation and growth factor (GF) signaling. This enzyme is well expressed in various retinal neurons and has emerged as an important player in regulating survival signaling networks in the neuronal tissues. The non-receptor phosphatase can translocate to lipid rafts in the membrane and has been implicated to regulate several signaling modules including PI3K/Akt, JAK-STAT and Mitogen Activated Protein Kinase (MAPK) pathways in a wide range of biochemical processes in healthy and diseased states. This review focuses on the roles of Shp2 phosphatase in regulating brain-derived neurotrophic factor (BDNF) neurotrophin signaling pathways and discusses its cross-talk with various GF and downstream signaling pathways in the retina. PTPN11 gene  is a 593 amino acid non-transmembrane protein tyrosine phosphatase (PTP) encoded by Shp2 plays prominent biological roles in regulating several signal transduction cascades affiliated with its function in the early development of vertebrates, cell proliferation, differentiation, transcription regulation and metabolic control  as well as multiple GF signaling networks by the Shp2 phosphatase and its implications in the retina.In the retina, Shp2 is well expressed in the ganglion cell layer (GCL) and inner nuclear layer (INL) and its reactivity has been detected in photoreceptors  are secreted proteins that regulate neural growth, survival and function by negatively affecting the induction of various cellular apoptotic pathways. Retinal ganglion cells (RGCs) express various neurotrophic factors and are also supported by neurotrophic factors obtained locally from the Muller cells and retrogradely from the brain through axonal flow , the prominent structural constituent of caveolae Figure . Shp2 waThe role of other significant caveolar proteins such as Cavin family members particularly polymerase I and transcript release factor (PTRF) which participate in caveolae formation through its interaction with Cav-1, have not been extensively investigated and their potential cross-talk with Shp2 remains to be explored  and in the RGCs In cerebellar granule neurons, Shp2 suppressing functions are reported to abolish axonal regeneration by paired immunoglobulin-like receptor PIR-B/Shp mediated TrkB inhibition , another member of the neurotrophin family, exerts its survival-promoting effects by stimulating neural development and differentiation through MAPK cascade  signaling in human glial cells in response to EGF treatment. Zhang et al.  demonstrThe EGF-inhibitory impact of Shp2 was also investigated in a glioma cell line (SNB19). Despite lack of proliferation ability of SNB19 in response to EGF stimulation, it was found that interfering Shp2 mutant could reverse the cell\u2019s ability to proliferate following EGF induction  signaling cascade which has major functions in cellular processes such as proliferation, differentiation and apoptosis  downstream signaling including Ras, Raf, MEK and MAPK cascade. Insulin receptor substrate 1 (IRS-1), one of the major IR substrate is a multisite docking protein which interacts with SH2 domain-containing proteins such as Shp2. Milarski and Saltiel  showed tPTPN11 gene mutation (Tartaglia et al., PTPN11 gene in animal studies resulted in extensive retinal degeneration, cell death and optic neuropathy during various developmental stages highlighting its regulatory function in retinal neuroprotection and progenitor retinal cell fate (Cai et al., Shp2 involvement in regulating retinal survival signaling pathways links dysregulation of this phosphatase to various physiological and pathological conditions. Under glaucomatous stress Shp2 leads to preferential RGC degeneration by inhibiting BDNF/TrkB downstream signaling through dephosphorylation and deactivation of TrkB (Gupta et al., in vivo and in vitro studies implied that the major effect of the phosphatase is mediated through its regulatory effects on various GFs and their downstream effectors which activates multiple signaling pathways. In this review we outlined and analyzed the existing evidence regarding Shp2 involvement in BDNF and other GF-dependant signaling networks with a specific focus on the retinal neuronal cells.Shp2 plays an emerging and important role in the retinal development and its preservation. Preliminary Although significant breakthroughs in the functional characterization of Shp2 have provided more knowledge of the physiological importance of the phosphatase, other areas of future study including manipulating Shp2 expression in retinal and other neuronal cell lineage or development of specific phosphatase inhibitors will further define the mechanisms through which Shp2 positively or negatively mediates various retinal signaling pathways. Another fascinating aspect would be considering Shp2 as a potential molecular target to modulate other neuronal signaling pathways thereby serving as mechanism-based therapy. The involvement of Shp2 in broad range of biochemical actions may make it a challenge to develop any specific therapeutic strategy to isolate a particular neuroprotective role. However, prospective investigations probing Shp2 protein expression, post-translational modifications, sub-cellular localization and interactome changes will unravel the role of this protein in various neurodegenerative disease and retinal disorders.The review was conceptualized, written and edited by each of the authors. Supervisor: SLG.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To the Editor: Zika virus infection is an emerging arboviral disease linked to an increased risk for severe neurologic outcomes and devastating adverse fetal complications, including pregnancy loss and congenital microcephaly (A 51-year-old man (patient 1) who regularly traveled to Samoa, a Pacific island with known Zika virus transmission, returned to New Zealand in late January 2016. He reported having been sexually abstinent while overseas. After 1 week he experienced onset of fever, rash, arthralgia, and ankle edema. Aware of the symptoms of mosquito-borne illnesses prevalent in his region of travel, he assumed he had a mild case of chikungunya and sought no medical attention.A 53-year-old woman (patient 2) who was the sexual partner of patient 1 experienced onset of sore throat, fever, arthralgia, and rash 17 days after her partner\u2019s return to New Zealand (10 days after he had onset of symptoms). She had had no recent overseas travel, had no blood transfusions, and was unaware of having any mosquito bites. Four days after symptom onset, she visited a general practitioner, whose investigations revealed mild neutropenia, normal liver and renal function, no evidence of streptococcal throat infection, and a demonstrated immunity to measles.The rash subsequently spread, and small joint arthralgia worsened. The patient returned to the general practitioner 9 days after symptom onset. Disclosing her partner\u2019s travel history and symptoms and reporting having unprotected sexual intercourse with him after his return to New Zealand (before and during the time he was symptomatic), she enquired about the possibility of Zika virus infection. After discussing the matter with a clinical microbiologist and securing the consent of the woman and her partner, the general practitioner ordered tests for arboviruses common in the male partner\u2019s region of travel. All laboratory tests for chikungunya and dengue viruses were negative for both patients. Testing for Zika virus RNA was performed by using real-time reverse transcription PCR (rRT-PCR) in accordance with published methods  (9). Sert] 25). Semen collected on days 35 and 76 also tested positive . Semen samples collected on days 99 and 117 tested negative for Zika virus RNA. Attempts at virus isolation from the semen sample collected on day 23 failed to cultivate infectious particles.Laboratory investigations for Zika virus RNA in patient 1 demonstrated negative rRT-PCR results for serum (first tested 19 days after symptom onset) and for urine (first tested 21 days after symptom onset). Serologic testing performed on day 21 detected Zika IgM and IgG (IgG titer 1:320). Semen collected on day 23 tested positive for Zika virus RNA (cycle threshold [CAedes species of mosquito capable of transmitting Zika virus infection is established in the country (It is very unlikely that transmission of Zika virus infection to patient 2 occurred through a mosquito bite. Although occasional interceptions of exotic mosquito species have occurred at international ports of entry into New Zealand, neither of the"}
+{"text": "The purpose of this study was twofold: (1) to compare whether children from polygamous family structures significantly differ from children from monogamous family structures with regard to the frequency of parent-child conflict, and (2) whether children from these two structures employ different patterns of family conflict resolution.To address these questions, a random sample of 212 high school students (60.8% monogamous) completed a self-administered survey. The results of MANOVA show no significant differences (p > 0.05) between these two structures with regard to the frequency of parent-child conflict. The results also show similar conflict management styles between these two family structures within each of the following five domains .This study is unique in that it is the first empirical research to be conducted in the field of conflict resolution among youth and adolescents in polygamous marital structures and therefore, further investigation is needed to replicate these results utilizing different cross-cultural populations practicing polygamy."}
+{"text": "A key factor in determining the likely outcome for a patient with colorectal cancer is whether or not the tumour has metastasised to the lymph nodes\u2014information which is also important in assessing any possibilities of lymph node resection so as to improve survival. In this review we perform a wide-range assessment of literature relating to recent developments in gene expression profiling (GEP) of the primary tumour, to determine their utility in assessing node status. A set of characteristic genes seems to be involved in the prediction of lymph node metastasis (LNM) in colorectal patients. Hence, GEP is applicable in personalised/individualised/tailored therapies and provides insights into developing novel therapeutic targets. Not only is GEP useful in prediction of LNM, but it also allows classification based on differences such as sample size, target gene expression, and examination method. Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide . Currenthttps://www.verywell.com, Updated 9 April 2017). In another report, nearly 30% of CRC cases with no record of their lymph node metastasis (LNM) status were found during the five-year follow-up to have died because of tumour recurrence. The authors of the latter study concluded that the presence of the occult lymph node metastases (micrometastases) that were not detected by routine examinations might be the cause [Curative surgery improves the CRC patient\u2019s status at least in early stage, but the healing process is not adequate by itself . For exahe cause .The prevalence of micrometastases in patients with early CRC has recently been widely investigated. Published data indicate that even patients with stage I, who seem to have localised disease, may harbor micrometastases that were missed during the clinicopathological tests . In line(1)(a)chromosomal instability (CIN) ,(b)CpG island methylator phenotype (CIMP) ,(c)microsatellite instability (MSI) .A model that consists of three molecular subtypes including:(2)(a)CMS1 (14%), microsatellite instability (MSI) and immune hyperactivation,(b)CMS2 (37%), epithelial involvement, wingless-type MMTV integration site family member (WNT) and MYC pathway interaction,(c)CMS3 (13%), epithelial and metabolic involvement,(d)CMS4 (23%), invasive and metastatic activation of transforming growth factor\u2013\u03b2 (TGF-\u03b2) .A model of four consensus molecular subtypes (CMSs). The members of this model show the following discriminating features:Like other cancer types, CRC occurs by multiple misregulation of oncoproteins or tumour suppressors that impair the intra- and extra-cellular signal balances. The two most applicable models in this field are as follows:These models facilitate the identification of germline mutations of the genes involved in DNA mismatch repair (MMR) including MutS protein homolog 2 and 6 , MutL protein homolog 1 (MLH1), and PMS1 homolog 2 (PMS2), which all cause MSI in patients with hereditary HNPCC/Lynch syndrome . As in MAs previously mentioned, DNA mutations have a huge impact on prognosis and survival rates. However, the impact of thousands of detected mutations on cancer progression has not yet been elucidated, and we are not sure whether some of these mutations cause the cancer (driver mutations) or emerge because of the cancer (passenger mutations). Currently, gene expression profiling of the primary tumours has received a great deal of attention due to its ability to create a detailed picture of the genetic and epigenetic alteration status of tumours.What is the actual value of the gene expression signatures for the prediction of key events such as recurrence or LNM in CRC patients? This question has been the subject of numerous previous studies . GeneralThe detection of high-risk patients with recurrent CRC is arguably the main challenge. In this regard, applying molecular assessment tools could be helpful in identifying cases of occult micrometastasis and potential suitability of adjuvant therapy ,41. AccoOver the last decade, gene expression profiling by microarray has been a pioneering method in the detection of disease-related molecules. Compared with other standard techniques such as RT-PCR, which is not able to evaluate a large number of targets at once, microarray screening provides fast and reliable data with high accuracy from various samples. With microarray, it is now possible to analyse the whole expression pattern of a human genome within 48\u201372 h, thus gathering precious details about related molecular subtypes .Using cDNA microarray technology, Kwon et al. (2004) examined and compared the expression profiling of 4608 genes in 12 CRC tumours versus in noncancerous tissues . AccordiWang et al. (2004) tried to identify new prognostic markers for cancer relapse by DNA chip technology. Their achievement was a 23-gene panel allowing prediction of recurrence in Dukes\u2019 B patients. The panel also provided insight regarding the underlying biological mechanism of rapid metastases; some of these genes are involved with tumour development and cell proliferation. For example, Tyrosine 3 mono-oxygenase tryptophan 5-monooxygenase activation proteins (YWHAH) and Regulator of chromosome condensation 1 (RCC1) are the most important genes governing the G2 checkpoint of the cell cycle and chromosome condensation initiation, respectively . In the Arango et al. (2005) proved that the downregulation of Ras homolog gene, a small GTPase protein known to regulate the actin cytoskeleton, was correlated with shorter survival. This approach is not only useful in Dukes\u2019 C patients\u2019 recurrence predictions but also can be used in the design of clinical management algorithms .Meeh and colleagues used digital long serial analysis of gene expression to elucidate the differences between node-negative and node-positive colorectal tumours. They reported that the development of node-positive CRC occurs, in part, through elevated levels of epithelial Fibronectin 1 (FN1). They suggested that the progression of the CRC from node-negative to node-positive disease may be facilitated partially by FN1 deregulation and the subsequent enhancement of tumour cell migration .In 2009, Watanabe and colleagues determined that gene expression programming could be a useful tool in predicting recurrence in stage III colorectal cancer, and also identified calcineurin binding protein 1 (CABIN1) among discriminating genes that may play a key role in the development of recurrence . AdditioThe other family involved in cancer metastasis is the Forkhead box proteins (FOX). For example, FOXC2, also known as Forkhead Box C2 (FKHL14), has been found to be significantly elevated in patients with lymph node involvement and correlated with the degree of LNM . UpregulIn 2011, Salazar and colleagues developed a robust gene expression classifier (ColoPrint) that can predict relapses in patients with early-stage CRC. According to their study, this method can identify patients with stage II CRC who will experience a recurrence within five years after surgery . The tecBesides ColoPrint, Lenehan et al. (2012) have developed a molecular prognostic examination able to identify tumour recurrence within three years in CRC cases having curative surgery. From analysing the expression changes of 18 key genes involved in regulation of cell signal transduction, gene expression, invasion, growth, angiogenesis, apoptosis, and antioxidation, they identified five genes that could be used in the prediction of tumour recurrence in CRC patients: BMI-1 polycomb ring finger oncogene (BMI), Vascular endothelial growth factor A (VEGFA), Ribosomal protein S10 (RPS10), Ets variant 6 (ETV6), and H3 histone, family 3B (H3F3B). However, the test was validated in stage I and II patients and the authors concluded that \u226512 lymph node samples would be required for accurate prognostication .The results of another study on 196 genes in CRC patients determined that use of the expression pattern of main genes such as Annexin A3 (ANXA3), C-type lectin domain family 4 member M (CLEC4D), Lamin B (LMNB1), proline rich and Gla domain 4 (PRRG4), TNF alpha induced protein 6 (TNFAIP6), Lamin B1 (TNFAIP6), Vanin 1 (VNN1), and Interleukin 2 receptor subunit beta (IL2RB) that participate in tumour initiation and development could act as novel biomarkers for early detection of CRC . In lineGEP has been investigated for its potential to predict the outcome of patients in other cancers, too. M\u00e9ndez et al. (2011) identified five genes (Receptor accessory protein (1REEP1), Ring finger protein 145 (RNF145), CTONG2002744, Myosin VA (MYO5A), and FBXO32) that were differentially expressed between node-positive and node-negative oral squamous cell carcinomas (OSCC), and suggested that this model is applicable for identification of occult metastasis in patients . SimilarAs already discussed, the GEP platform provides a unique opportunity to examine tens of thousands of different candidate genes at a given time. However, like other laboratory methods, GEP technology is limited. The data obtained from GEP are very simple and only consist of the candidate genes. GEP is not able to detect the interactions or signaling crosstalks. Therefore, other data analyses must be performed to elucidate the underlined network, for example, behind the antitumour drug resistance. Thus, different perceptions may be derived from a single raw data point. The other limitation of the GEP approach is the sample type and the method of preparation. The DNA of different types of cells and tissues of the body undergo multiple modifications and express various genes; hence, the quality of DNA extraction and isolation is directly related to the GEP output. This noise is usually resolved by increasing the sample size, but in particular cases, other alternatives such as RNA sequencing technology ,53 or siOverall, for prediction of tumour recurrence and metastasis, GEP analysis has marked advantages compared to routine clinical exams. Using microarray technology, various genes are identified that allow prediction of LNM in CRC cases. Based on this approach, a new classification of CRC has been introduced that reflects the different biological pathways and distinct prognostic features, allowing preselection of patients who would benefit from adjuvant therapies. However, more investigations are also needed to identify the genes associated with poor prognosis profiles, since these may actually prove interesting potential targets for rational development of new cancer drugs."}
+{"text": "Arabidopsis thaliana is the most widely used model organism for research in plant biology. While significant advances in understanding plant growth and development have been made by focusing on the molecular genetics of Arabidopsis, extracting and understanding the functional framework of metabolism is challenging, both from a technical perspective due to losses and modification during extraction of metabolites from the leaves, and from the biological perspective, due to random variation obscuring how well the function is performed. The purpose of this work is to establish the in vivo metabolic profile directly from the Arabidopsis thaliana leaves without metabolite extraction, to reduce the complexity of the results by multivariate analysis, and to unravel the mitigation of cellular complexity by predominant functional periodicity. To achieve this, we use the circadian cycle that strongly influences metabolic and physiological processes and exerts control over the photosynthetic machinery. High resolution-magic angle spinning nuclear magnetic resonance (HR-MAS NMR) was applied to obtain the metabolic profile directly from intact Arabidopsis leaves. Combining one- and two-dimensional 1H HR-MAS NMR allowed the identification of several metabolites including sugars and amino acids in intact leaves. Multivariate analysis on HR-MAS NMR spectra of leaves throughout the circadian cycle revealed modules of primary metabolites with significant and consistent variations of their molecular components at different time points of the circadian cycle. Since robust photosynthetic performance in plants relies on the functional periodicity of the circadian rhythm, our results show that HR-MAS NMR promises to be an important non-invasive method that can be used for metabolomics of the Arabidopsis thaliana mutants with altered physiology and photosynthetic efficiency. Arabidopsis thaliana play a central role in understanding biological functions across plant species and in characterizing phenotypes associated with genetic mutations  have been overlaid for assignment purpose.(TIF)Click here for additional data file.S3 FigReference spectra of glucose (purple), sucrose (green) and fructose (red)  have been overlaid for assignment purpose.(TIF)Click here for additional data file.S4 Fig\u03b1-glucose and \u03b2-glucose has been overlaid on experimental data with purple colour.Reference spectra of (TIF)Click here for additional data file.S5 FigLeaves were collected at different time points throughout 24h light/dark period (Time points are same as mentioned in (TIF)Click here for additional data file.S1 TableHR-MAS NMR conditions used in earlier studies for obtaining metabolic profile in various plant materials.(DOCX)Click here for additional data file."}
+{"text": "With the rapid development of computer science and technologies in recent years, there has been dramatic advance in anterior segment imaging.As we have mentioned in the call for papers for this special issue, manuscripts are covering the topics of anterior segment imaging techniques including anterior segment optical coherence tomography (OCT), specular microscopy, corneal topography, confocal microscopy, and ultrasound biomicroscopy (UBM). These techniques have enabled precise visualization and objective assessments of anterior segment structures; thus, these devices have become essential tools for better diagnosis and treatment of anterior segment diseases including corneal disorders, cataract, glaucoma, and even disorders of the lacrimal system. Future development of novel modalities, that is, en face OCT or ultrahigh-resolution OCT, is expected to allow more detailed visualization at a microscopic level, which would provide even more understanding of anterior segment pathology at a cellular level. In this special issue, the authors contributed 15 original articles and 4 review papers regarding technologies of the anterior segment imaging and clinical application of the imaging devices.The authors have contributed the results of their original researches on various topics on anterior segment imaging: (1) agreement between gonioscopic examination and swept source OCT imaging; (2) preliminary outcomes of accelerated corneal collagen cross-linking using topography-guided ultraviolet-A energy emission; (3) anterior segment changes before and following laser peripheral iridotomy of iris bombe in patients with uveitic secondary glaucoma; (4) anterior segment measurements with swept source OCT before and after ab interno trabeculotomy; (5) effects of a new type implantable collamer lens implantation on vision-related daily activities; (6) corneal epithelial remodeling after transepithelial photorefractive keratectomy for myopia; (7) measurement of anterior chamber volume in cataract patients using swept-source OCT; (8) biomechanical findings in contact lens-induced corneal warpage; (9) quantitative analysis of lens nuclear density using OCT with a liquid optics interface; (10) rotating Scheimpflug imaging indices in different grades of keratoconus; (11) evaluation of outflow structures in vivo after the phacocanaloplasty; (12) evaluation of corneal epithelial thickness in asymmetric keratoconic eyes and normal eyes using Fourier domain OCT; (13) central corneal thickness measured using spectral-domain OCT and associations with ocular and systemic parameters; (14) anterior segment changes in pseudophakic eyes after pars plana vitrectomy with silicone oil or gas tamponade using UBM imaging; and (15) UBM comparison of ab interno and ab externo intraocular lens scleral fixation.This special issue also includes review articles on the following topics: (1) application of Scheimpflug imaging in glaucoma management; (2) anterior segment imaging in ocular surface squamous neoplasia; (3) applications of anterior segment OCT in cornea and ocular surface diseases; and (4) the role of anterior segment OCT and UBM in corneal and conjunctival tumors.We hope these articles will provide readers with useful information on anterior segment imaging and new ideas for researches on related topics."}
+{"text": "Multicellular organisms rely on the precise and consistent regulation of gene expression to direct their development in tissue- and cell-type specific patterns. This regulatory activity involves arrays of DNA-binding transcription factors and epigenetic factors that modify chromatin structure. Among the chromatin modifiers, trithorax (trxG) and Polycomb (PcG) group proteins play important roles in orchestrating the stable activation and repression of gene expression, respectively. These proteins have generally antagonistic functions in maintaining cell and tissue homeostasis as well as in mediating widespread transcriptional reprogramming during developmental transitions. Plants utilize multiple trxG factors to regulate gene transcription as they modulate their development in response to both endogenous and environmental cues. Here, I will discuss the roles of trxG factors and their associated proteins in post-embryonic plant development. The development of multicellular organisms is driven by precise patterns of gene transcription that are tightly regulated in a spatial and temporal manner. Establishing and sustaining specific transcription states at gene loci are complex, multi-step processes. They require repertoires of sequence-specific DNA-binding transcription factors as well as epigenetic factors that alter chromatin structure and thereby affect accessibility by the transcriptional machinery. Epigenetic regulators classified as trithorax group (trxG) and Polycomb group (PcG) factors are critical for maintaining the stable transcription patterns at developmental regulatory loci by organizing chromatin in an active or inactive state, respectively . trxG anDrosophila as positive regulators of PcG developmental target genes (Table 1). The chromatin remodeling proteins include members of the SWI/SNF, ISWI, and CHD families that utilize ATP to alter nucleosome assembly and distribution  AP2 domain transcription factor (TF) genes, which are essential for root stem cell niche maintenance  maintenance. The RAM generates the entire underground root system and has a stereotypical organization. Four rarely dividing cells known as the quiescent center (QC) act as a niche  that maintenance .Figure 1A). The SET domain protein SET DOMAIN GROUP 2 (SDG2) is the major H3K4 trimethyltransferase in Arabidopsis and is necessary for genome-wide H3K4me3 deposition  and BRAHMA (BRM) also regulate RAM activity in Arabidopsis. PKL acts antagonistically to the PRC2 PcG factor CURLY LEAF (CLF) to maintain RAM stem cell activity -CLAVATA (CLV) signal transduction pathway. The homeobox TF gene WUS is expressed in the core of the meristem and confers stem cell identity on the overlying cells . In contrast, the SAND domain-containing proteins ULTRAPETALA1 (ULT1) and ULT2 restrict shoot and floral stem cell activity by limiting the size of the WUS expression domain , FLOWERING LOCUS D (FD) and SOC1, which promote the transition to flowering  and APETALA1 (AP1), which confer floral meristem (FM) identity on the primordia that form on the flanks of the primary SAM  to reproductive organs (flowers). The timing of this dynamic meristem cell fate switch is critical for plant reproductive success and occurs in response to endogenous pathways such as the age, GA and autonomous pathways (APs) as well as environmental cues including photoperiod, vernalization and temperature . The MADlowering . FT protmary SAM .FLC, SOC1 and FT are crucial to the timing of the floral transition, and a number of trxG factors are involved in these processes . Because the role of epigenetic factors in FLC regulation during vernalization has been extensively reviewed  couple removal of repressive histone marks with deposition of active marks and transcription initiation/elongation to sustain high levels of FLC expression. ATXR7/SDG25 also represses the floral transition by binding to the FLC promoter and augmenting both H3K36me3 and H3K4me3 accumulation , a core component of the Arabidopsis COMPASS-like complex (AtCOMPASS) that also binds the FLC locus and promotes its expression by elevating H3K4me3 levels   . SVP forSE (SVP) . SVP expcription . BRM repactivity . Thus thFLC transcription is crucial for the transition from the vegetative to the reproductive state. The JmjC domain-containing H3K27 demethylase REF6/JMJ12 promotes flowering independently of photoperiod by repressing FLC transcription  that produces floral meristems (FMs) instead of leaves. A small suite of floral homeotic transcription factor genes then specifies the identity of each floral organ \u2013 sepals, petals, stamens, and carpels \u2013 from the outside to the inside of the flower . The actAPETALA3 (AP3) and AGAMOUS (AG) that specify petal, stamen, and carpel identity in the developing flower , which recruit SYD to the AP3 and AG loci  by activating AP3 and AG expression, antagonizing CLF activity at the two loci by reducing H3K27me3 deposition and enhancing H3K4me3 deposition (The plant specific TF LFY and the MADS domain TF SEPALLATA3 (SEP3) play crucial roles in activating the expression of MADS box-containing floral homeotic genes such as g flower . SYD and AG loci . At the  AG loci   enhance ult1 FM phenotypes, and ALP1 promotes floral organ identity gene expression in the absence of LFY . It is becoming clear from recent research that members of all of these categories of proteins play important roles in regulating landmark post-embryonic developmental processes such as meristem maintenance and floral induction. Moreover some trxG factors, such as BRM and ATX1, mediate multiple developmental processes during plant growth whereas others appear to have more restricted roles. The coupling of a core set of reiteratively used trxG components together with stage-, tissue- or process-specific trxG components may provide a flexible mechanism for tailoring the basic process of transcription activation to discrete gene networks in response to changing endogenous and environmental signals during the life cycle.A variety of trxG factors exist in plants that carry out diverse biochemical activities to promote active gene expression states: chromatin-remodeling ATPases, histone methyltransferases, AtCOMPASS core components, histone demethylases, as well as DNA-binding and accessory proteins (Although significant progress has been made in determining the roles of trxG factors in plant development, many gaps in our understanding remain. It still remains to be determined how many trxG complexes exist in plants, not to mention their full composition and whether that composition is static or changes depending on the developmental stage or tissue. The DNA binding proteins that recruit trxG factors to developmental regulatory loci are only beginning to be identified, while elucidating the chromatin signatures of plant stem cell populations can provide a valuable starting point for determining how tissue- and stage-specific epigenetic states are ultimately achieved during development. Finally, much work remains to decipher how developmental switches between trxG and PcG activities are implemented at individual loci as well as broadly across the genome to coordinate widespread transcriptional reprogramming. Further investigation in these areas will provide a more complete picture of how plants are able to maintain and as necessary adjust their gene expression programs during development in response to a wealth of endogenous and environmental cues.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Introduction: Considering importance of fatty acids in developing coronary artery disease (CAD) and lack of information about saphenous vein which is commonly used as coronary arterial bypass, in this study we investigated differences in fatty acids composition between saphenous vein and aorta tissues in patients with CAD.Methods: Biopsy samples of aortic tissues and saphenous veins as well as blood samples were obtained form 42 patients with CAD. Fatty acids composition of the tissues was determined using gas chromatography and also serum lipid profile was evaluated by commercial kits.Results: Levels of palmitic acid (16:0) were significantly higher in aorta in compared with saphenous (P < 0.001). Also levels of most unsaturated fatty acids  were statistically higher in saphenous tissue than aorta tissue (P < 0.05). Mean levels of linoleic acid (18:2 n-6) was higher in aorta tissue in comparison with saphenous tissue (P = 0.01). We observed positive correlations between serum levels of LDL-C with elaidic acid and linoleic acid levels in saphenous. Evaluation of aorta tissue fatty acids revealed that palmitoleic acid (16:1) had positive and arachidonic and linoleic acids had negative correlations with serum HDL-C levels.Conclusion: Our results revealed difference between fatty acids composition of aorta and saphenous vein tissues and existence of correlations between the fatty acids levels with serum lipid profile. The saphenous vein had higher poly-unsaturated fatty acids in compared to aorta tissue and thus this vein is not at risk of atherosclerosis and can be used as coronary arterial bypass. Although many studies have evaluated effects of dietary fatty acids as well as plasma levels of them on coronary atherosclerosis,12 but there is no enough information about fatty acids content and their possible roles in the tissues which are involved in the atherosclerosis.Many studies have been conducted to investigate lipid accumulation in the arterial wall of patients with atherosclerosis but many questions about mechanisms of dyslipidemia and progression of atherosclerotic lesions have been remained unanswered.14 However existence of higher free cholesterols than cholesterol esters in the plaques15 which is in contrary with the finding about high ratio of cholesterol esters/free cholesterol in plasma,16 led to arise theory of coming the lipids from vessels growing into the plaque.17 On the other hand higher levels of fatty acid synthesis in atherosclerotic arteries in compared with intact arteries highlights possible role of fatty acid metabolism in tissues which are involved in atherosclerosis.18It has been reported that cholesterol as one of the major lipids in atherosclerotic plaques which possesses fatty acids, enters from the blood rather than in situ synthesis.19 Also Bahrami et al20 have demonstrated lower levels of unsaturated fatty acids and higher amounts of saturated fatty acids in atherosclerotic aorta in compared with the internal mammary arteries. Furthermore different fatty acids composition of aorta artery and adipose tissue between patients with and without CAD has been shown previously.21 These finding emphasize on importance of local fatty acids composition in developing atherosclerosis and CAD. However there is no information about fatty acids composition of saphenous vein which is commonly used as coronary arterial bypass and also has structural differences with arteries.22 The aim of this study was to investigate differences in fatty acids composition between saphenous vein and aorta tissues, as well as associations between the fatty acids levels with serum lipid profile in patients undergoing CABG.In a study it has been reported that the fatty acids composition of coronary arteries was significantly different between sudden cardiac death and traffic accident victims.2 and the patients with class II and III obesity (BMI \u226539 kg/m2) were not involved. The exclusion criteria were: having acute inflammation, auto-immune diseases, kidney and liver diseases, diabetes, anemia or malignant tumors. Also patients with prior CABG as well as aortic or mitral valve replacement were excluded from the study.Frothy-two individuals (mean age: 53.2\u00b17.5 years), documented as CAD patients were included in this study. All patients had at least two vessels coronary artery disease (\u226550% stenosis) based on the angiographic data and were scheduled for CABG at Shahid-Madani heart hospital in Tabriz, a northwest city of Iran. Also we recruited patients with body mass index (BMI) \u226434.9 kg/mBiopsy samples (1-2 g) were obtained during the surgery from aortic tissues and saphenous veins and then were dissolved in hexane and kept frozen at - 70\u00b0C in glass vials for fatty acid measurement. Also in order to lipid profile analysis, approximately 5 mL of venous blood samples in the fasting state at 8:00 am were taken from all participants and the serums were separated using centrifugation.23 and the percentage of each fatty acid was determined using gas chromatography. In brief, the solution of fat extract in hexane was evaporated under a stream of nitrogen to near dryness, and the lipids were esterified with methanol during catalysis with acetyl chloride. Then fatty acid methyl ester derivatives were separated on a 60- x 0.25-mm Teknokroma TR-CN100 column using gas chromatograph system  equipped with a split injector and a flame ionization detector. The oven temperature program was 170-210\u00b0C, 1\u00b0C/min, and then isothermal for 45 minutes. The combined inter- and intra assay of variation was 2.1% for palmitic acid (16:0), 2.7 for linoleic acid (18:2n-6), 18.6 for eicosapentaenoic acid (EPA), and 11.2 for docosahexaennoic acid (DHA). The known fatty acids from Sigma chemicals was employed as standards to peak retention times identification. The levels of fatty acids were calculated as the percentage of each fatty acid of the total.Fatty acids were extracted using the Bligh and Dyer methodThe levels of triglycerides (TG), total cholesterol (TC) and high density lipoprotein-cholesterol (HDL-C) determined by enzymatic colorimetric method  with an automated chemical analyzer . Low-density lipoprotein-cholesterol was calculated using the Friedewald formula.t test was used to compare fatty acids levels between saphenous vein and aorta tissues in each patient. Also the Pearson correlation test was applied to investigate possible associations between the fatty acids levels with serum lipid parameters. P values <0.05 were considered significant. SPSS V.16 software was used for the statistical analysis.The data are reported as mean \u00b1 standard deviation (SD). Normal distribution of the data was confirmed by Kolmogorov-Smirnov test. The paired Demographic and clinical characteristics of the studied population are shown in In studied patients mean levels of total cholesterol was higher than normal range (214 \u00b1 45 mg/dL) and mean levels of triacylglycerol, 178 \u00b1 50 mg/dL, was borderline high . Also thP < 0.001). Levels of most unsaturated fatty acids  were statistically higher in saphenous tissue than aorta tissue (P < 0.05). On the other hand, mean levels of linoleic acid (18:2 n\u20106) was higher in aorta tissue in comparison with saphenous tissue . Comparing the mono-unsaturated fatty acids levels between saphenous and aorta demonstrated that levels of palmitoleic acid and oleic acid as well as its trans isomer (elaidic acid) were significantly lower in aorta than saphenous vein. The poly-unsaturated fatty acids levels were also different between the two vessels as we observed significantly lower proportions of the trans isomer of linoleic acid (18:2 t), linolenic acid (18:3 n-9) and docosatrienoate acid (22:3 n-3) in aorta in compared to the saphenous. Based on our knowledge, there is no report on differences of fatty acids composition between saphenous and aortic tissues of CAD patients. However, in accordance with our results, in previous studies higher levels of palmitic acid and also lower levels of poly-unsaturated fatty acids in phospholipids of aorta and coronary arteries of patients with CAD in compared with control individuals have been reported.21 Moreover in a study on fatty acids composition of aorta and internal mammary of patients with CAD same as our results, lower levels of unsaturated fatty acids  and higher percentage of palmitic acid in aorta samples than internal mammary have been reported.20 Moreover they also found statistically different levels of stearic acid (18:0), arachidonic acid (20:4n-6) and eicosapentaenoic acid (20:5-n3) between aorta and internal mammary arteries.20 We did not find such differences between aorta and saphenous vein maybe due to structural differences between saphenous vein and internal mammary artery.The assessment of fatty acids contents in saphenous vein and aorta of CAD patients indicated that the fatty acids composition between these vessels was different. We found higher concentration of palmitic acid as saturated fatty acid in aorta in compared with saphenous vein  were found in aorta tissue as compared to the saphenous vein. Higher levels of linoleic acid in aorta and coronary arteries of individuals with CAD compare to non-CAD subjects and also in aorta in compared with internal mammary artery in patients with CAD have been shown previously.20 However there is no enough information about pattern of fatty acids modification and its role in atherosclerosis pathogenesis.Such differences between fatty acids composition of aorta artery and saphenous vein could be partly due to structural differences between arteries and veins but some part of these differences could also be because of atherosclerosis and cardiovascular complications that the aorta was involved. Reports about different fatty acids composition between aorta and internal mammary of patient with CAD confirm this possibility.33 and thromboxane A2 production.34 In our previous study we also found negative correlations between levels of linoleic acid in epicardial and subcutaneous adipose tissues with serum levels of HDL-C and a positive correlation between this fatty acid content in subcutaneous adipose tissue with serum LDL-C in patients with CAD.35 There are wide evidences that the HDL-C and LDL-C are protective and risk factors for atherosclerosis and its complications, respectively37 and on the other hand linoleic and arachidonic acids have been documented as atherogenic fatty acids which cause inflammation and platelet aggregation.32 So finding the associations between these fatty acids with LDL-C and HDL-C seems reasonable. Moreover, we observed a positive correlation between the HDL value and palmitoleic acid in aorta which confirms the protective effect of palmitoleic acid as MUFAs against CAD.39In this study we detected inverse correlations between serum HDL-C with linoleic acid levels in saphenous and aorta tissues and also with arachidonic acid levels of aortic tissue. Besides, linoleic acid levels in saphenous vein were positively correlated with LDL-C in serum. The negative correlation between HDL-C and arachidonic acid could be explained by results of previous study reported that in CAD patients, HDL-hypocholesterolemia decreases ability of platelet to produce nitric oxide (NO) and consequently reduction in NO levels itself inhibits arachidonic acid metabolism. NO induces the inhibitory influence through various direct and indirect ways such as inhibition of cyclooxygenase activities40 Moreover results of a 25-year follow up study conducted in seven countries, have been showed positive correlation between dietary intake of elaidic acid and serum cholesterol.41 These reports confirm our finding about existence of positive correlation between elaidic acid in saphenous and serum total cholesterol.It has been demonstrated that elaidic acid (18:1t) is cholesterol elevating factor.43 exerts its effects partly via changing serum lipid profile and consequently vessel wall fatty acids composition. Although observed differences in fatty acids composition between aorta and saphenous vein tissues and also between aorta tissues of CAD and NON-CAD patients21 as well as aorta and internal mammary arteries of CAD patients20 emphasize that in addition to diet, local lipid metabolism and existence of atherosclerosis can be determinative factors for fatty acid composition of vessel walls. However the ways that different dietary intake or lipid metabolism could influence tissue fatty acids composition still remain to be elucidated. However, in our study we did not have information about dietary habits and life-style which could possibly affect the fatty acids composition of the tissues. Although it should be noted that in the present study the comparisons were done between two tissues of each patient, so any confounding factor such as dietary habits which could affect the evaluated parameters, affects the parameters of both saphenous and aorta tissues in same patient and consequently could not affect the overall result of our study. Another limitation of our study was lack of proper control without CVD because of impossibility of taking such samples from healthy individuals. However further studies could be conducted on immediately dead persons without CVD or animal models.Considering the association between fatty acids composition of aorta and saphenous tissues with serum lipid profile that was found in the present study, it can be concluded that composition of dietary fatty acids which has been suggested as important factor for CAD developmentIn this study due to the unavailability of healthy individuals saphenous and aorta tissues we could not compare the results with control. Also due to difficulty in finding patients our study was conducted with almost small sample size. Another limitation of our study was lack of information about diet of patients as it can has effect on fatty acids composition of saphenous and aorta tissues.In conclusion our results revealed difference between fatty acids composition of aorta and saphenous vein tissues in CAD patients and existence of correlations between the fatty acids levels and serum lipid profile. Owing our results about higher levels of PUFAs in saphenous vein compared to aorta tissue, it is likely that the vein has almost low risk for atherosclerosis and may be able to be used as coronary arterial bypass.All authors declare no competing financial interests exist.Approval for this study was granted by the ethical committee of Tabriz University of Medical Sciences and the informed written consent was obtained from all participants The work was supported by a grant from the Cardiovascular Research Center, Tabriz University of Medical Sciences. This article was extracted from the M.Sc. thesis of Mirhamid Paytakhti Oskouei."}
+{"text": "A patient aged 58 years, presented with 2 months history of an erythematous, painful and bleeding nodule, after labial herpes (A). The dermoscopic examination confirms the diagnosis of a pyogenic granuloma (B). The dermoscopic criteria are: the reddish homogeneous area (green line) whose color varied from completely red to red with whitish zones which is corresponded to proliferating vessels. A white collarette (yellow line) corresponds to the hyperplastic adnexal epithelium that embraces the lesion at the periphery. The white lines (blue line) like a double rail which is corresponded to a fibrous septa that criss-cross the lobules. And finally ulceration or hemorrhagic crusts (black line) which are frequently observed in pyogenic granuloma."}
+{"text": "Many alien plants use animal vectors for dispersal of their diaspores (zoochory). If alien plants interact with native disperser animals, this can interfere with animal-mediated dispersal of native diaspores. Interference by alien species is known for frugivorous animals dispersing fruits of terrestrial plants by ingestion, transport and egestion (endozoochory). However, less attention has been paid to possible interference of alien plants with dispersal of diaspores via external attachment , interference in aquatic ecosystems, or positive effects of alien plants on dispersal of native plants. This literature study addresses the following hypotheses: (1) alien plants may interfere with both internal and external animal-mediated dispersal of native diaspores; (2) interference also occurs in aquatic ecosystems; (3) interference of alien plants can have both negative and positive effects on native plants. The studied literature revealed that alien species can comprise large proportions of both internally and externally transported diaspores. Because animals have limited space for ingested and adhering diaspores, alien species affect both internal and external transport of native diaspores. Alien plant species also form large proportions of all dispersed diaspores in aquatic systems and interfere with dispersal of native aquatic plants. Alien interference can be either negative  or positive . I propose many future research directions, because understanding whether alien plant species disrupt or facilitate animal-mediated dispersal of native plants is crucial for targeted conservation of invaded (aquatic) plant communities. Dispersal of plant diaspores by animals (zoochory) is a globally important mechanism regulating species diversity of plant communities. Key disperser species include birds, mammals, and fish\u2013of which many forage on plant diaspores, transport them internally during digestion, and defecate viable diaspores in new locations  alien plant species may interfere with both internal and external animal-mediated dispersal of native diaspores; (2) interference by alien plants also commonly occurs in aquatic ecosystems; and (3) interference by alien plants can have both negative and positive effects on native plants. I focus on zoochory of plant diaspores  by vertebrate animals. \u201cAlien species\u201d is used as the terminology throughout this study to refer to all non-native, invasive, introduced or exotic species that established a self-sustaining reproductive population outside their native geographic area  feed selectively on Eurasian grasses in Canada  and mule deers (Odocoileus hemionus) remove fruits of an alien succulent faster than those of a native species in the same genus  studying interference of alien plants with ectozoochory by itself, and simultaneously with interference of endozoochory in single model systems; and (2) comparing the relative effectiveness of alien and native diaspores for endo- and ectozoochory in choice and attachment experiments  AND TS = (seed OR diaspore* OR fruit OR nut); combined with either TS = (frugivor* OR endozoochor*) or with TS = (ectozoochor* OR epizoochor* OR exozoochor*). This resulted in respectively 376 and 36 studies that addressed dispersal of alien plants for endo- and ectozoochory. Addition of the term TS = (aquatic OR wetland OR freshwater OR riparian) reduced the publication counts to respectively 16 and 6, indicating that a low percentage of all studies involved aquatic habitats.To compare study effort on alien interference between habitats and among disperser animals, I performed a standardized search for publications reporting the presence of alien and native aquatic diaspores in single samples of feces or attached to native vertebrate animals in ISI Web of Science. On the 11th of January 2018 I entered the following search string: TS =  and 55% for ectozoochory . In 5 of the 19 reports on endozoochory and 8 of the 15 reports of ectozoochory more alien than native diaspores were dispersed. However, these numbers should be interpreted with caution because variation among geographic locations and studied species was large, and studies reporting only dispersal of native diaspores were not included.All aquatic studies jointly reported 34 cases of potential interference by alien plants with dispersal of native diaspores\u2014by native disperser animals\u2014and in aquatic ecosystems Tables , 2. The The presented cases illustrate that patterns of alien interference thus far primarily described in terrestrial ecosystems may also apply to aquatic ecosystems. Future research should focus on under-examined disperser animals like fish, bats and reptiles  although the phenomenon has been primarily studied for endozoochory by frugivorous birds and mammals in terrestrial ecosystems, alien species may also interfere with ectozoochory and this warrants further studying; (2) interference of alien species with zoochory can similarly be found in aquatic ecosystems; (3) alien plant species can also provide resources such as food or nesting habitat to animals, which can increase densities of native disperser animals or attract new disperser animal species. Through these mechanisms alien plants can also positively affect dispersal of native plants, which warrants further studying. This study illustrates that the impacts of alien plant species on native plant species, whether positive or negative, can vary among native plant species relying on different dispersal mechanisms. Understanding species interactions is crucial for effective conservation, especially in invaded ecosystems.CvL designed the study, collected and analyzed the data, and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To respond to the World Health Assembly call for dissemination of lessons learnt from countries that have begun implementing the International Health Regulations, 2005 revision; IHR (2005).In November 2015, we conducted a systematic search of the following online databases and sources: PubMed\u00ae, Embase\u00ae, Global Health, Scopus, World Health Organization (WHO) Global Index Medicus, WHO Bulletin on IHR Implementation and the International Society for Disease Surveillance. We included identified studies and reports summarizing national experience in implementing any of the IHR (2005) core capacities or their components. We excluded studies that were theoretical or referred to IHR (1969). Qualitative systematic review methodology, including meta-ethnography, was used for qualitative synthesis.We analysed 51 articles from 77 countries representing all WHO Regions. The meta-syntheses identified a total of 44 lessons learnt across the eight core capacities of IHR (2005). Major themes included the need to mobilize and sustain political commitment; to adapt global requirements based on local sociocultural, epidemiological, health system and economic contexts; and to conduct baseline and follow-up assessments to monitor the status of IHR (2005) implementation.Although experiences of IHR (2005) implementation covered a wide global range, more documentation from Africa and Eastern Europe is needed. We did not find specific areas of weakness in monitoring IHR (2005); sustained monitoring of all core capacities is required to ensure effective systems. These lessons learnt could be adapted by countries in the process of meeting IHR (2005) requirements. First introduced in 1969, IHR is global legislation requiring countries to link and coordinate specific actions.,,IHR (2005) also requires all countries to develop, strengthen and maintain eight core public health capacities.Although IHR (2005) describes what must be achieved by countries, there is limited knowledge on how countries should proceed in achieving the core capacities. To fill this gap and accelerate implementation of IHR (2005), the World Health Assembly in 2015 identified a need to evaluate and share the lessons learnt from countries that have implemented IHR (2005).,,This systematic review was conducted in accordance with Enhancing Transparency in Reporting the Synthesis of Qualitative Research guidelines, using a predefined protocol .Box\u00a01Component 1A: National legislation and policyComponent 1B: FinancingComponent 2A: IHR coordination, communication and advocacyComponent 3A: Indicator-based surveillanceComponent 3B: Event-based surveillanceComponent 4A: Rapid response capacityComponent 4B: Case managementComponent 4C: Infection controlComponent 4D: Disinfection, decontamination and vector controlComponent 5A: Public health emergency preparedness and responseComponent 5B: Risk and resource management for IHR preparednessComponent 6A: Policy and procedures for public communicationsComponent 7A: Human resource capacityComponent 8A: Policy and coordination of laboratory servicesComponent 8B: Laboratory diagnostic and confirmation capacityComponent 8C: Laboratory biosafety and laboratory biosecurity (biorisk management)Component 8D: Laboratory-based surveillanceIHR: International Health Regulations.Source: International Health Regulations (2005).Two authors independently screened all abstracts, articles and reports and then matched the full texts selected during screening against the inclusion criteria. The reference lists of relevant articles and reviews were also searched for additional studies and reports. Articles meeting the inclusion criteria were included in the review. Three authors completed the data extraction using standardized extraction tables.,Two authors independently read and assessed the quality of included studies using the Critical Appraisal Skills Programme qualitative research checklist.,\u2013,We used the Cochrane qualitative systematic review method, including meta-ethnography, to synthesize qualitative data.\u2013http://www.who.int/bulletin/volumes/96/2/16-189100). A more detailed summary of the included articles and themes identified is available from the corresponding author. Some articles reported national experience in IHR (2005) implementation in multiple countries. In total, 77 countries were represented from all WHO Regions: 23 from Western Pacific, 16 from Europe, 14 from Africa, 11 from the Americas, eight from Eastern Mediterranean and five from South-East Asia  from central government, subnational levels of government, civil society and the scientific community.,,2. Developing appropriate policies and allocating responsibilities for the workforce is needed at both central and subnational levels of government.,,3. Legislation and policies should strive to incorporate and balance global, regional, national and subnational priorities for health security.,,4. For sustainable financing, detailed long-term national strategic plans with budget allocations should be developed in partnership between government, national stakeholders, and non-state actors .,5. The national health system and sociocultural context of a country will determine priorities for funding and other resource needs for IHR (2005) core capacity development, emergency response and the health workforce.,,6. Creating and empowering a national secretariat responsible for mobilizing and securing resources from state and non-state actors can help ensure sustainable and continuous financing.,,1. Existing regional and global intergovernmental organizations can be recruited to collaborate and co-manage international epidemics.,,2. A strong programmatic structure at the national and subnational levels, including intersectoral national technical working groups, can assist with comprehensive and effective coordination.,,3. Establishing roles, responsibilities and terms of reference of national focal points within national legislation, and disseminating information inside government, to national stakeholders, and to WHO, improves coordination and communication.,,,4. Adequately resourced communication channels and standard operating procedures, from the subnational to the inter-governmental level, facilitate the timely transmission and retrieval of information.,1. It is important to create and empower a national government entity to coordinate disease surveillance and control efforts.,2. Strategic plans for disease surveillance at both the national and subnational levels can enable long-term sustainability of these efforts.,,3. Key communicable diseases need to be categorized based on epidemiological context .,4. Surveillance at the subnational level can be sustained by developing legislation that outlines the requirements, mechanisms  can develop capacity for collection, analysis and use of data at subnational levels.,,6. A unified and dynamic surveillance system to track alerts, updates and early warnings and response, and using technologies appropriate to the national context , encourages appropriate information use and accurate reporting.,,,7. Standardizing passive data collection, management and validation procedures across all reporting sites, and actively searching for potential surveillance intelligence through local communication channels , improves the usability and timeliness of data.,1. Defining criteria for an emergency public health event  assists with the initiation of an appropriate and timely response.,,,2. Establishing roles, responsibilities and terms of reference for a multidisciplinary response unit supports coordination of public health emergency responses at the national and subnational levels.,,3. Including national and international stakeholders in the development of guidelines for rapid and emergency response facilitates wide technical ownership and financial support.,4. Designing and resourcing health facilities to minimize nosocomial infection transmission improves the efficacy of response without encouraging further spread .Box\u00a03,1. Comprehensive national and subnational budgeted plans for preparedness of emergency public health events are needed to support timely action.,2. Exercises, drills, assessments and evaluations can test capacity to implement the response plans and ensure they are adequate and operational.,,3. A national reserve of medicines, vaccines and laboratory supplies and reagents helps with management of public health emergencies.,,1. An intersectoral system for risk communication of public health emergencies, functioning at all levels of government, ensures timely action and response.,,2. Risk communication systems should be bidirectional, with linkages to national and international public health partners, to collect and disseminate information about threats.,,3. Regular and emergency information to national and international stakeholders assists in building and maintaining effective communication channels and relationships.,,4. Standard operating procedures ensure personnel are ready to investigate and communicate emerging epidemics and support preparedness for activation of early warning systems.,,,5. Using a combination of media to send and receive information ensures wide access and use.,,1. Identifying competency gaps in the workforce ensures that training and resources are targeting the highest priority needs .,,2. Selecting appropriate media for developing competencies based on health system context and social and cultural preferences can increase the efficacy of training.,,3. Establishing workforce oversight mechanisms for long-term maintenance of current and future needs assists with sustainability of individual training efforts.,,4. Nationally agreed strategies to recruit, train and retain health workforce can help support IHR (2005) competency development at all levels of the health system.,,,,1. It is important to create a governmental entity at the national level to coordinate national strategic plans for laboratory response and develop national standards, guidelines and operating procedures for laboratory surveillance at national and subnational levels.,,2. Regional and global reference laboratories can be helpful when developing laboratory surveillance networks.,,3. Validated criteria and mechanisms to accredit laboratories for core surveillance tasks help ensure high-quality testing.,4. Laboratory training, routine assessments and feedback, and quality assurance systems can help improve surveillance capacity and function of national and subnational laboratories.,5. Bidirectional flows of data, specimens and communication between national and subnational levels of government improve laboratory system effectiveness and adequate public health investigation.,,6. Specific policies, strategies, regulations and standard operating procedures for high-containment biosafety laboratories help ensure the safety and efficacy of laboratory testing.,,1. Conducting a baseline needs assessment can help to identify the status of a country\u2019s health system and actions needed to meet IHR (2005) requirements.,,2. Ensuring flexible systems can improve response to known epidemics and detection of new threats.,,3. A country\u2019s\u2019 sociocultural, epidemiological, health system and economic context and priorities will guide national implementation of IHR (2005) core capacities.,4. Although early warning systems are part of core capacity in surveillance, they also affect coordination, risk communication and response for new epidemics.,,,5. Having a skilled workforce in place, from frontline staff to senior management, is important for ensuring sustainable expertise, implementation and commitment.IHR (2005): International Health Regulations, 2005 revision: WHO: World Health Organization. Notes: Framework for the analysis was based on the eight core capacities of the International Health Regulations (2005).,\u2013,\u2013,,,\u2013,,,\u2013,,,,\u2013A total of 33 articles from 60 countries reported experience implementing the national legislation, policy and financing core capacity.\u2013,,,\u2013,\u2013,\u2013,,,,,,,,,,,,,Experience implementing the coordination and communications capacity was reported in 33 articles from 51 countries.\u2013,\u2013,,,\u2013,,,,,,,,,,\u2013,,,Forty articles from 63 countries reported experience implementing the surveillance core capacity.\u2013,,,,,,\u2013,,,,,,,Experience implementing the response core capacity was reported by 27 articles from 47 countries.,,,,\u2013,,,,,,,,,Thirteen articles from 37 countries reported experience implementing the preparedness core capacity.\u2013,,,,,,,\u2013,,,,,,,,A total of 23 articles from 36 countries reported on implementing the risk communication core capacity.,,\u2013,\u2013,,,\u2013,\u2013,\u2013,\u2013,,\u2013,,,,,,,,A total of 37 articles from 49 countries reported experience implementing the human resources core capacity.\u2013,,,\u2013,,,,\u2013,,,,,,,,,Experience implementing the laboratory core capacity was reported in 26 articles from 44 countries.We identified five global lessons learnt that related to multiple IHR (2005) core capacities . Some maWe found substantial documentation of lessons learnt from implementing IHR (2005) core capacities globally. Although many factors affected implementation in a country, the structure of the health system, sociocultural factors, economic status and type of governance, we were able to extract some common themes. We found few gaps in implementation in direct relation to the IHR (2005) core capacities. Nonetheless, additional research could be useful in evaluating countries\u2019 core capacity performance against actual disease epidemics. Specifically, we did not identify any documentation evaluating IHR (2005) core capacity development with national performance in preventing, detecting and responding to disease epidemics. This type of evaluation could provide useful data for future revisions of the IHR. Moreover, defining fundamental data needs for new treatments and vaccines could help develop national research capacity to shorten the development window during future disease epidemics. Finally, additional documentation of experience from Eastern Europe and Africa could help fill knowledge gaps.,Countries had different national health plans outlining how to organize their systems and strategies for managing threats and hazards.Most countries reported some experience in implementing communicable disease surveillance as part of IHR (2005).,,Although complementary in nature, the preparedness and response core capacities were often implemented independently of one another. For example, areas requiring coordination across both of these core capacities, such as case management or infection control, were not well-documented. Taking a holistic approach to IHR (2005) core capacity development could avoid these issues.,,,Risk communication focuses primarily on effective communication strategies during disease epidemics. Some of the articles we identified primarily discussed communication systems.Global strategy on human resources for health: workforce 2030.,,The World Health Assembly recently approved the \u2013Laboratory networks are an essential part of national and regional health systems. Global laboratory networks are in place for polio, immunization programmes and influenza.\u2013,\u2013Given the many priorities in development, and limited national budgets to achieve them, external funding opportunities often help mobilize political commitment and national action. Experience from South Africa suggested that while external funding sources can be inflexible and unsustainable within national governance frameworks, such funding could create momentum in generating domestic financing and accelerate progress in implementing IHR (2005).,Along with financial and technical support, additional international measures could help accelerate IHR (2005) core capacity development. For example, since past disease epidemics affected regional and global economic growth, economic issues are relevant.This study has several limitations. We focused only on IHR (2005) core capacities and not on the core capabilities of points of entry, zoonotic events, food safety, chemical events and radiation emergencies.Despite considerable progress, countries that are yet to implement IHR (2005) core capacities may have insufficient human and financial resources to meet their obligations in the near future. Recent global epidemics have galvanized high-level political commitment towards ensuring global health security. We can leverage this commitment by mobilizing resources and securing wider collaboration to apply the lessons outlined here and accelerate the development of IHR (2005) core capacities globally."}
+{"text": "Sholl analysis confirmed regular pattern of dendritic branching. The total length of dendrites was around 2100 \u03bcm with the average length of individual branching (intermediate) segment around 22 \u03bcm and for the terminal segment around 100 \u03bcm. Even though each experimental group underwent the same strictly defined protocol in tissue preparation and Golgi staining, we found inconsistency in dendritic volume and soma surface. These changes could be methodologically influenced during the Golgi procedure, although without affecting the dendritic length and tree complexity. Since the neuronal activity affects the dendritic thickness, it could not be excluded that observed volume inconsistency was related with functional states of neurons prior to animal sacrifice. Comprehensive analyses of tree complexity and dendritic length provided here could serve as an additional tool for understanding morphological variability in the most numerous neuronal population of the striatum. As reference values they could provide basic ground for comparisons with the results obtained in studies that use various models of genetically modified mice in explaining different pathological conditions that involve MSNs.In this study we have provided a detailed quantitative morphological analysis of medium spiny neurons (MSNs) in the mice dorsal striatum and determined the consistency of values among three groups of animals obtained in different set of experiments. Dendritic trees of 162 Golgi Cox (FD Rapid GolgiStain Kit) impregnated MSNs from 15 adult C57BL/6 mice were 3-dimensionally reconstructed using Neurolucida software, and parameters of dendritic morphology have been compared among experimental groups. The parameters of length and branching pattern did not show statistically significant difference and were highly consistent among groups. The average neuronal soma surface was between 160 \u03bcm The medium spiny neurons (MSNs) are the most numerous striatal neurons. Data about their morphology are needed to understand basal ganglia circuitry structure and function in normal conditions and in related disorders  kindly provided by the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany , group 2 (n = 4) and group 3 (n = 5). All work with the animals used in this study was performed in accordance with the governmental and institutional ethical guidelines and with the approval of Ethics Committee from Max Planck Institute for Evolutionary Anthropology in Leipzig and School of Medicine University of Zagreb.Brain tissue was processed separately in three sets of experiments performed at different times and defined as group 1  before euthanizing. Brains were not perfused and were removed quickly from the skull to avoid any damage to the tissue. After rinsing, the tissue was sliced in approximately 10 mm thick blocks. The blocks were stained with the FD Rapid GolgiStain\u2122 kit . They were first immersed in the impregnation solution (A and B) which was replaced after 6\u201312 h and then kept in dark for 15\u201316 days. Afterwards, the blocks were put in Solution C which was replaced after 24 h and kept in dark for the next 48\u201360 h. Cryomicrotome  was used to cut 200 \u03bcm thick slices. Slices were mounted on a gelatin-coated microscope slides, stained, and dehydrated and coverslipped with Permount. The tissue obtained from group 3 was additionally treated with Toluidine blue stain before dehydration.Tissue preparation and staining were all done by the same person (U.B.) following the FD Rapid GolgiStain\u2122 kit manufacturer\u2019s protocol.z-axis motorized Olympus BX61 microscope equipped with x-y motorized stage guided by MAC5000 stage controller .In total 162 MSNs were three-dimensionally reconstructed using motorized microscope-computer based system and the Neurolucida software version 10 . System was composed of Only neurons with cell bodies located in the dorsal part of striatum within the middle third of the section thickness were included in the analysis. Figure By using a Neurolucida software extension NeurolucidaExplorer, from each reconstructed neuron the following parameters of somato-dendritic morphology have been extrapolated to numeric values: (1) cell surface; (2) number of primary dendrites; (3) total number of segments; (4) total dendritic length; (5) average length per dendrite; (6) average number of segments per dendrite; (7) average length and volume of individual intermediate (branch); (8) terminal; and (9) incomplete segment.For the analysis of segment length and volume, each segment was defined as branch (intermediate), terminal, or incomplete  per group using average values per neuron as raw data. We applied the STATISTICA software for statistical analysis. The dendritic variables were tested separately using one-way analysis of variance .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Vibrio parahaemolyticus (Vp) is found naturally in coastal saltwater. In the United States, Vp causes an estimated 35,000 domestically acquired foodborne infections annually (Vibrio Surveillance system. Vp isolates are distinguished by serotyping (>90 serotypes have been described) and by pulsed-field gel electrophoresis (PFGE).annually , of whicVp serotypes O4:K12 and O4:K(unknown) comprise the Pacific Northwest (PNW) strain and, within the United States, had not been associated with shellfish outside the Pacific Northwest before 2012. During May\u2013July 2012, Vp of the PNW strain associated with shellfish from Oyster Bay Harbor in New York caused an outbreak of 28 illnesses in nine states. Simultaneously, Vp of the PNW strain caused an outbreak of illnesses on a cruise ship docked on the Atlantic Coast of Spain; illness was associated with cooked seafood cooled with ice made from untreated local seawater. All Vp isolates from ill persons in the U.S. and Spanish outbreaks that were further subtyped were indistinguishable by PFGE  facilitates identification of Vibrio species. Consumers can reduce their risk for Vp infection by avoiding eating raw or undercooked shellfish, especially oysters and clams.\u2020This PNW strain is possibly becoming endemic in an expanding area of the Atlantic Ocean. The mechanisms for this introduction are not known. During the 2014"}
+{"text": "Myriad roles of mucins in normal tissues have been well documented, including lubrication of the epithelial surfaces; protection from physical damage; facilitation in cell-cell signaling and suppression of inflammatory activity. Pathological expression of mucins has been noted in cancer development and progression. This study sought to identify and quantify the types of mucins produced during various histological grades of colon cancer and to assess the diagnostic significance.Formalin fixed, paraffin-embedded tissue blocks, comprising three (3) normal colon and twenty-two (22) colon cancer tissues, were retrieved from the archives of the histopathology department of the Komfo Anokye Teaching Hospital. They were stained with Haematoxylin and eosin (H&E) for diagnosis and grading of tumours. Tissues were pre-digested with diastase and stained with Alcian blue (pH 2.5)/Periodic Acid Schiff to characterize the mucin variants present.Our findings indicated that normal colonic tissues expressed exceptionally high amount of acid mucin and low amount of neutral mucin. However, there was a general decrease in mucin expression in colon cancers compared to normal colon tissues. Additional findings suggested that as cancer progresses from low grade to high grade of adenocarcinoma of the colon, there was generally a considerable decrease in the acid mucin production and an increase in the neutral mucin expression. In contrast, a sizeable subpopulation of high-grade adenocarcinomas of colon showed a rather opposite mucin expression pattern- increase in acid mucin and a decrease in neutral mucin.As colonic cancer progresses, there are corresponding changes in the mucin types and content such that there are decrease in acid mucin and increase in neutral mucin expressions. Initiation and development of cancers, particularly colonic cancer is a very complex one with several variables playing crucial roles in sustaining the viability of the cancer. Even though initiations of colonic cancers are well attributed to genetic imbalances, which could be inherited  or somatTwenty-five formalin fixed, paraffin embedded (FFPE) colonic tissues, which were retrieved from the archives of Histopathology Unit of the Department of Pathology, Komfo Anokye Teaching Hospital, Kumasi-Ghana, following ethical approval from both the hospital and Committee for Human Research, Publication and Ethics of School of Medical Sciences, KNUST. Two tissue sections at 3\u03bcm from each FFPE tissue block were produced. One batch of the sectioned FFPE colonic tissues was stained with Haematoxylin and Eosin (H&E) and were histologically diagnosed and graded by three independent pathologists. The second batch of the sectioned FFPE colonic tissues was dually stained with Alcian blue, pH 2.5 to demonstrate acidic mucins (sulfated and carboxylated) and Periodic Acid Schiff (PAS) to demonstrate glycogens and mucins. In order to exclusively demonstrate neutral mucins, dewaxed colonic sections were pretreated with diastase for 60 minutes to digest at existing glycogen in the tissue . PositivHaematoxylin and eosin (H&E) based diagnosis and grading colonic cancer tissues: Normal colon and colonic cancer tissues were H&E stained to confirm the diagnosis and grades of the tumours. Five of the 22 colonic cancers were diagnosed and graded as Grade 2, Well Differentiated Adenocarcinoma (G2WDA); 13 of the 22 colonic cancers as Grade 2, Moderately Differentiated Adenocarcinoma (G2MDA); 3 of the 22 colonic cancers as Grade 2 Adenocarcinomas (G2A) and only 1 case as Grade 3 Poorly Differentiated Adenocarcinoma (G3PDA) ( (G3PDA) . The colDifferential mucins staining with Alcian Blue/Diastase-Periodic Acid Schiff staining: in order to correlate the mucin content/amount and types with different grading of colonic cancers, we performed Alcian blue (pH 2.5)/Diastase-Periodic Acid Schiff staining. The sensitivity and specificity of the staining mucin staining were tested using appropriate controls. This was also part of the quality assurance procedure. Quality controls for mucin demonstration For a positive control, normal colon stained blue for acid mucins using Alcian Blue (pH 2.5), Diastase Periodic Acid Schiff (DPAS) staining on prostate, and DPAS/Alcian blue (pH 2.5) staining on colon (results not shown). For a negative control, liver tissues stained negative for Alcian Blue (pH 2.5), indicating absence of acid mucins, but stained magenta in DPAS, indicating the presence of neutral mucins. Further, an omission of the periodic acid oxidation step in DPAS resulted in a negative staining on human liver (results not shown).Mucin content/amount and types in colonic cancers: in this study, the total mucin content in 22 colonic cancer cases was semi-quantified after double Alcian blue (pH 2.5) and Diastase-PAS staining. The mucin types  were also determined in each case. Both mucin content and types were estimated and correlated with tumour grade  mucins but scanty neutral mucins;It is widely postulated that sulfated mucins play a role in the control of cell division;Production of mucins, in general, is remarkably reduced in adenocarcinomas of colorectal tissues.We, in this study, demonstrated that there is a progressive decline of acid mucin from low-graded to high graded adenocarcinoma of colorectal with corresponding increase in neutral mucins;We also demonstrated for the first time that a subgroup of moderately differentiated adenocarcinomas had rather an increase in acid mucins coupled with decrease neutral mucins in humans.The authors declare no competing interest."}
+{"text": "Based on a two-end-member mixing model, all target consumers relied on energy sources from coupled benthic and planktonic pathways, but the predominant energy source for most species was highly variable across seasons, showing seasonal trophic shift of littoral consumers. Seasonality in energy mobilization of consumers focused on two aspects: (1) the species number of consumers that relied mainly on planktonic carbon showed the lowest values in the fall and the highest during spring/summer, and (2) most consumer species showed seasonal variation in the percentages of planktonic reliance. We concluded that seasonal trophic shifts of fishes and invertebrates were driven by phytoplankton production, but benthic resources were also important seasonally in supporting littoral consumers in Meiliang Bay. Energy mobilization of carnivorous fishes was more subject to the impact of resource availability than omnivorous species.We evaluated the seasonal variation in the contributions of planktonic and benthic resources to 11 littoral predators in eutrophic Lake Taihu (China) from 2004 to 2005. Seasonal fluctuations in consumer \u03c3"}
+{"text": "GABAergic and glutamatergic systems play an important role in the neurobiology of schizophrenia, and changes in their markers are reported in both postmortem human brain and in animal models. Recent studies have demonstrated that abnormalities in DNA methylation may underlie the alterations in various indicators of GABAergic and glutamatergic functions in schizophrenia. As our group previously found decreased NR2 protein plasma levels and downregulation of parvalbumin (PVALB) mRNA in first episode of psychosis (FEP) patients, we hypothesised that changes in DNA methylation may be responsible for these indicators of glutamatergic and GABAergic deficits in FEP patients.Blood samples were collected from patients in FEP (n = 35) after their first contact with the mental health assistance, siblings (n = 21) and population-based controls (n = 35). Bisulfite conversion and pyrosequencing were used to determine methylation levels in 4 CpG sites in promoter sequence of PVALB and 5 CpG sites at GRIN2B (gene which encodes NR2).We found hypermethylation at a CpG site within the PVALB promoter sequence in patients and their siblings compared to population-based control group (p< 0.001) while overall hypomethylation was found in the 5 CpGs analysed within GRIN2B promoter sequence (p < 0.01).Our PVALB findings are consistent with our previous studies showing that PVALB promoter methylation is elevated in schizophrenia and, additionally this is the first evidence showing changes in GRIN2B promoter methylation in psychosis. These results together suggest that these epigenetic findings may relate to the reduction of protein expression of indicators of glutamate and GABA systems seen in this disease."}
+{"text": "This article contains the clinical characteristics of the paradoxical embolized patients and the following up results. Data included are related to the article \u201cParadoxical embolism: Experiences from a single center\u201d   Specifications TableValue of the data\u2022These data provide the clinical characteristics and follow-up results of paradoxical embolism.\u2022Most patients had one or more risk factors for thrombosis and inducing or exacerbating factor.\u2022Long term coagulation is necessary and effective for paradoxical embolism.1The data presented include the clinical characteristics of the paradoxical embolized patients, the administrated treatment and the following up results .2Twelve patients diagnosed of paradoxical embolism in Fuwai Hospital from January 1994 to October 2015 were included. All clinical data related were collected from medical records, such as (1) demographic data; (2) case history and risk factors for thromboembolism; (3) clinical, laboratory and imaging findings of deep venous thrombosis, pulmonary embolism and systemic arterial embolic events; (4) imaging findings of an abnormal communication that allowed right to left shunt; (5) treatment and outcome; (6) follow-up data. Follow-up data were obtained from hospital records or by telephone interview with the patients or their family members. Follow-up ended on November 1st, 2015 There was no conflict of interest to declare."}
+{"text": "Our study samples showed high levels of proinflammatory cytokine levels  in all patient groups but only high levels of \u03b11-antichymotrypsine in VD patients compared to controls. There is no significant correlation between the laboratory and clinical variables except for a link between IL-1\u03b2 and NPI scores of AD. In conclusion, this study yielded evidence of some shared mechanisms underlying AD and VD and thus motivates further studies of inflammatory markers in various types of dementia and MCI.In the past years, the possible involvement of inflammation in the pathogenesis of dementia has been the subject of several investigations. However there are restricted data about the profile of the inflammatory and soluble proteins in well evaluated Alzheimer\u2019s disease (AD), vascular dementia (VD), mild cognitive impairment (MCI) and healthy controls. There are also no reliable data regarding the relationship between the overlapping protein levels and cognitive or functional decline. We measured levels of IL-1"}
+{"text": "The early recognition of risk factors for the occurrence of palatally displaced canines (PDC) can increase the possibility of impaction prevention.  To estimate the risk of PDC occurrence in children with dental anomalies identified early during mixed dentition. The sample comprised 730 longitudinal orthodontic records from children  with an initial mean age of 8.3 years (SD=1.36). The dental anomaly group (DA) included 263 records of patients with at least one dental anomaly identified in the initial or middle mixed dentition. The non-dental anomaly group (NDA) was composed of 467 records of patients with no dental anomalies. The occurrence of PDC in both groups was diagnosed using panoramic and periapical radiographs taken in the late mixed dentition or early permanent dentition. The prevalence of PDC in patients with and without early diagnosed dental anomalies was compared using the chi-square test (p<0.01), relative risk assessments (RR), and positive and negative predictive values (PPV and NPV). PDC frequency was 16.35% and 6.2% in DA and NDA groups, respectively. A statistically significant difference was observed between groups (p<0.01), with greater risk of PDC development in the DA group (RR=2.63). The PPV and NPV was 16% and 93%, respectively. Small maxillary lateral incisors, deciduous molar infraocclusion, and mandibular second premolar distoangulation were associated with PDC. Children with dental anomalies diagnosed during early mixed dentition have an approximately two and a half fold increased risk of developing PDC during late mixed dentition compared with children without dental anomalies. According to the guidance theory, local conditions, such as maxillary lateral incisor agenesis or microdontia, are related to canine displacement,,,,,The study by Sacerdoti and Baccetti,-,Ectopic eruption of maxillary canines has two major clinical concerns: the consequent impaction of the canine and the possibility of incisor external root resorption,,,Conversely, when there is an early orthodontic diagnosis of PDC, simpler clinical approaches such as deciduous canine extraction and rapid maxillary expansion can lead to spontaneous canine eruption in a high percentage of childrenThis retrospective longitudinal study was approved by the Research Ethical Committee of the Hospital for Rehabilitation of Craniofacial Anomalies, University of S\u00e3o Paulo (HRAC-USP) (379/2010). The patient records were anonymized and de-identified prior to analysis. The initial sample was composed of the orthodontic files of 810 children treated from 1980 to 2005 at the Society for the Social Promotion of Cleft Lip and Palate Patients (PROFIS). Inclusion criteria were: presence of an initial panoramic radiograph taken during the first transitional period or inter-transitional period of mixed dentition, according to the Van der LindenThe final sample was composed of 730 orthodontic records from children with an initial mean age of 8.3 years (SD=1.36), from both genders . A rough estimate of the ethnic background of the sample based on facial photograph was: White (84%), Black (12%), and Asian (4%). The experimental and control groups included 263 and 467 records, respectively, and were composed based on the analyses of the initial panoramic radiographs and dental casts to investigate the presence of the following dental anomalies: 1. Agenesis of any permanent teeth, except for third molars; 2. Microdontia of maxillary lateral incisors; 3. Infraocclusion of deciduous molars; 4. Distoangulation of mandibular second premolars; 5. Tooth transpositions.All the records were analyzed by a single calibrated examiner (ML). The examiner was precalibrated showing an agreement index ranging from 90 to 100% (Kappa test). The maxillary lateral incisor was considered as presenting microdontia when the maximum mesiodistal crown diameter was smaller than the same dimension of the opposing mandibular lateral incisor in the same patient, using the dental castsThe sample was divided into two groups. The dental anomaly group (DA) was composed of 263 patients with at least one dental anomaly identified in the initial or middle mixed dentition. Records from children without these dental anomalies in the early/middle mixed dentition (n=467) composed the non-dental anomaly group (NDA). Age and gender distribution in both groups is presented in Panoramic radiographs from late mixed dentition and/or early permanent dentition were evaluated to assess risks for the development of PDC in both groups. Considering the findings of Ericson and KurolThe frequency of PDC development was calculated in DA and NDA groups. Intergroup comparisons were performed using the Chi-square test with a significance level of 5%. In order to measure the strength of associations between occurrences of early-diagnosed dental anomalies and PDC, the relative risk (RR) at the 95% confidence interval and the positive and negative predictive values (PPV and NPV) were calculated. Additionally, the frequency of PDC development was separately calculated for each dental anomaly and compared with the control group using the Chi-square test (p<0.01) and relative risk assessment.Seventy-two individuals were affected by PDC (9.86%) with a male:female ratio of 1:3 in the combined DA and NDA groups (n=730). In this subgroup of individuals with PDC, 29.1% (n=21) showed bilateral expression, 31.9% (n=23) unilateral right expression, and 38.9% (n=28) unilateral left expression.The DA group presented PDC frequency of 16.3% compared with 6.2% of the NDA group . This diStatistically significant associations were observed between increased frequencies of PDC development and some of the dental anomalies were separately evaluated . The relThe frequency of RME performed during the mixed dentition was similar in both DA and control groups . No otheThis study evaluated longitudinal records from patients with early-diagnosed dental anomalies to estimate risks for developing PDC during the late mixed dentition.,,Previous cross-sectional studies showed an association between PDC and other dental anomalies including small maxillary lateral incisors, tooth agenesis, deciduous molar infraocclusion, and other slight tooth ectopia,,The present study is the first to evaluate a large sample with longitudinal records for dental anomalies that could be used as markers to estimate PDC risks,,Small maxillary lateral incisors and mandibular second premolar distoangulation were the main risk factors for PDC among the early-diagnosed dental anomalies . These r,,Deciduous molar infraocclusion was also confirmed to be a risk factor for PDC ; this as,,No significant differences were observed between PDC development in individuals with agenesis of maxillary lateral incisors or second premolars, and the NDA group . Peck, PA limitation of this study is the possibility of false-positive diagnosis for PDC using panoramic radiographs,Our results show that small maxillary lateral incisors, distoangulation of mandibular second premolar, and deciduous molar infraocclusion are early risk markers for PDC. Pediatric and orthodontic population with such dental anomalies diagnosed during the early mixed dentition should be carefully monitored during the critical age period for early diagnosis and intervention of maxillary canine ectopic eruption. The recognition of risk markers for the occurrence of PDC can increase the possibility of early diagnosis and intervention. Future longitudinal studies could contribute to identify other potential risk indicators for PDC including family history, female gender, hypodivergent pattern, and enamel hypoplasiaChildren with some dental anomalies diagnosed during the early mixed dentition have an approximately two and a half fold increase in risk of developing PDC during the late mixed dentition compared with children without these dental anomalies. Microdontia of maxillary lateral incisors, mandibular second premolars distoangulation, and deciduous molar infraocclusion constitute early risk markers for PDC development. When the maxillary canines are not palpable, a panoramic radiograph is highly recommended in 10-year-old children with clinically or radiographically diagnosed DA in order to investigate PDC."}
+{"text": "Novel insights into the epigenetic control of chronic liver diseases are now emerging. Recent advances in our understanding of the critical roles of DNA methylation, histone modifications and ncRNA may now be exploited to improve management of fibrosis/cirrhosis and cancer. Furthermore, improved technologies for the detection of epigenetic markers from patients' blood and tissues will vastly improve diagnosis, treatment options and prognostic tracking. The aim of this review is to present recent findings from the field of liver epigenetics and to explore their potential for translation into therapeutics to prevent disease promoting epigenome reprogramming and reverse epigenetic changes.  If taken literally this could include all of the events involved in the regulation of gene expression. However for the purpose of this review discussion will be limited to those regulatory mechanisms that operate at the level of DNA methylation, histone modifications and the activities on non-coding regulatory RNA molecules. But in addition, readers should be aware of the critical role that transcription factors play in determining gene expression and cell phenotype. Transcription factors, which operate by recognising specific DNA motifs in the promoter/enhancer regions of genes and then modulate the activity of RNA polymerase II, are increasingly featuring as important drug targets in chronic liver disease. Typical examples being the peroxisome proliferator-activated receptors and the farnesoid X receptor for which ongoing clinical trials are determining efficacy in non-alcoholic fatty liver disease (NAFLD) and autoimmune liver disease de novo methyltransferases, establishing methylation patterns during development DNA methylation is a direct chemical modification of DNA in which methyl groups are predominantly added to cytosine residues within the context of a CpG dinucleotide DNA is packaged into chromatin of which the unit structure is the nucleosome which is comprised of two copies each of histones H2A, H2B, H3 and H4 that assemble into an octamer around which 146\u2013147\u00a0bp of DNA is tightly wrapped. The nucleosome is a highly dynamic structure and dictates the degree to which DNA is accessible for transcription; this being determined by its degree of compaction and by post-translational modifications (PTMs) on the N-terminal tails of its constituent histones The vast majority of the human genome is transcribed, however only 2% encodes proteins. The vast majority of the transcriptome consists of non-coding RNAs (ncRNAs) that have regulatory functions and include micro RNAs (miRNA), small nucleolar RNAs (snoRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs) and the long non-coding RNAs (lncRNAs). The miRNAs are an extensively studied class of single-stranded 18\u201322 nucleotide ncRNAs that fine-tune expression of the genome either by decreasing the stability or suppressing translation of messenger RNAs Here we will consider recent advances in the role of DNA methylation, histone modifications and ncRNAs in chronic liver diseases and in particular how new knowledge of these epigenetic mechanisms may be exploited for improving the management of the two major liver disease endpoints, fibrosis/cirrhosis and cancer.2The liver must adapt on a daily basis to a constant flux of environmental variations including circadian oscillators, nutritional/metabolic fluxes, exposure to xenobiotics, viral infections, alterations in the microbiome and the demands for epithelial repair and regeneration. Using a deep sequencing approach, Vollmers and colleagues systematically mapped the epigenetic changes occurring over 24\u00a0h in the mouse liver via its induction of hepatic reactive oxygen species (ROS) promotes H3K9 acetylation leading to increased expression of alcohol-metabolising enzymes that induce further ROS and acetylation potentially establishing feed-forward epigenetic re-landscaping HDAC3 is an important circadian regulated epigenetic writer critical for hepatic triglyceride homoeostasis and when deleted in mice results in steatosis, inflammation and fibrosis via its ability to influence DNMT activity and in addition recruits the histone acetyltransferases p300/CBP to induce IL-8 and proliferating cell nuclear antigen (PCNA) which are involved in inflammation and cell proliferation respectively Hepatitis C virus (HCV) infection promotes multiple changes in DNA methylation including at enhancer elements associated with altered expression of genes implicated in cancer and control of stem cells Hence, in summary the epigenetic landscape of the liver is acutely sensitive to environmental cues resulting in modifications that impact on its circadian controlled patterns of gene expression. In obesity and alcoholic disease the disturbance to the hepatic epigenetic landscape may promote microenvironments in which steatosis advances to inflammation, fibrosis and cancer.3Myofibroblasts are the major cellular drivers of liver fibrosis and appear during conditions of liver damage and/or infection mainly through the process of hepatic stellate cell (HSC) transdifferentiation. The conversion of quiescent HSC to their activated myofibroblast state involves vast changes in transcriptome expression that dramatically alter the phenotype and behaviour of the cell. In the past decade we have begun to shed light on the epigenetic events that reprogram the HSC transcriptome, thus revealing new regulators of fibrogenesis as well as potential biomarkers for tracking disease progression.3.1in-vivo transdifferentiation of HSC can be recapitulated in a cell culture model in which isolated HSC are maintained for several days on plastic in serum-containing media. In this widely used model, HSC transdifferentiation was accompanied by a >\u00a020% methylation change (hypo- or hyper-methylation) in ~\u00a0400 methylated regions including DNMT3A and DNMT3B 4) induced liver fibrosis 4 mouse fibrosis model Many of the regulatory events associated with DNA methylation in the PPAR\u03b3 gene promotor has also been shown to be relevant in human disease. In a well phenotyped cohort of patients with biopsy proven NAFLD Zeybel et al. demonstrated that hypermethylation at discreet CpG dinucleotides within the human PPAR\u03b3 gene promotor could be used to stratify patients with mild fibrosis (Kleiner score 0\u20132) from those with severe fibrosis (Kleiner score 3\u20134) in vivo models of chronic liver disease (bile duct ligation (BDL), CCl4 and methionine-choline deficient (MCD) diet) de novo methyltransferases DNMT3A/B expression, diminution of TET protein expression and remodeling of the HSC DNA methylome. Moreover, culture activated HSC and ex-vivo purified HSC from CCl4 injured rats also demonstrated increased DNMT3A and DNMT3B, with knock-down of the latter enzymes resulting in reduced fibrogenic features. Of note, similar fibrosis-associated epigenetic changes were observed in mechanistically distinct examples of chronic human liver disease supporting the concept that fibrosis is in part driven by alterations in the balance between the DNMTs and TETs As previously explained DNA methylation is a dynamic epigenetic marker that is regulated by DNMT and TET enzymes that stimulate CpG methylation and demethylation respectively 3.2Schistosoma mansoni and BDL induced liver fibrosis in vivo delivery of histone methyltransferase inhibitors to HSC can potently inhibit liver fibrosis 4-induced liver damage in vivoHistone acetylation is associated with active transcription and is under the control of HATs and HDACs. Niki et al. first described the anti-fibrotic effects of HDAC inhibitors showing that trichostatin A (TSA) treatment of cultured HSC suppressed fibrogenic gene expression and proliferation 3.34 exposure or BDL, this observation being confirmed in human liver with advanced fibrosis in vivo relevance in vivo and in vitro during liver fibrosis, with HOTAIR knockdown suppressing HSC activation. The authors further demonstrated that HOTAIR downregulates miR-29b expression, attenuating its control on epigenetic regulation, leading to enhanced phosphatase and tensin homolog (PTEN) methylation, which contributes to the progression of liver fibrosis A large number of miRNAs have been described that both promote  and suppress  HSC transdifferentiation 4Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer deaths worldwide and treatment options are severely limited. There is a clear need for the identification of the molecular drivers of HCC if progress is to be made in developing new medicines. Deep sequencing studies have been instrumental in identifying gene mutations and potential disease drivers in HCC. Alongside these genetic approaches is an increasing awareness of the role of epigenetic regulators in HCC which have strong potential for drug and biomarker design.4.1DNA methylation changes are common in human cancers and it was therefore unsurprising that 3700 hypomethylated promoters were identified in HCC tumour samples in vivo. Reduced SMPD3 expression was associated with early HCC recurrence following resection in vivo in a xenograft HCC HepG2 model. CDKN2A, DLEC1 and RUNX3 promoters were all confirmed to be demethylated in HCC lines following Guadecitabine treatment and correlated with inhibition of cell growth. Importantly, in contrast to decitabine, Guadecitabine was able to overcome the inhibitory effects on cell growth by macroH2A1 (variant of histone H2A), highlighting Guadecitabine as a potential HCC therapeutic, particularly in advanced disease There is vast potential for alterations in DNA methylation in HCC to be exploited for future drug and biomarker development. The de-methylating agent decitabine has been used to validate the expression of hypermethylated TSG in primary HCC and also re-expression of genes in HCC cell lines. 13 candidate TSG were identified in this study including DGK1, LDHB, NEFH, SMPD3, ACTL6B and PRPH. Functional characterisation of 2 candidates, SMPD3 and NEFH, revealed that overexpression leads to inhibition of cell proliferation, whereas by contrast knockdown increased tumour formation 4.2in vitro and in vivoHistone modifying enzymes offer much promise for HCC therapy since they are tractable targets for the design of small molecule inhibitors. The H3K27 methylase EZH2 is up-regulated in HCC tissue and is associated with cancer progression, invasion and proliferation 4.3Previous and emerging studies in HCC are now beginning to incorporate ncRNAs into our molecular understanding of HCC pathogenesis and progression As the complexity of these molecular interactions unravel, we can begin to appreciate that in most scenarios these modulators likely work together as a network of epigenetic regulators. This highlighted by a study demonstrating how HULC and MALAT1 combine in complex with TRF2 to significantly increase telomerase activity and microsatellite instability in liver cancer stem cells NCT02603224).Therapeutic targeting of ncRNA in HCC is now an imminent challenge. Emerging pre-clinical studies utilizing sophisticated drug delivery nanoparticles and animal proof of concept models such as this study successfully targeting the lncRNA TUG1 show promise for therapeutic development of antisense oligonucleotides 5The hepatic epigenome is remarkable in its capacity to adapt to dietary, metabolic, xenobiotic and microbial challenges in order to maintain cellular and functional homeostasis. However, when this capacity is breached epigenetic adaptions can become problematic and contribute to disease pathogenesis. We are now aware of how key components of the epigenetic machinery such as DNA methylation, histone PTMs and ncRNAs alter their expression or function in the context of fibrosis/cirrhosis and liver cancer. The next steps are to convert this information into bespoke medicines that either prevent disease-driving epigenome reprogramming or that reverse specific disease-promoting epigenetic changes. Furthermore there is vast potential to use the appearance of liver-derived epigenetic markers in the patient circulation for the diagnosis and prognostic tracking of chronic liver disease using no more than a few drops of blood, avoiding the need for biopsy or complex and expensive imaging modalities."}
+{"text": "Scientific Reports6: Article number: 34474; 10.1038/srep34474 published online: 09292016; updated: 05082017.As the authors of references 25 and 26 also employed plasma-assisted molecular beam epitaxy for the synthesis of hexagonal boron nitride films, the authors would like to make the following changes to the Introduction section of their Article:23,24,25,26 and atomic layer deposition27 of hBN on metal substrates; this approach must typically be complemented by complex protocols for the removal and transfer of the grown films\u201d.\u201cIn addition the direct growth of hBN on a two-dimensional material (HOPG) offers an alternative to chemical vapour depositionShould read:23,24, MBE25,26 and atomic layer deposition27 of hBN on metal substrates; this approach must typically be complemented by complex protocols for the removal and transfer of the grown films\u201d.\u201cIn addition the direct growth of hBN on a two-dimensional material (HOPG) offers an alternative to chemical vapour deposition"}
+{"text": "The variables were related to brightness, color, physical aspects, soluble and total collagen as well as chemical traits. The physiological stage was defined as a classification variable in order to proceed ANOVA tests and comparison of means (P<0.05). Multivariate analysis was used to identify patterns of similarity and differentiation between samples of different physiological stages . The results revealed that meat quality varies according to different physiological stages, especially between lambs (a) and cull ewes (c). As a consequence, the physiological stage at slaughter should be taken into consideration to cote the quality of meat from indigenous sheep raised in tropical regions. The results contribute towards sensorial evaluation and the characterization of potential food products derived from indigenous sheep bred under tropical climate in developing countries.This study configures a first report regarding the variability of meat quality of locally adapted Pantaneiro sheep depending on different physiological stages and breeding systems. Pantaneiro sheep are raised in Brazil under a tropical wetland ecosystem denominated Pantanal. Twenty-nine Pantaneiro sheep from different sex and physiological stages were sorted into three groups, simulating three of the most representative ovine meat products commercialized by South American industries: a) non castrated male lambs (n = 11); b) wethers (n = 9); c) cull ewes (n = 9). Animals from each physiological stage were submitted to different breeding systems, resembling farming strategies adopted in several developing countries of South America. The effect of physiological stages on the quality of meat was accessed using 16 variables measured in the  The Midwest of Brazil presents the highest growth rates of sheep farming in the country . This reSeveral factors limit sheep breeding to play a more significant role on rural development and become a source of financial income in developing countries such as Brazil , 3. The Progress has been reported, but market and merchandising of sheep products in many developing countries still contrast with global market trends which requires urgent adjustments \u201313There is considerable lack of information regarding breed, geographical provenance, breeding system and traceability of age category , which may denote the quality of meat after slaughter.Food originated from indigenous breeds of sheep is an option to access and develop alternative markets \u201316. HoweIt is reasonable to consider that the diversification of products and market niches require efforts towards characterization , 19\u201321. The quality of meat has been an important subject , includiStill, in countries such as Brazil, three top products derive from sheep farming: meat from lambs (a), wethers (b) and cull ewes (c). Demands for each one of these products vary according to local market trends in different macro regions of South American countries . PhysicoConsidering some of the aspects of indigenous sheep farming, this study was designed to generate a first report on meat quality of Pantaneiro sheep, encompassing physicochemical and sensory characterization of the most common physiological stages commercialized in South American sheep industries.All protocols of experimental procedures were approved by the Animal Experimentation Ethics Committee (CEUA) of the Federal University of Grande Dourados (UFGD), The criteria to slaughter lambs (a) and wethers (b) was the body condition, which ranged from 2.5 to 3.0 . Cull ew-1 [The uncastrated lambs (a) were weaned with average weight of 19.5\u00b14.10 kg and finished in feedlots with an 80% concentrate and 20% forage (20%) diet . The die-1 . Lambs (Cynodon spp. (Tifton85) and supplemented (1% of body weight) with the same concentrate used for lambs (water ad libitum). These animals were slaughtered at the age of 12.5\u00b11.18 months. The cull ewes (c) were kept in extensive systems with tropical pastures of Brachiaria brizantha cv. Piat\u00e3 with ad libitum mineral salt. Cull ewes (c) were slaughtered at the age of 68\u00b113 months (The wethers (b) were kept in tropical pastures based on 3 months .All animals  were slaughtered after 16-hours of fasting (solids). Desensitization was carried out by electronarcosis (8 seconds of 220-V discharge) followed by cutting of jugular veins and carotid arteries with subsequent evisceration. Lambs (a), wethers (b) and cull ewes (c) showed initial average weight of 19.64, 19.90 and 45.04 kg, respectively. Final average weight was 35.72, 43.04 and 49.58 kg, respectively longissimus thoracis et lumborum (LM) and semimembranosus (SM) muscles were removed for meat quality analysis. All samples were analyzed with one replicate, and the final value of each variable was determined calculating a simple average for each variable.After slaughter, the carcasses were stored in a cold room at 4\u00b0C during 24 hours. Subsequently, the Evaluation of meat was performed based on color, physical characteristics, soluble and total collagen and chemical characteristics Tables The color was evaluated in lyophilized samples, submitted to acid digestion, filtration, neutralization, dilution and oxidation for colorimetric reaction. The results were based on the hydroxyproline values from absorbance readings performed in a spectrophotometer with a wavelength of 570 nm. The sample color was evaluated after 30 minutes of exposure to air to allow myoglobin reaction with oxygen . BrightnThe physical characteristics of meat were evaluated regarding water retention capacity (%) according to the method described by . The sheThe pH and temperature of the warm and the cold carcass  were monitored using a digital thermometer and pH-meter with a Testo 205/206 penetration probe. The determination of the soluble and total collagen content (%) followed the method described by  modifiedRegarding the chemical composition of meat, moisture was evaluated according to the method 950.46 . Total nlongissimusthoracis et lumborum (LM) and semimembranosus (SM) muscles. This was done using a univariate approach (PROC GLM) (p<0.05). Analyses were performed using the software SAS 9.2 . A multivariate method was used to standardize data (PROC STANDARD procedure) and to develop clustering analysis (PROC FASTCLUS procedure) assuming three clusters.The experimental design was arranged as an exploratory study. Animals were sampled from an on farm conservation flock and sorted according to pre-established physiological stages. The Shapiro-Wilk test was performed to verify the residue data normality, and the Bartlett test was performed to verify homogeneity of variances. Similar to a nested analysis approach, the effect of physiological stages (fixed effect) (lambs (a), wethers (b) and cull ewes(c)) was evaluated on the versus SM) regarding each physiological stage (The meat from lambs (a) showed different values compared with cull ewes (c) with only one exception  of the LM muscle al stage . Means bWater retention capacity, shear force and losses of weight after cooking presented similar averages (P>0.05) between physiological stages The highest concentration of total collagen was found in the meat from cull ewes. Physiological stages presented different values of total collagen All variables related to chemical composition were effected (P<0.05) by the physiological stage. The chemical analysis showed significant differences between means of lambs and cull ewes, except for the ash content of the SM muscle.The meat from wethers showed the same ether extract content than the cull ewes, regardless of the muscle type Lambs showed greater moisture content in the LM muscle Considering all 15 variables used to evaluate the quality of meat from different physiological stages, only three variables  may present similar aspects to the meat of lambs (a). The meat of some cull ewes (c) maybe similar to the meat of wethers (b). However, no cull ewes (c) presented similar meat quality compared to lambs (a) In general, the variables related to brightness (L*), the intensity of yellow (b*) and red (a*) varied according to physiological stages There is a trend to believe that many physical aspects of meat vary according to the age of animals at slaughter , 40. AgiCarcasses from older animals are associated to greater stability and texture of muscle fiber showing less soluble collagen . The samIn general, meat from different physiological stages showed appropriate quality values of collagen and pH, configuring soft meat The chemical characteristics of meat also differed between physiological stages The variation of meat quality regarding muscle types was considered to be random. However, diversifying aspects related to flavor and nutritional aspects of indigenous sheep meat was observed between different physiological stages.Fine discrimination observed with multivariate analysis Evaluation of meat from indigenous Pantaneiro sheep of different sex and physiological stages revealed suitable standards of meat quality produced in a rough and typically unique tropical ecosystem. Notable differences were observed between the quality of meat originated from lambs and cull ewes. This fine discrimination opens the door to valuable validation of how meat quality relates to sensorial aspects and consumer preferences regarding the preparation of dishes and consumption.Characterization of food products derived from locally adapted livestock in developing countries is an effort towards the development of new products with added value which may enhance merchandising, marketing strategies and consumption.S1 FileProtocols of experimental procedures were approved by commuittes(PDF)Click here for additional data file."}
+{"text": "Data presented within this article supports the findings of the manuscript \u201cA systematic review of fantasy driven vs contact driven internet-initiated sexual offences: Discrete or overlapping typologies?\u201d  [1]. Inclusion and Exclusion criteria of study selection, PICO Formulation of Study Appraisal, as well as the Study Characteristics and Methodology of included studies are presented. Specifications TableValue of the data\u2022The data allows for interpretation and assessment of studies examining the behavior of internet-initiated sexual crimes against minors, including study characteristics and methodology.\u2022The data enables comparison of two distinct classification of internet-initiated offences commonly referred to in the literature: fantasy vs contact driven crimes.\u2022Studies within this field primarily rely on the use of decoy victims, i.e. adults posing as children/young people who engage in proactive investigations. This data enables researchers to identify those studies that use decoy and real child victims.1The data set contains information on the Inclusion and Exclusion Criteria for Study Selection , and PIC2The process of study selection is defined in n = 5).Studies included in Broome et al."}
+{"text": "Scientific Reports 10.1038/s41598-017-05445-3, published online 20 July 2017Correction to: This Article contains errors in the Materials and Methods section under subheading \u2018Sample selection\u2019.\u201cAll participants provided informed consent that explicitly allowed their coded genome sequencing data to be shared with other investigators\u201d.should read:\u201cUniv. of Pennsylvania samples were obtained from The Coriell Institute for Medical Research (CIMR). Collection of blood/tissue samples followed diagnostic consensus, using two informed consent forms: a) one with annual Univ. Miami IRB approval defining (with language appropriate for Old Order Amish) how their cells would be preserved for medical research on Major Affective Disorders; and, b) the Informed Consent Form required by the Institute for Medical Research (CIMR), later Coriell - National Institute for General Medical Sciences (NIGMS) Human Genetic Cell Repository (HGCR).The CIMR/NIGMS Informed Consent Forms makes no reference to specific diseases, types of genetic analysis that will be performed in future studies. Analysis of whole-genome re-sequencing data from consented individuals in this pedigree was also approved by the IRB of the Weill Cornell Medical College and the Perelman School of Medicine at the University of Pennsylvania. All other participants provided informed consent that explicitly allowed their coded genome sequencing data to be shared with other investigators\u201d."}
+{"text": "Recently, Seddik Hammad from Heidelberg University published an interesting report about a frequent misinterpretation in research on liver fibrosis : in mic4 mediated pericentral killing of CYP2E1 positive hepatocytes, which after repeated CCl4 administration leads to fibrotic bridging of pericentral areas . Hammadal., 2017).in vitro systems in toxicology aim for mimicking some of the zonated features of the liver lobule (Frey et al., 2014[Studies of hepatotoxicity often rely on the correct interpretation of histology (Schenk et al., 2017; Reif etal., 2014; Leist e"}
+{"text": "The extent to which poor academic achievement is associated with later schizophrenia is unclear. The aim of the present study was to update our prior meta-analyses which examined academic achievement in youth aged 16 years or younger who later developed schizophrenia or schizophrenia spectrum disorders (SSD) and those who did not . We also conducted a new meta-analysis on published studies that reported on general academic achievement in youth at-risk for schizophrenia/SSD aged 16 years or younger compared to typically developing youthIn addition to the five studies included in our earlier meta-analyses, a further three prospective investigations of birth or genetic high-risk cohorts were identified that reported results using objective measures of general academic achievement and of mathematics achievement for individuals who did and did not develop schizophrenia/SSD in adulthood. For our new meta-analysis we identified a total of seven studies that met the following inclusion criteria: (1) written in English; (2) objective measure of general academic achievement consisting of scores on least two core academic subjects  at age 16 years or younger; (3) results provided for youth at high risk for developing schizophrenia/SSD in adulthood by virtue of having at least one first-degree relative with the disorder or reporting psychotic like-experiences (PLEs); and (4) sufficient data to calculate effect sizes.Meta-analyses showed that by age 16 years, individuals who later developed schizophrenia/SSD presented with significantly poorer general academic achievement (d=-0.26) and mathematics achievement (d=-0.21). Findings also indicated that during adolescence, youth with a family history of schizophrenia/SSD and youth reporting PLES were characterised by significantly lower general academic achievement than healthy peers .These results show that poor academic achievement precedes illness onset, and may represent an easily identifiable non-specific marker of biological, psychological and social risk processes underpinning the development of schizophrenia/SSD."}
+{"text": "Although some studies have suggested that transfusion recipients may have better medical outcomes if transfused with red blood cell units stored for a short time, the overall body of evidence shows mixed results. It is important to understand how using fresher stored red blood cell units for certain patient groups may affect blood availability.Based on the Stock-and-Flow simulation model of the US blood supply developed by Simonetti et al. 2014, we evaluated a newly implemented allocation method of preferentially transfusing fresher stored red blood cell units to a subset of high-risk group of critically ill patients and its potential impact on supply.Simulation results showed that, depending on the scenario, the US blood total supply might be reduced between 2-42%, when compared to the standard of care in transfusion medicine practice. Among our simulated scenarios, we observed that the number of expired red blood cell units modulated the supply levels. The age threshold of the required red blood cell units was inversely correlated with both the supply levels and the number of transfused units that failed to meet that age threshold.To our knowledge, this study represents the first attempt to develop a comprehensive framework to evaluate the impact of preferentially transfusing fresher stored red blood cells to the higher-risk critically ill patients on supply. Model results show the difficulties to identify an optimal scenario. Observational studies have estimated the effects of red blood cell (RBC) storage time on clinical outcomes among different patient groups. Some studies have shown that transfusing certain high-risk patients, such as cardiac surgery patients, with RBC units that have been stored for prolonged time may increase the risk of adverse outcomes \u20136. OtherResults from randomized clinical trials (RCT) have varied in their outcomes. The RECESS RCT from the National Heart, Lung, and Blood Institute  found noBased on the Stock-and-Flow simulation model of the US blood supply developed by Simonetti et al. 2014 , we explThe US blood supply model developed by Simonetti et al.  evaluateThe Collector attempted to supply the Hospital with enough young RBC units to meet the HRGs expected demand of blood for the next day. The Hospital received blood from the Collector to fulfill any need of blood demand regardless the RBCs age, while maintaining an inventory of 6 days of supply. Transfers of blood from the Collector to the Hospital occurred by using \u2018standard\u2019 phenotype compatibility rules . We defiThe daily predictions of supply and demand were derived using aggregated blood donation information from America\u2019s Blood Centers (ABC) , and updWe used the annual average daily (AAD) age of RBCs as a summary measure for the overall evaluation of the performance of the blood system for each simulated scenario. Specifically, we used the weighted AAD age of RBCs, which represented the distribution of RBC units among different blood ages. Other measures of performance were \u2018unmet RBC units by age\u2019 and \u2018percentage of unmet RBC units by age\u2019 for HGRs and BBRs. \u2018Unmet RBC units by age\u2019 represented the amount of RBC units that failed to meet the age requirement derived from the literature \u20136. \u2018PercWe identified three HRGs\u2014Cardiac Surgery (CS), Trauma (TR) and Intensive Care Unit (ICU) patients , 5\u2014from To evaluate the impact on supply of transfusing a subset of HRGs with fresher stored RBCs, we compared the baseline blood recipients to several selected scenarios  in context, we may help understanding the effect on the US blood supply if transfusing fresher storedRBC units is proven beneficial to improve recipient outcomes. However, under current assumptions, we demonstrated how the newly developed allocation method allows a relatively efficient distribution of blood while preferentially providing fresher stored RBCs to the high-risk blood recipient except for some disruptions in the US blood supply observed in certain simulated scenarios. Most importantly, implementing \u2018ad-hoc\u2019 models can help assist stakeholders and the blood community to make informed decisions that may impact the availability of blood in the US blood supply.S1 FigA flowchart of the \u2018Threshold Method\u2019 (TM) algorithm to illustrate the mechanism of allocating blood into the system 1) from the Hospital to the HRGs recipients; and 2) from the Collector Bank to the Hospital, on each day of the Monte Carlo simulation.(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S4 FigThe Annual Average Daily (AAD) number of RBC units available in the system for: (A) Total Supply , average values (red), and percent reduction in total supply with respect to baseline scenario (BBR-LO) (above bars for scenarios 2 to 11); (B) Expired RBC Units,  and percentage of expired units at collector only are shown on bars; (C) Unmet RBC Units by Age by blood type at the hospital, the percentage of unmet units by age (above bars), and mean age of the transfused blood at the hospital . The scenarios are sorted in a descending order according to their total supply. Error bars represent 95% confidence intervals.\u201d(DOCX)Click here for additional data file.S5 FigDescription of each element of the half-pie chart from inner to the outer layer as follows: 1) percentage of total RBC units transfused among elderly for the overall HRGs (blue) versus BBR (tan); 2) percentage of total RBC units transfused decomposed by HRGs ; 3) allocation method used for each recipient group ; 4) mean age of the blood transfused to each recipient group and the percentage of \u2018met\u2019 (green) and \u2018unmet\u2019 (red) RBC units by age for HRGs only (in parenthesis); and 5) mean age of the overall transfused blood given to HRGs (bold red).(DOCX)Click here for additional data file.S6 FigThe mean age of blood for the overall transfused blood at the hospital is shown above the bars.(DOCX)Click here for additional data file.S7 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 TableScenario illustration, group description, and allocation method used for each scenario are also presented.(DOCX)Click here for additional data file."}
+{"text": "G2 and the McMaster techniques for counting of gastrointestinal nematode eggs in the faeces of alpacas using two floatation solutions (saturated sodium chloride and sucrose solutions). Faecal eggs counts from both techniques were compared using the Lin\u2019s concordance correlation coefficient and Bland and Altman statistics. Results showed moderate to good agreement between the two methods, with better agreement achieved when saturated sugar is used as a floatation fluid, particularly when faecal egg counts are less than 1000 eggs per gram of faeces. To the best of our knowledge this is the first study to assess agreement of measurements between McMaster and FECPAKG2 methods for estimating faecal eggs in South American camelids.This study aimed to compare the FECPAKThe online version of this article (10.1186/s13071-018-2861-1) contains supplementary material, which is available to authorized users. Parasitic gastroenteritis caused by gastrointestinal nematodes (GINs) is responsible for significant clinical and subclinical problems in domesticated South American camelids (SACs), alpacas and llamas, resulting in economic losses arising from lowered production of fibre, meat and/or leather , 2. AlthIn SACs, the burden of GINs can be assessed using various coprological methods originally developed for domestic ruminants , with esG2 method uses a floatation-dilution approach similar to the McMaster technique, but involves capturing digital images of samples without the use of a microscope. Digital images of samples are stored, ready for assessment by trained technicians for identification and counting nematode eggs  [G2 methods assessed using the Lin\u2019s concordance correlation coefficient [epiR package [The arithmetic means of EPG were calculated for faecal egg counts obtained using the two methods and differences in arithmetic means were tested using the Wilcoxon signed rank test. A G + 15)] , and agrfficient . To provfficient . These l package  implemen package .G2 methods . Using sugar solution, more samples had at least more than one EPG using the McMaster technique  compared with FECPAKG2  in the proportions of positive samples tested by both methods when salt solution was used   plots showing line of perfect concordance (dotted line) and estimated concordance (solid line) between McMaster and FECPAKG2 methods using salt solution (a) and sugar solution (b). (TIF 520 kb)"}
+{"text": "Left ventricular (LV) fractal dimension (FD) on cardiac magnetic resonance (CMR) balanced steady-state free precession (SSFP) cines has already proven to be useful in making a diagnosis of non-compaction cardiomyopathy. Normal FD values for SSFP cines have been established (Captur 2015).Fast gradient echo (fGRE) sequences have different contrast between blood pool and myocardium, which affects measurement of FD. However, if FD could be measured on fGRE it would allow for retrospective analysis of scans acquired before implementation of SSFP or in patients with devices that underwent fGRE.The aim of this study was to establish a correlation between FD measured on SSFP and fGRE sequences in the same subjects.Twelve participants of Barts Cardiovascular Registry who underwent cardiac magnetic resonance (CMR) imaging with 1.5T scanners for various clinical reasons had cine short axis stack (SAX) acquired with both SSFP and fGRE sequences.We measured FD in 57 corresponding (positioned in the same LV location) SAX cine slices on SSFP and fGRE using dedicated MATLAB script and an Osirix \"LVFractalAnalysisFilter\" plugin written in Objective-C with equivalent architecture. The same region-based level-set segmentation and fractal procedure was implemented. Briefly: the scale parameter specifying the size of the neighbourhood (sigma) was set to 2%; size of the initial contour was set to 6 \u00d7 9 pixels; and maximum initial grid-size for fractal analysis was 45% of the original size of the region of interest estimated through the application of a scaled bounding box.We used Pearson's correlation coefficients and two-way random single measures of consistency intraclass correlation coefficients (ICC) to compare FD from SSFP and fGRE, first for values derived in MATLAB and then in Osirix.FD on fGRE was around 6.5% larger than on SSFP in MATLAB and 4.3% in Osirix (p < 0.001 and p < 0.05). There was a good agreement between the FD derived from SSFP and fGRE sequence in both MATLAB and Osirix tools .Detailed results are presented in the table and the figure.This proof-of-principle analysis shows a significant correlation between FD on SSFP and fGRE sequences. FD measured on fGRE may have utility as a research tool and further ground-truth validation of the method is encouraged."}
+{"text": "To clarify the prognostic role of tumour protein 53 (TP53) mutations in patients with oesophageal adenocarcinoma (OAC) as there is a need for biomarkers that assist in guiding management for patients with OAC.A systematic review was conducted using MEDLINE, Embase, PubMed and Current Contents Connect to identify studies published between January 1990 and February 2015 of oesophageal cancer populations (with OAC diagnoses >50% of cases) that measured tumoural TP53 status and reported hazard ratios (HR), or adequate data for estimation of HR for survival for TP53-defined subgroups. Risk of bias for HR estimates was assessed using prespecified criteria for the appraisal of relevant domains as defined by the Cochrane Prognosis Methods Group including adherence to Grading of Recommendations, Assessment, Development and Evaluation and REporting recommendations for tumor MARKer prognostic studies guidelines, as well as assay method used (direct TP53 mutation assessment vs immunohistochemistry) and adjustment for standard prognostic factors. A pooled HR and 95% CI were calculated using a random-effects model.2=33%). A greater prognostic effect was observed in a sensitivity analysis of those studies that reported survival for OAC-only cohorts and were assessed at low risk of bias .Sixteen eligible studies (11 with OAC only and 5 mixed histology cohorts) including 888 patients were identified. TP53 mutations were associated with reduced survival (HR 1.48, 95% CI 1.16 to 1.90, IPatients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage. Oesophageal adenocarcinoma (OAC) remains one of the few GI malignancies where molecular information is not taken into account to guide patient management.Current clinicopathological staging fails to accurately identify patients with OAC with good or poor prognosis.Recent genomic findings have identified a high tumour protein 53 (TP53) mutation rate in OAC, but the prognostic impact of this remains unclear due to conflicting reports in the literature.This is the first dedicated systematic review and meta-analysis regarding the prognostic impact of TP53 mutations in patients with OAC including 16 studies with >850 patients.We identify a significant negative prognostic impact of TP53 mutations on overall survival of patients with OAC.A greater prognostic effect can be corroborated in studies that report tumour-stage adjusted survival for OAC-only cohorts and are assessed at being at low risk of bias.This study suggests that TP53 gene mutations have a clinically important negative prognostic impact on patients with OAC.In light of recent genomic findings highlighting a central role of this gene in OAC pathogenesis and drugs currently in development and testing that directly target this gene, a role for identifying TP53 mutations in OAC can be suggested.The incidence of oesophageal adenocarcinoma (OAC) has increased faster than any other cancer since the 1970s in many Western countries with highest incidence rates found in Northern and Western Europe, Northern America and Oceania,Fewer than half of the patients with a new diagnosis of OAC are eligible for curative treatment, and OAC continues to have one of the highest cancer case-fatality rates with population-based 5-year survival rates typically around 15%.The tumour-suppressor gene tumour protein 53 (TP53) , which encodes the p53 protein and is sometimes called \u2018the guardian of the genome\u2019,18Recent large-scale whole-genome and whole-exome sequencing studies have shown that both OAC and dysplastic BO harbour a very high TP53 mutation rate of up to 70%,We aimed to resolve the existing uncertainty regarding the prognostic value of TP53 for staging OAC by conducting a systematic review and meta-analysis of all published data with subgroup analysis of studies assessed as low risk of bias, and studies using direct TP53 gene mutation analysis techniques to determine TP53 mutation status, since these are the most accurate methods for determining tumoural TP53 mutations.Gastroenterology), American Society for Clinical Oncology  and American Association for Cancer Research  from 1990 to 2015.The electronic bibliographic databases MEDLINE, Embase, PubMed and Current Contents Connect were searched to identify eligible studies published between January 1990 and 8 February 2015 using MeSH terms and text words for adenocarcinoma*, o/esophagus* or o/esophageal*, TP53* or p53* or 17p13* or 17p*. In an attempt to minimize the risk of publication bias, conference abstracts and proceedings were searched through Web of Science, Embase and Scopus using the terms o/esophagus* and p53*. Further, the following major GI and oncological conferences were searched for relevant reports: Digestive Disease Week  scanned the search results (title and abstract) and retrieved full text publications using the criteria outlined below to identify eligible studies. Reference lists of relevant studies identified from the search including reviews were further screened to identify studies that may not have been identified by the strategy outlined above.Study inclusion criteria were prospective or retrospective clinical studies of OAC populations that assessed TP53 mutation status and/or p53 expression in primary tumours, and compared overall survival for TP53 mutation versus TP53 non-mutation subgroups with calculation of HR and 95% CIs, or reported adequate data for their estimation. To include all available data, we also included studies of oesophageal cancer cohorts that included patients with squamous cell carcinoma if at least \u226550% of the patient cohort had a diagnosis of OAC.Study exclusion criteria were studies of TP53 DNA germline mutations or autoantibody detection in blood; and reports available in abstract form only that did not report adequate information to determine study eligibility or to assess study methods for risk of bias.If studies did not report sufficient data to calculate HRs or in case of missing/unclear data, the corresponding author was contacted by email to request this information. If the same research unit (identified from author names and institution) published multiple reports with overlapping patient recruitment time periods, HR estimates were extracted from the most recent publication with the largest patient numbers to avoid duplication of data.Three investigators  reviewed eligible studies and extracted the following variables into a standardised data extraction form: author's name; publication year; country where study was conducted; number of patients included and general patient demographics; tumour histology (number and proportion of OAC tumours included); treatment modality ; tissue specimen type ; TP53 assay methods , immunohistochemistry (IHC), and type of antibody, dilution for IHC); criteria or cut-point used to define TP53 mutation status for the survival analysis; study prevalence of TP53 \u2018mutation\u2019 and \u2018non-mutation\u2019 subgroups; median survival of all patients and by TP53 mutation status; unadjusted and adjusted HR with 95% CI and corresponding p values where available. For consistency and to facilitate further quantitative analyses, the authors\u2019 definitions for TP53 \u2018mutations\u2019 were used for studies performing only IHC as the respective studies did not use uniform staining classification criteria. As such, nuclear p53 protein overexpression was interpreted to represent TP53 mutations by all authors of the included studies, although loss of p53 protein expression has also been associated with tumoural TP53 gene mutations.http://www.gradeworkinggroup.org),et al's27All studies were assessed for risk of bias for the study estimate of the impact of TP53 on survival by appraising six domains  using prespecified criteria adapted from the Grading of Recommendations, Assessment, Development and Evaluation  TP53 mutation database (R17)10.1136/gutjnl-2015-310888.supp1Supplementary materialsTo estimate the effect of TP53 mutation status on OAC survival, we calculated a pooled HR and 95% CI using the generic inverse variance method. If the HR was not reported, it was estimated from the corresponding Kaplan\u2013Meier curves using the Parmar method.2 statistic.27Because different TP53 mutation analysis methods were used across studies, we expected heterogeneity in study estimates of the TP53 mutation effect on survival, and thus we applied a random-effects model to estimate the HR.Sensitivity analysis was performed to assess the impact of tumour histology and assay type on survival by repeating the pooled HR analysis in the following subgroups: (i) OAC-only versus OAC-mixed study populations; (ii) IHC versus direct TP53 gene mutation analyses; and (iii) studies assessed as having low versus high risk of bias. Differences between subgroups were assessed with a test for interaction.34ggplot2 package.metafor and forestplot for R.38Descriptive statistics as well as quantitative analysis of the IARC TP53 mutation database to guide risk of bias assessment were performed using R statistical softwareThe search strategy yielded 323 studies, of which 16 met our eligibility criteria . Study cHalf of the studies (n=8) assessed TP53 mutation status by IHC,The clinicopathological variables and survival times reported in the included studies are summarised in HRs were reported in nine studies and extrapolated from five studies. In addition, individual patient data were available for two studies to calculate tumour stage-adjusted HR and 95% CIsFour studies2=33%, p heterogeneity=0.1). The analysis of studies including pure OAC patient cohorts showed similar results with low heterogeneity  compared with studies performing direct TP53 gene assessments (sequencing and SSCP) or LOH analyses . This difference was borderline statistically significant (p for interaction=0.05). A similar effect was seen in the subset of studies containing pure OAC cohorts . This effect size was similar in the three studies with low risk of bias that contained pure OAC cohorts  and the study appraised as being at low risk of bias  were significant sources of heterogeneity .This study indicates that mutated TP53 negatively impacts overall survival in patients with OAC, independent of tumour stage. This effect is estimated as a relative increase in hazard of death of 48%, with up to a 211% increase when studies of mixed histology cohorts or high risk of bias are excluded. This corresponds to a reduced survival time of approximately 7\u2005months based on median survival from the included studies. This effect size is similar to the difference in median survival of stage IIIA compared with stage IIIC OAC.55To our knowledge, this is the first comprehensive systematic review and meta-analysis of the prognostic impact of TP53 mutations in patients with OAC that includes an assessment independent of tumour stage. Two previous systematic reviews and meta-analyses of various prognostic biomarkers in OAC have included an analysis of TP53 mutations.This study is timely because recent whole-genome sequencing studies have shown a high mutation rate of TP53 in OAC.58One potential explanation for earlier conflicting results for the prognostic significance of TP53 status in OAC is the use of different and potentially less accurate assay methods for TP53 mutation detection. Our study identified considerable variability in IHC methods across the included studies, such as the use of different antibodies, antibody dilutions and variable scoring systems for immunopositivity. Further, none of the included studies used loss of p53 expression as a method for interpreting the presence of TP53 gene mutations.22Recent genomic studies have found that TP53 gene mutations remain the most common genetic alteration in both OACet al,The two main limitations of this study that may affect the validity of our findings are the quality of the primary studies and data limitations to explore potential confounders. First, more than half of the studies were assessed as high risk of bias based on criteria defined by Hayden Further studies are warranted to better estimate the size of the prognostic effect independent of tumour, node, metastasis staging. Given the substantial amount of heterogeneity identified, adherence to REMARK guidelineshttp://www.clinicalTrials.gov identifier NCT00525200; http://www.p53.at) has recently completed recruitment. Moreover, multiple therapeutic options directly targeting the TP53 gene are either currently in clinical trials or are already clinically available.One approach to collect high-quality data is to include TP53 mutation analysis using targeted gene sequencing in the baseline analysis of trials of OAC therapies. If validated, TP53 analysis could be used to stratify patients in future trials. Stratifying patients based on TP53 mutation status may also have a role in clinical practice to guide treatment selection. For example, data suggest that TP53 mutation status may predict response to standard chemotherapeutic regimens such as fluorouracil or cisplatin,In summary, OAC remains one of the few GI malignancies for which molecular information is still not used to guide patient management. This study suggests that TP53 gene mutations have a clinically important negative prognostic impact on patients with OAC, which is relevant in light of recent genomic findings highlighting a central role of this gene in OAC pathogenesis and drugs currently in development and testing that directly target this gene. High-quality studies with large patient cohorts using modern sequencing technologies for TP53 mutation analysis are needed to confirm the independent prognostic effect of this frequent gene mutation."}
+{"text": "This data aimed to audit the dental sciences related articles published in Iranian Journal of Basic Medical Sciences (IJBMS) from 2007 to 2015 over a 9 year period performed using web-based search. The data were analyzed for topic of dental sciences, type of article, international collaborations, source of funding, number of authors and authorship trends. Out of the total 18 data related to dental sciences, original articles (12), review articles (4) and short communications (2) contribute the major share. Regarding the relationship with dental sciences, the maximum number of data were related to oral pathology and microbiology (16) followed by oral medicine and radiology (7) and periodontics (7). Among the data related to dental sciences, oral cancer (3) and gingival and periodontal diseases (3) followed by dental plaque and caries (2) and orthodontic tooth movement (2) form the major attraction of the contributors. The largest numbers of data related to dental sciences were received from Mashhad University of Medical Sciences, Mashhad (4) and Tehran University of Medical Sciences,Tehran (2).The present data were compared with previous bibliometric studies done related to dental sciences  Specifications TableValue of the data.\u2022These date describe the majority of dental sciences articles published as original articles (12),review articles (4) and short communication (2)\u2022These data describe specialty wise majority of dental articles related to oral pathology and microbiology (16) followed by oral medicine and radiology (7),periodontics (7), community dentistry (2),orthodontics (2), prosthodontics (1) and oral and maxillofacial surgery (1).\u2022These data describe topic wise majority of dental articles related to oral cancer (3) and gingival and periodontal diseases (3) followed by dental plaque and caries (2) and orthodontic tooth movement (2)\u2022The data presented in this paper can be used as a guide for conducting similar studies around the globe.These data describe the dental sciences related articles published in a Basic Medical Sciences Journal from Iran.1See 2http://ijbms.mums.ac.ir/ .Bibliometric information about dental sciences articles data in a clinical medical journal from Iran and ayurveda journals from India is evident in the literature  The data published were analyzed for topic of dental sciences, type of article, international collaborations, source of funding, number of authors and authorship trends.The data regarding articles in press (articles that are not yet assigned to an issue) in IJBMS were excluded. The contents of the data were grouped into seven individual dental sciences specialities such oral pathology and microbiology, oral medicine and radiology, oral and maxillofacial surgery, periodontics, prosthodontics, orthodontics and community dentistry. The data was scrutinized for dental sciences related topic. The datas which are interdisciplinary in approach were counted under all the dental sciences specialities it belonged. The data were checked for authorship trends according to the institution of the first author.The data was analyzed using descriptive statistics."}
+{"text": "Since 2011, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) has typically been notified of three or fewer cases of hepatitis A virus (HAV) infection each year among men who have sex with men (MSM) who reported no travel to countries where HAV is endemic. This year, DOHMH noted an increase in HAV infections among MSM with onsets in January\u2013March 2017, and notified other public health jurisdictions via Epi-X, CDC\u2019s communication exchange network. As a result, 51 patients with HAV infection involving MSM were linked to the increase in NYC.Confirmed cases were defined as symptomatic HAV infections with onset after December 31, 2016, in NYC residents who reported being MSM or having sexual contact with MSM, and reported no travel to areas of high or intermediate HAV endemicity. Probable cases were defined as onset of symptomatic HAV infection after December 31, 2016, in NYC residents who, irrespective of travel, reported being MSM or having sexual contact with MSM. For the period January 1\u2013August 31, 2017, DOHMH identified 46 cases in MSM or persons with sexual contact with MSM; 36 confirmed and nine probable cases occurred in 45 MSM patients and one was in a female (confirmed case) who reported sexual contact with a bisexual male resident of a New York county outside New York City. Fifteen (33%) of the 46 patients were hospitalized, and three (7%) reported previous receipt of hepatitis A vaccine. Nineteen (41%) patients had traveled domestically during their incubation period, and eight (17%) had traveled to Western European countries where outbreaks of HAV infection among MSM are ongoing (NYC routine surveillance identified another case of HAV infection (in addition to the 46 NYC patients), in a man who was hospitalized in New York City but resided in the New York county that had been visited by the female patient. Several Colorado jurisdictions also contacted DOHMH to report increases in HAV infections among MSM. In total, 51 patients were linked to the increase in NYC, either through epidemiologic or laboratory evidence, including five non-NYC patients .Three of the 46 NYC patients and the one patient from Oregon reported sexual contact with four NYC outbreak patients . The OreSerum specimens from 25 NYC MSM patients, the NYC female patient, and the New York (non-NYC) MSM patient were sent to CDC\u2019s Division of Viral Hepatitis Laboratory for molecular sequencing. Sequences of HAV isolated from the serum of 24 patients, including four of the eight who had traveled to Europe, matched the strains of genotype IA HAV circulating among European MSM: HAV16\u2013090 (14 patients), VRD_521_2016 (eight), V16\u201325801 (two); two patients had sequences matching three Colorado MSM patients, and one had a unique sequence .Only three patients with HAV infection reported previous receipt of HAV vaccine; this ongoing investigation highlights the importance of HAV vaccination among MSM, and of determining MSM status during HAV investigations. One patient received 1 dose (as postexposure prophylaxis), but the doses for the other two patients were unknown; both reported previous receipt of HAV vaccine but did not know the number of doses. Since 1996, the Advisory Committee on Immunization Practices has recommended that all MSM receive 2 doses of HAV vaccine administered at least 6 months apart ("}
+{"text": "Nature Communications7 Article number:11362 10.1038/ncomms11362 (2016); Published 05062016; Updated 09292016.The HTML version of this Article previously published omitted Supplementary Data 8. This has now been corrected in the HTML version of the Article; the PDF was correct from the time of publication."}
+{"text": "The A2AAR is widely expressed on cells of the immune system and numerous in vitro studies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-\u03baB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings from in vivo studies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A"}
+{"text": "Altered immune response is associated with many psychiatric disorders, but whether and how these changes confer increased risk remains unclear. In schizophrenia, robust association between illness risk and the MHC region general, and complement component 4 (C4) specifically, has been demonstrated, along with evidence from both gene enrichment and other genetic analysis highlighting the broader role of genetic variation in additional immune related networks to schizophrenia risk.In a series of recent studies from our group, we examined the effects of immune-related genetic variation, based on gene ontology, implicated in neural function both behaviourally in samples of ~1200 cases and controls, and cortically in samples of ~150 cases and controls.We found that (1) increased predicted C4A RNA expression predicted poorer performance on measures of memory recall  and a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing ; (2) variation in a curated gene set associated with both increased Schizophrenia risk and immune function  were associated with both variation in both episodic memory and general cognitive ability.Based on these findings we conclude that schizophrenia risk associated with variation within immune related genes is likely to be conferred at least partly via effects on cognition, and the molecular mechanisms involved may include effects on inflammatory response."}
+{"text": "TNNT1) was found in the Amish populations in Pennsylvania and Ohio. This single nucleotide substitution causes a truncation of the ssTnT protein at Glu180 and the loss of the C-terminal tropomyosin (Tm)-binding site 2. As a consequence, it abolishes the myofilament integration of ssTnT and the loss of function causes an autosomal recessive nemaline myopathy (NM). More TNNT1 mutations have recently been reported in non-Amish ethnic groups with similar recessive NM phenotypes. A nonsense mutation in exon 9 truncates ssTnT at Ser108, deleting Tm-binding site 2 and a part of the middle region Tm-binding site 1. Two splicing site mutations result in truncation of ssTnT at Leu203 or deletion of the exon 14-encoded C-terminal end segment. Another splicing mutation causes an internal deletion of the 39 amino acids encoded by exon 8, partially damaging Tm-binding site 1. The three splicing mutations of TNNT1 all preserve the high affinity Tm-binding site 2 but still present recessive NM phenotypes. The molecular mechanisms for these mutations to cause myopathy provide interesting models to study and understand the structure-function relationship of TnT. This focused review summarizes the current knowledge of TnT isoform regulation, structure-function relationship of TnT and how various ssTnT mutations cause recessive NM, in order to promote in depth studies for further understanding the pathogenesis and pathophysiology of TNNT1 myopathies toward the development of effective treatments.Troponin T (TnT) is the sarcomeric thin filament anchoring subunit of the troponin complex in striated muscles. A nonsense mutation in exon 11 of the slow skeletal muscle isoform of TnT (ssTnT) gene ( A nonsense mutation in TNNT1 was first identified in the Old Order Amish  in the C-terminal end segment, partial deletion (W287ter) or error-splice out of exon 17 encoding this segment in cardiac TnT have been found to cause cardiomyopathy , slow skeletal muscle (TNNT1) and fast skeletal muscle (TNNT3) isoforms of TnT  expresses exclusively slow skeletal muscle TnT together with cardiac forms of TnI and myosin  express only cardiac TnT in the cardiac muscle. Analysis of cardiac function demonstrated that toad hearts generated lower maximum stroke volume but significantly higher resistance to the increase of afterload than that of frog hearts  contains 14 constitutively expressed exons and three alternatively spliced exons  encoding a short segment of 2 or 3 amino acids between the T1 and T2 regions of mammalian cardiac TnT  each encoding a segment of 14 amino acids also occurs in TNNT3 gene undergoes a high to low molecular weight, acidic to basic isoelectric point splice form switch during development due to alternative inclusions of N-terminal exons , but not type 2, Charcot-Marie-Tooth disease  was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited NM  did not report notable clinical symptom (Johnston et al., TNNT1 myopathies may cause conditional slow TnT deficiency with symptoms such as experiencing conditional fatigue intolerance and other slow muscle-related dysfunctions.Genetically modified mice with a knockdown of the expression of slow TnT exhibited decreased muscle resistance to fatigue (Feng et al., The potential cytotoxicity of non-myofilament associated slow TnT fragments (Jeong et al., The transient expression of cardiac TnT and embryonic splice forms of fast skeletal muscle TnT in embryonic and neonatal skeletal muscle may explain the postnatal onset of ANM (Jin et al., TNNT1 myopathy patients should be able to readily rescue muscle growth and functions. The maintained slow fiber cellular environment and active regeneration also indicate that translational read-through of the nonsense stop codon in the muscles of ANM and S108ter patients may effectively restore muscle function and growth.Soleus muscle of slow TnT knockout mouse maintains a slow fiber cellular environment and exhibits signs of active regeneration (Wei et al., TNNT1 myopathies is no longer considered as a isolated disease of the Amish, and the power of genetic testing is anticipated to identify more myopathic mutations of the gene, researchers are urged to add joint effort in TnT gene expression and structural-function relationship studies, including the utilization of genetically modified mouse models of the human diseases, toward the development of effective targeted treatment of these lethal muscle diseases.Since TNNT1 myopathies demonstrate an excellent example for what we can learn from pathogenic mutations of a myofilament protein as well as how knowledges learned from protein structure-function relationship research can help us to understand the pathogenesis and pathophysiology of genetic diseases. Therefore, we hope this focused review will benefit readers with the vision beyond TNNT1 myopathy studies.In conclusion, AM: Drafting and revising the text, making figures, approval submission; JJ: Deciding the topic and contents, drafting and revising the text, making figures, approval submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We present a review of the literature on Primary Progressive Aphasia (PPA) together with the analysis of neuropschychological and neuroradiologic profiles of 42 PPA patients. Mesulam originally defined PPA as a progressive degenerative disorder characterized by isolated language impairment for at least two years. The most common variants of PPA are: (1) Progressive nonfluent aphasia (PNFA), (2) semantic dementia (SD), (3) logopenic progressive aphasia (LPA). PNFA is characterized by labored speech, agrammatism in production, and/or comprehension. In some cases the syndrome begins with isolated deficits in speech. SD patients typically present with loss of word and object meaning and surface dyslexia. LPA patients have word-finding difficulties, syntactically simple but accurate language output and impaired sentence comprehension. The neuropsychological data demonstrated that SD patients show the most characteristic pattern of impairment, while PNFA and LPA overlap within many cognitive domains. The neuroimaging analysis showed left perisylvian region involvement. A comprehensive cognitive, neuroimaging and pathological approach is necessary to identify the clinical and pathogenetic features of different PPA variants."}
+{"text": "DEAR EDITOR1Studies of quality of life measures in scar patients reveal significant interference with physical comfort as well as in social and professional life. The lay population often refers to a scar as an unsightly healed wound. Conversely, surgeons tend to think of surgical scars as an expected outcome of a violation of the dermis. Before initiating treatment, the physician must take the time to understand and diagnose each element. The extent of scar must be considered along with the patient\u2019s intent in getting treatment.2,3This is a prospective study of 50 cases of scar revision performed in our department from 2011- 2014. Mature scars more than 2mm in diameter broad were included in the study. Patients were analysed in terms of patient satisfaction with the post-operative outcome. Patients were followed up for a minimum period of 6 months. Exclusion criteria were (i) pregnant patients, (ii) paediatric patients and (iii) patients with a follow up period of <6 months. Patients were analysed regarding their satisfaction with their post-operative outcome in the form of scar related parameters and psychological parameters. Post-operative patient satisfaction was assessed using pre and post procedure Vancouver Scar Scale scores.The largest number of cases were seen in the age group 16-30 years (78%), of which 21 patients (53.8%) were satisfied with the outcome of their corrective procedure. The preponderance in this age group could be due to the fact that young adults are highly conscious regarding their appearance . Among 2The incidence of post-operative satisfaction was slightly higher among 25 unmarried enrolled patients (60%) compared to 25 studied married patients (52%). No significant difference in post-operative satisfaction could be found in patients with decreased (n=10) or unchanged scar visibility (n=10) following operative procedure. Scars which were converted to lie parallel to Relaxed Skin Tension Lines (RSTL) were seen to have the maximum satisfaction with post-operative results (83%) compared to other patients (72%). However the small number of patients in the category (5 and 8 patients) precludes any statistically significant difference to be obtained. Eighteen patients noticed gain of function of the affected part following scar revision (n=38).All patients with gain of function in the affected part showed satisfaction with their post-operative outcome. The highest incidence of post-operative satisfaction correlates with anxiety relief following correctional procedure (84% of 13 enrolled patients). The highest post-operative satisfaction was seen to correlate with alleviation of depression following correctional procedures (89% of 19 studied patients). No significant difference was seen in post-operative satisfaction rates in patients with either increased or high self-esteem following surgical procedure. However patients with low self-esteem demonstrated lower satisfaction rates compared to their counterparts (40% vs. 56% and 60%). The highest percentage of post-operative satisfaction was seen in patients with improved social acceptance following correctional procedure (73%) when compared to others (50% and 30%). Patients with change of 4 or more between pre and post operative Vancouver Scar Scale scores were satisfied with the outcome of the revisional procedures while those with scores less than 4 were either dissatisfied or neither satisfied nor dissatisfied with the outcome. Post-operative satisfaction in an individual is multifactorial. Females appear to be marginally more satisfied as compared to males with their post operative outcomes. Patients who underwent correctional procedures for cheek scars showed maximum satisfaction post operatively probably because the cheek is an exposed area and defects if an are promptly visible. Even a small improvement in a scar in such a cosmetically important area can bring great satisfaction to the patient.4,5 Following scar revisional procedures, marked reduction in anxiety and depression as compared to pre-operative status was noticed. Also, patients with low self esteem tended to be unsatisfied with their post operative outcome. Increased social acceptance, either real or apparent, could be a major factor leading to this conclusion. Patients in whom scars came to lie parallel to or within RSTL\u2019s post operatively, as compared to pre-operative status in which they did not, showed the maximum level of satisfaction with their corrective procedures.The authors declare no conflict of interest."}
+{"text": "Coxiella burnetii infection(s). Use of these methods and development of criteria to define and treat such infections, especially cardiovascular infections, will improve the prognosis for patients previously thought to have chronic Q fever.Modern diagnostic methods enable clinicians to look beyond a diagnosis of chronic Q fever and discern whether patients instead have persistent focalized  We read with interest the article by Kampschreur et al. (Coxiella burnetii infection(s). The obsolete term chronic Q fever should be abandoned to prevent confusion between endocarditis, vascular infections, osteoarticular infections, lymphadenitis, genital infection, and pericarditis, which occurred in 68%, 20%, 7%, 6%, 3%, and 1%, respectively, of 494 patients with persistent focalized infection(s) who we followed during 2007\u20132015 at the French National Referral Center for Q Fever in Marseille, France (unpub. data).Kampschreur et al.\u2019s use of the term chronic Q fever is misleading because it may lead to inadequate treatment of persistent focalized Another example of the deleterious effect of the Dutch Q Fever Consensus Group guidelines is the absence of screening echocardiography in the standard work-up for patients with Q fever in the Netherlands  and by avoiding drug side effects in patients with isolated elevated serologic test results. Clinicians should look beyond a diagnosis of chronic Q fever to determine whether a patient might have persistent focalized infection(s). The term fever in Q fever has evolved from a pathologic picture per se to a clinical epiphenomenon; it is now time to evolve from the concept of chronic Q fever to one of persistent focalized C. burnetii infection(s) (Accurate identification of persistent focalized"}
+{"text": "Magnetic resonance (MR) imaging has become an important diagnostic tool for the detection of impaired myocardial motion, which has been considered as a common consequence of most ischemic or non-ischemic heart diseases. Both cine DENSE and TPM have been independently adopted to delineate abnormal regional myocardial motion patterns for the estimation of the progression of cardiovascular diseases or for the evaluation of individual cardiovascular responses to treatments. However, although the similarities and differences between cine DENSE and TPM are well understood from a technical point of view, the interchangeability of those two imaging techniques in cardiovascular risk stratification is still not fully understood. The aim of the present study was to test the hypothesis that clinical metrics derived from cine DENSE and TPM are correlated for characterizing regional myocardial motion.This study complied with HIPAA regulations. Thirteen healthy volunteers and 4 asymptomatic recipients of heart transplant (HTx) were recruited following the approval of the institutional review board (IRB). For each participant, two-dimensional (2D) cine DENSE and TPM were performed at basal, midventricular and apical locations at the left ventricle (LV) with the short-axis view. DENSE-derived myocardial metrics, including peak radial strain (Err), circumferential strain (Ecc), first principal strain (E1), second principal strain (E2) and twist were measured and correlated with TPM-derived indices, including peak radial velocity (Vr), circumferential velocity (V\u03a6) and time to peak (TTP) in systole and diastole using Pearson correlation coefficient (r).DENSE and TPM data were successfully acquired in 17 participants and resulted in 51 data points  for comparisons. On a per-slice basis, peak Err had moderate correlations with peak Vr in systole  and in diastole . Peak E1 was moderately associated with Vr-sys  and Vr-dia . Peak twist was moderately correlated with peak V\u03a6 in diastole . See figures DENSE and TPM can provide correlated clinical metrics for quantitatively characterizing regional myocardial motion from different technical aspects."}
+{"text": "ER causing neuropathology and memory loss in AD. This review highlights molecular signatures of UPRER and its key molecular alliance that are affected in aging leading to the development of intriguing neuropathologies in AD. We present a summary of recent studies reporting usage of small molecules as inhibitors or activators of UPRER sensors/effectors in AD that showcase avenues for therapeutic interventions.Alzheimer\u2019s disease (AD), a neurodegenerative disorder, is most common cause of dementia witnessed among aged people. The pathophysiology of AD develops as a consequence of neurofibrillary tangle formation which consists of hyperphosphorylated microtubule associated tau protein and senile plaques of amyloid-\u03b2 (A\u03b2) peptide in specific brain regions that result in synaptic loss and neuronal death. The feeble buffering capacity of endoplasmic reticulum (ER) proteostasis in AD is evident through alteration in unfolded protein response (UPR), where UPR markers express invariably in AD patient\u2019s brain samples. Aging weakens UPR Alzheimer\u2019s disease (AD), the most common form of dementia faced by more than 40 million people worldwide, significantly affect morbidity and mortality in aged people  imposed on the neuronal cell due to misfolded protein aggregates. Also, we have discussed various therapeutic interventions targeting the molecules involved in UPR pathways aiming at averting the neuropathologies of AD.The expression pattern of neurodegenerative pathologies shows distinct molecular signatures, such as misfolded A\u03b2 aggregation and tau protein hyperphosphorylation in the brain  microenvironment like nutrient deprivation, changes in redox potential, calcium homeostasis, hypoxia and accumulation of unfolded/misfolded protein triggers the UPRER embodies a complex network comprised of three stress-responsive transmembrane proteins, Protein Kinase RNA like ER kinase (PERK), Inositol Requiring Element 1 (IRE1) and Activating Transcription Factor 6  domain  models expressing aggregation-prone mutant tau variants, XBP-1 was identified to be playing a similar protective role  ensuing after accumulation of unfolded peptide load is well documented. The pathway focuses on invigorating folding and degradation of misfolded peptides in mitochondrial matrix through the execution of retrograde transcriptional activation , but also showed reduction in beta-amyloid aggregation in worms and transgenic mouse models of AD  revealed a deranged glucose metabolism in brain regions. Aging registers diminished brain glucose utilization that surges in AD  instates mitigating effect on hexosamine pathway (HBP), due to which O-GlcNAcylation is compromised with hyperphosphorylation on tau protein  when fed with the drug metformin showed mitigated levels of GRP78 with ensuing gain in lifespan, additionally the expression of GLUT1 and its association with the beginning of UPRER exerted neuroprotective effect , has been known to inhibit BACE1 translation through dephosphorylation of eIF2\u03b1-P  resulted in establishing long-term hippocampus memory (Mart\u00ednez et al., 2+ equilibrium, thereby maintains the proper signaling in brain. The disruption in neuronal physiology is quite evident in age-related AD where ER dysfunctions are prominently expressed in the form of imbalance in proteostasis. Advancements in studies based on AD models have clearly shown how we can intervene the molecular pillars of UPRER and its associated signaling cascades to manage neurodegeneration in age-related AD. The present review is an attempt to revise functional relevance of the studies conducted in the field of management of age-related AD through therapeutic interventions on the UPRER pathway and its associate\u2019s molecules. Studies reinforce that the strategies where intervening the molecules, which are involved in transposing effects of aging on neurodegeneration, will cause reduction in probability of AD pathology. The manifestation of ER proteostasis is a direct indication of healthy nervous system. Progression in AD witnesses glucose hypo-metabolism in brain, reduction in glucose transporters in neurons and endothelial cells of blood brain barrier in direct proportion with the amount of neurofibrillary tangles. Type 2 diabetics with higher insulin resistance are at a greater risk of AD. Recent reports elucidate that managing UPRER can exert neuroprotective effect in AD (Smith and Mallucci, mt can impede plaque formation. Aliev et al., also demonstrated link between cancer and AD where mtDNA over-proliferation and deletion induces cell cycle dysregulation prompting oncogenic pathway (Aliev et al., ER, being a central organelle in nerve cells, coordinates with the cellular homeostasis by managing translation/modification of proteins and CaER in aging-induced neuropathology in AD can be ventured upon, so that pharmacological as well as genetic tools could underscore the significance of UPRER as well as UPRmt in aged brain.We still need extensive and efficient model systems where the molecular intricacies of weakened UPRSR and RM conceived the idea. SR, ATJ, AA and RM contributed to writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized  Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterised by the retrograde degeneration of the longest motor neurons (MNs) in the corticospinal tract, leading to muscle weakness and spasticity of the lower limbs.Historically HSP was grouped into two classifications: \u2018pure HSP\u2019 exclusively exhibiting lower limb spasticity and \u2018complicated HSP\u2019 in which patients presented with additional symptoms including dementia, seizures and amyotrophy in vivo studies consistently reveal that loss of ER-shaping proteins causes profound disruption to the organisation of the ER. Expression of an SPG3A mutant form of Atlastin-1 was found to alter ER-morphology in HeLa cells from a reticular to a more tubular organisationDrosophila nervous system results in visible fragmentation of the ERER-shaping proteins comprise intramembrane hairpin-loop domains by which they localise to and insert into the ER membrane. Spastin, Atlastin-1 and REEP1 are hairpin-loop domain containing ER-shaping proteins which account for ~50% of all autosomal dominant cases of HSP (AD-HSP). Spastin gene mutations cause spastic paraplegia 4 (SPG4) subtype, which represent about 40% of AD-HSPin vivo we have recently reported on models of HSP which we have generated and characterised in the fruit fly, Drosophila melanogasterDrosophila orthologs of RTN2 and ARL6IP1 (Rtnl1 and Arl6IP1 respectively). Gene knockdown models were selected as they likely reflect the loss-of-function genetic variants expressed in SPG12 and SPG61 patients. Mutations in RTN2 include a complete gene deletion and a frameshift mutation predicted to produce a highly truncated protein, suggesting that SPG12 acts via a haploinsufficiency mechanismTo begin to understand the role of ER-shaping proteins in MNs Drosophila MNs. Specifically, mitochondria appear increasingly elongated within axon bundles and mitochondrial load within neuromuscular junction synaptic boutons is significantly reduced in loss of Arl6IP1 and loss of Rtnl1 Drosophila . Importantly, these MAMs mediate mitochondrial fission in which the ER functions to mark mitochondrial constriction sites prior to the recruitment of mitochondrial fission factors such as dynamin related protein 1 (Drp1)s of HSP . In contWhile our Rtnl1 and Arl6IP1 models of HSP represent very rare forms of disease,  family which act as microtubule motor proteins involved in the transport of membranous organelles. Mutations in KIF5A cause Charcot-Marie Tooth Disease Type 2 (CMT2) and SPG10Together these data suggest that disruption to the neuronal mitochondrial network, either directly via mitochondrial mutations or indirectly via disrupted tubular ER, underpins much of the axonal degeneration associated with HSP. Altered mitochondrial distribution could disrupt the bioenergetics of different cellular compartments, given the peculiar morphology of neurons with long axons and the requirement for energy at axonal terminals this may cause failure of normal neuronal function. This work illustrates how models of very rare forms of disease may provide novel insights into the molecular mechanisms underpinning HSP more generally and suggest novel targets for therapeutic investigation for these currently untreatable neurodegenerative disorders."}
+{"text": "In 2016, CDC saw an increase in cases of acute flaccid myelitis (AFM); 144 persons in 37 states and the District of Columbia were confirmed to have AFM. After investigations in California (3 when corrected for red blood cells). A confirmed case must have an MRI demonstrating lesions restricted primarily to the gray matter of the spinal cord, in addition to acute onset of flaccid limb weakness , but MRI results indicated alternative etiologies . The case that met the probable case definition had pleocytosis (CSF WBC = 7/mm3), but MRI findings were inconsistent with AFM, and no other plausible diagnosis was identified.The 2015 Council of State and Territorial Epidemiologists and CDC case definition for probable AFM requires acute onset of flaccid limb weakness and cerebrospinal fluid (CSF) pleocytosis  or gastrointestinal illness (one patient), with onset dates for those illnesses occurring during August 14\u2013September 13. Their illness began a median of 2 days (range = 2\u20135 days) before onset of focal limb weakness; three patients experienced tactile or measured fever preceding onset of neurologic symptoms . Among p3 (range = 50\u2013207), and initial viral testing at the hospital included CSF reverse transcription\u2013polymerase chain reaction (RT-PCR) assays for enterovirus (three patients) and West Nile virus (WNV) (two patients), polymerase chain reaction (PCR) assay for herpes simplex virus (two patients), and enzyme immunoassay to detect immunoglobulin M (IgM) or immunoglobulin G (IgG) for WNV (three patients). All results were negative. All four CSF specimens were negative on TGen amplicon sequencing assay . Serum collected from one patient at initial evaluation was negative for WNV IgM and IgG on a hospital immunoassay; serum collected from the same patient 47 days after onset of focal limb weakness and from two additional patients  were negative for WNV IgM and St. Louis encephalitis IgM at the Arizona State Public Health Laboratory.CSF was collected from all four patients with confirmed AFM. Median CSF WBC count was 133/mmThree of the four patients had nasopharyngeal (NP) swabs available from initial evaluation that were forwarded to CDC; one specimen was positive for enterovirus/rhinovirus on a panviral respiratory PCR panel at the admitting hospital laboratory and for EV-D68 at CDC. RNA extracted from NP swabs from all three patients was positive by the TGen amplicon sequencing test for EV-D68 (GenBank Bioproject); an NP specimen from a patient who did not meet the AFM confirmed or probable case definitions also was positive for EV-D68 by the same assay.Stool specimens were collected from two patients at the time of initial evaluation; vital cultures of these specimens were negative on viral. One available specimen and three additional specimens, collected 28, 47, and 63 days after onset of focal limb weakness, were sent to CDC for four enterovirus/parechovirus RT-PCR assays. A stool specimen, collected at day 28 from the patient who did not have an NP swab available, was positive for coxsackievirus A10.This cluster of AFM at one children\u2019s acute care hospital is the largest cluster identified to date in Arizona and is part of a nationally identified increase in AFM cases. Although no statewide surveillance system specific to AFM is available, this cluster was detected by physician reporting, highlighting the need for physicians to remain vigilant for this emerging disease and to report cases that fit the AFM case definition to their local health department. Metagenomic analyses identified EV-D68 in NP swabs from the three patients for whom specimens were available, along with a specimen from a patient who did not meet the AFM case definition; therefore, no single etiology or risk factor was associated with only confirmed cases. Patient and family history of asthma was the most common comorbidity reported among confirmed AFM cases and should be considered in future case investigations. Expanded analysis of infectious, postinfectious, and noninfectious etiologies might provide further insight into the mechanism of AFM."}
+{"text": "Epidemiology of drug resistant HIV has focused on trends and less attention has been given to identification of factors, especially behaviors including substance use, in acquisition of drug-resistant HIV. From 2009 to 2012 The Metromates Study enrolled and followed for one year men who have sex with men (MSM) seeking testing for HIV in a community clinic in Los Angeles assessing those testing positive for acute and recent HIV infection. Behavioral data were collected via Computer-Assisted Self-Interview from 125 classified as newly HIV infected and 91 as chronically infected (newly HIV-diagnosed); specimens were available and viable for resistance testing for 154 of the 216 HIV positives with new diagnoses. In this community clinic we found prevalence of resistance among MSM with new HIV-diagnosis was 19.5% (n = 30/154) with no difference by recency of HIV infection. Sexual partnership characteristics were associated with resistance; those who reported transgendered sex partners had a higher prevalence of resistance as compared to those who did not report transgendered sex partners , while those who reported having a main partner had a lower prevalence of drug resistance . In multivariable analyses adjusting for HIV recency and antiviral use, reporting a main partner decreased odds , reporting a transgendered partnered increased odds ; and being African American increased odds of drug resistance . This suggests African American MSM and TG individuals in Los Angeles represent pockets of exceptional risk that will require special approaches to prevention and care to enhance their own health and reduce their likelihood to support transmission of drug resistance in the US. Among those with a new diagnosis of HIV infection, some are infected by a strain of HIV-1 resistant to one or more drugs, known as primary or transmitted drug resistance (TDR)  but evidBetween 2009\u20132012 321 MSM enrolled in the NIDA funded Metromates Cohort Study conducted at The Los Angeles LGBT Center, a community-based organization providing sexual health services, social services and HIV care in Los Angeles. Men at least 18 years of age reporting sex with a man in the past 12 months who sought HIV testing at the LGBT Center were offered an opportunity to undergo a consent process including a written consent with a full description of the study with choices about if and how to participate in specimen donation, and then were provided a copy of their written consent form . Those who tested HIV-positive provided a specimen for testing of recency of infection using the Vironostika detuned assay (BioSystems Laboratory in San Francisco) a validated assay for use of detection of early HIV infection, 14; negA Computer-Assisted Self-Interview (CASI) assessed sexual partner type ; types of sexual activity ; substance use . Also assessed was use of ARV drugs for treatment, pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), substance use, and sexual behavior. \u201cTreatment status\u201d was determined from reports of date starting ARVs as some men started ARVs before enrollment due to a lag between communication of an HIV positive test result and study enrollment. Initiation of care was not an exclusion criteria for this analysis. The questions and scales used in this study were developed from two previous studies of men with acute HIV infection or previous diagnosis; with careful attention to included comparable questions/measures to the previous cohort that identified behavioral factors associated with resistant HIV \u201317. The http://hivdb.stanford.edu/). Samples were classified as \u201cresistant\u201d if results indicated reduced sensitivity to at least one class of ARVs.HIV genotyping was performed using stored plasma samples collected at study enrollment. The testing of those assessed as acutely infected (n = 104) was conducted at the HIV Genotyping Laboratory at Johns Hopkins University (JHU) and the other new diagnoses at University of California Los Angeles (UCLA) School of Medicine (n = 69). Testing at JHU was conducted using the ViroSeq HIV Genotyping System v2.8 . This system provides HIV sequences for the region encoding HIV protease (amino acids 1\u201399) and HIV reverse transcriptase (amino acids 1\u2013335). Testing at UCLA was done using the UltraSens Viral Isolation kit (Qiagen) according to the manufacturer\u2019s protocol. The Reverse Transcriptase (RT) and Protease (PRO) genes were amplified and sequenced according to the previously published protocol of Snoeck et al. using SuperScript III RT (Invitrogen) for RT and KOD high fidelity polymerase (Novagen) for PCR. PCR products were directly sequenced using the BigDye v3.1 Kit (Applied Biosystems) according to the manufacturer\u2019s protocol using the primers described in Snoeck et al. SequencDifferences in ARV drug resistance to at least one class of HIV drugs by demographics and behaviors were evaluated using t-tests, Wilcoxon rank sum, chi-square methods, Fisher\u2019s exact tests and multivariable logistic regression analysis. Behaviors included in the analyses were selected based on findings from the research team\u2019s previous work with this population and this topic, 17 as wAmong the 154 recently HIV-diagnosed MSM with testable plasma the mean age was 30 years, nearly half identified as Hispanic (48%), followed by white (29%) and African American (17%); 58% were identified as having an acute/recent HIV-infection. The median number of sexual partners in the past 12-months was eight [interquartile range (IQR) 4\u201320], with a median of two anonymous partners and one one-time partner. More than half the participants  reported substance use in the past 3 months, including marijuana (41%), methamphetamine (20%), cocaine (15%), and opioids (3%). Eleven (7%) reported sex with both men and women; and 30 (19.5%) reported a transgender partner in the last 12 months; 30 (19.5%) reported transactional sex in the past 3 months. Between screening and enrollment 30 men (19%) had initiated ARV therapy. Among these HIV positive men more methamphetamine use was reported among newly infected than chronically infected .Drug resistance to at least one class of ARVs was identified in 30 (19.5%) of the 154 participants. Most of the resistance was to NNRTIs: 25/30 cases of resistance. The prevalence of ARV resistance did not vary significantly by HIV diagnosis group  althoughReporting a main partner decreased odds of drug resistance , reporting a transgendered partnered increased odds ; and being African American increased odds of drug resistance .The prevalence of drug resistance of 19.5% among MSM in Los Angeles with new HIV diagnosis is relatively high compared to other reports  even wheThe increased risk of resistance among men who have sex with transgendered (TG) partners is a new finding. TGs represent a marginalized group of individuals among whom adherence to HIV treatment is particularly poor and who Our findings point to the role of the main partner in providing protection against acquiring resistant virus and the increased risk with having casual partners. Clearly the more exposures, the more likely one of these is to someone with a resistant virus. Yet this also suggests that sexual networks are playing an increasingly important role in the transmission of resistance. It points to the need to counsel men without main partners that when they have unprotected sex with casual partners whose HIV status or use of therapy is unknown they may be at higher risk of acquiring resistant virus and that this has the potential to affect their therapeutic options.Our finding that African American MSM were more likely than other MSM in Los Angeles to acquire resistance raises continuing concerns about the epidemic among African American MSM. These men are most likely to acquire HIV in general in the US\u2013with African Americans representing half of all new infections in 2009 and AfriGiven the challenges of enrolling individuals into studies at the time of their HIV diagnosis and identifying those with acute or recent infection in any community, the sample size for this study was relatively small. This limited the power to more sensitively detect factors associated with resistance that were low prevalence. Although the study used computer-assisted interviewing and emphasized the conduct of the study in the most sensitive way for individuals with new HIV diagnosis, behavioral reports are always prone to mis-reporting and that could result in misclassification of participants in the analysis. Finally, the study and was initiated and tools developed in 2008 and earlier, when awareness of and well-developed tools for studying transgender individuals were not yet evolved fully limiting our ability to better study how them.Our findings support the rationale for examining behavioral characteristics of resistance because we could not confirm findings from earlier studies that identified strong use, notably methamphetamine use, as a driver of multi-resistant HIV suggestiThese findings indicate trends in HIV transmission patterns among MSM in Los Angeles. As a case of multi-drug resistant HIV has been documented among an individual on pre-exposure prophylaxis with emtricitabine (FTC)\u2013tenofovir disoproxil fumarate (TDF) that was identified as transmitted and not acquired there cl"}
+{"text": "The mechanistic data presented in this interesting review suggests that long-term exposure to safe levels of ultra-violet radiation (UVR) has protective effects against the development of obesity and cardiovascular dysfunction beyond those induced by the cutaneous synthesis of vitamin D3 through factors such as the induction of cutaneous NO secretion . Evidenc"}
+{"text": "This article contains one NVivo 10\u00ae file with the complete 432 projects design documents (PDD) of seven waste management sector industries registered as Clean Development Mechanism (CDM) under United Nations Framework Convention on Climate Change (UNFCCC) Kyoto Protocol Initiative from 2004 to 2014. All data analyses and sample statistics made during the research remain in the file. We coded PDDs in 890 fragments of text, classified in five categories of barriers (nodes): technological, financial, human resources, regulatory, socio-political. The data supports the findings of author thesis [4] Specifications TableValue of the data\u2022The UNFCCC raw data source is mixed up, disconnected, fragmented, and laborious.\u2022This data is all inclusive . Therefore, any other CAQCA can be immediately made for the WM sector.\u2022The data is standardized by UNFCCC, which means that it can be easily appended, replaced, compared or transposed to the others 14 sectors and 4.000 projects .\u2022The dataset is an instructive example of a Computer Assisted Qualitative Content Analysis (CAQCA) using the features of a CAQCA Software1Despite a clear indication that waste management research needs a more system-oriented approach This data article shares, in a single NVivo 10\u00ae software file, 432 large waste management projects design documents (PDD) from 2004 to 2014 1)the entire PDD documents;2)a qualitative data analysis (QDA) aiming the study of the project's designers declared barriers;3)results of a primary search for the stated barriers (890 text fragments);4)we code (hermeneutic) fragments into five barriers categories: technological, financial, human resources, regulatory, and socio-political.The sample selected from CDM Project Search site of UNFCCC The data is standardized following the main UNFCCC guidelines for any project 2The computer assisted qualitative content analysis (CAQCA) drives the data file design. CAQCA is a well-known methodology largely used in social applied and human sciences The use of software  to treat a large volume of data produced almost in real time had a significant impact on research institutions and doctoral programs because part of those research without the QDAS would be impractical and impossible. This fact explains why the more Universities offers the QDAS at an institutional level The search criteria used to the content selection (raw data) from the UNFCCC Project Search site The projects have many possible statuses . We choose the registered status because no other guarantees UNFCCC consent for the registered operation. At last, the sort by reference number is strategic considering that the computer database key-index system is more reliable than registration date.The results by the host country and year are in the original article There is also an abnormal concentration of 124 projects in 2012 After the simple search for the term \u2018barrier\u2019 that returned more than a thousand occurrences, took place the coding second part by semantic-hermeneutic analysis of fragments. Some of these fragments proof meaningless and discarded. The rest classified in categories for future interpretation and pattern identification."}
+{"text": "Functional neurological changes after surgery combined with diffusion tensor imaging (DTI) tractography can directly provide evidence of anatomical localization of brain function. Using these techniques, a patient with dysgraphia before surgery was analyzed at our hospital in 2011. The patient showed omission of kana within sentences before surgery, which improved after surgery. The brain tumor was relatively small and was located within the primary sensory area (S1) of the inferior parietal lobe (IPL). DTI tractography before surgery revealed compression of the branch of the superior longitudinal fasciculus (SLF) by the brain tumor. These results suggest that the left SLF within the S1 of IPL plays a role in the development of dysgraphia of kana omission within sentences."}
+{"text": "Prostaglandins E2 and F2 alpha  were measured by gas liquid chromatography--mass spectrometry (glc-ms) in extracts of primary tumours from 78 patients with early breast cancer. These levels have been related to factors of established prognostic value and the patients disease-free interval. Although there was a wide variation in amounts of both prostaglandins extracted from different tumours, no significant relationship was observed between levels of prostaglandins and oestrogen receptors (ER), tumour size, presence of lymph node involvement and disease-free interval following primary treatment. It therefore seems unlikely that the level of these particular prostaglandins within breast carcinomas plays a fundamental role in the prognosis of the disease."}
+{"text": "The present study tests whether a combined treatment of acupuncture and transcutaneous electrical nerve stimulation (TENS) is more effective than acupuncture or TENS alone for treating knee osteoarthritis (OA).Thirty-two patients with knee OA were randomly allocated to four groups. The acupuncture group (ACP) received only acupuncture treatment at selected acupoints for knee pain; the TENS group (TENS) received only TENS treatment at pain areas; the acupuncture and TENS group (A&T) received both acupuncture and TENS treatments; the control group (CT) received topical poultice (only when necessary). Each group received specific weekly treatment five times during the study. Outcome measures were pain intensity in a visual analogue scale (VAS) and knee function in terms of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).The ACP, TENS and A&T groups reported lower VAS and WOMAC scores than the control group. Significant reduction in pain intensity (P = 0.039) and significant improvement in knee function (P = 0.008) were shown in the A&T group.Combined acupuncture and TENS treatment was effective in pain relief and knee function improvement for the sampled patients suffering from knee OA. Osteoarthritis (OA) is the most common form of joint disease and most often affects the knee ,2. OA ofThe present study aims to test whether TENS or a combined treatment of acupuncture and TENS is more effective than acupuncture or TENS alone for treating knee OA in older patients.Outpatients aged 60 years or older with knee OA were recruited from the Meiji University of Oriental Medicine Hospital. The patients had been clinically and radiologically diagnosed of knee OA according to the criteria of the American College of Rheumatology. Further inclusion criteria for the present study were: (1) knee pain lasting for six months or longer; (2) no radiation of knee pain; (3) radiographic evidence of at least one osteophyte at the tibiofemoral joint (Kellgren-Lawrence grade \u2265 2); (4) normal neurological functions of lumbosacral nerve, including deep tendon reflexes, voluntary muscle action and sensory function; and (5) not receiving acupuncture treatment for more than six months. Exclusion criteria were: (1) major trauma or systemic disease; and (2) receiving conflicting or ongoing co-interventions. Patients under drug treatment were included if there had been no change in medicine and its dosage for one month or longer. This study was approved by the Ethics Committee of the Meiji University of Oriental Medicine.All enrolled patients gave their written informed consent. According to a block randomised allocation table , the enrolled patients were allocated to (1) the control (CT) group, (2) the acupuncture (ACP) group, (3) the transcutaneous electrical nerve stimulation (TENS) group or (4) the acupuncture and TENS (A&T) group.The design of this study was a randomly controlled clinical trial using a block randomised procedure. Each patient received a total of five treatments, once per week, and follow-up was measured for ten weeks after the first treatment.The CT group patients did not receive any specific treatment, but when necessary, were allowed to use topical poultice containing methylsalicylic acid.Liangqiu (ST34), Dubi (ST35), Zusanli (ST36), Yinlingquan (SP9), Xuehai (SP10) and Yanglingquan (GB34). Disposable stainless steel needles  were inserted into the muscle to a depth of 10 mm using the 'sparrow pecking' acupuncture technique  by acupuncturists who had four years of acupuncture training and three to eight years of clinical experience. When the subject felt dull pain or the acupuncture sensation (de qi) was achieved, the needle manipulation was stopped and the needle was left in place for ten more minutes.The ACP group patients received acupuncture treatment at selected acupoints for 15 minutes on the OA affected knee. The selected acupoints are widely accepted for treating knee pain -13, name2 and 5688 mm2 were respectively placed on the site with the most tenderness and the opposite side of the site. Two electrodes were different in size (ratio: 1:7). The smaller one was placed on the site of tenderness. The intensity of TENS stimulation was adjusted so that a tingling sensation 2\u20133 times of the subject's sensory threshold was produced.The TENS group patients received treatment at the OA affected knee for 15 minutes from a single-channel portable TENS unit , which sends between two electrodes a premixed amplitude-modulated frequency of 122 Hz (beat frequency) generated by two medium frequency sinusoidal waves of 4.0 and 4.122 kHz (feed frequency). Surface disposable electrodes of 809 mmThe treatment for the A&T group combined the treatments for the ACP and TENS groups. The patients received 15 minutes of TENS, and then 15 minutes of acupuncture treatment at the OA affected knee.We confirmed that the patients in all groups did not receive any other co-interventions including analgesics, anti-inflammatory agents or topical hyaluronic acid injection during the study period.Primary outcome measures were: (1) pain intensity, quantified with a 10 cm visual analogue scale  and (2) pain disability measured with the Western Ontario and McMasters Universities Osteoarthritis Index  . The WOMThe VAS scores were measured immediately before the first treatment and subsequently at one, two, three, four, five and ten weeks after the first treatment. The WOMAC scores were measured immediately before the first treatment and subsequently five and ten weeks after the first treatment. Each VAS and WOMAC score was measured immediately before treatment of the specified week.Repeated measures analysis of variance (ANOVA) was used to study the changes in the VAS and WOMAC scores in the three groups. Changes in the time course among groups were considered significant when the interaction was significant at a level of 0.013 (0.05/4). After detection of significant changes in the overall time course with repeated measures ANOVA, pair comparisons were detected with Bonferroni correction. StatView for Windows (version 5.0) or SYSTAT 10 (SYSTAT Inc) was used for the statistical analysis. The results with P values of less than 0.05 were considered statistically significant.A total of 32 patients  were randomly allocated to four groups for specific treatment. Before the treatments, no significant difference was found in baseline variables including age, disease, pain duration, and pain intensity VAS scores among the four groups.i.e. deterioration of symptoms). The total dropout rate was the same in every group. The analyses were performed on the 24 patients who completed the study and provided required information  compared to the CT group during treatment Table . The treThe present study demonstrated that acupuncture and TENS treatments were effective in pain relief. TENS is a common modality for treating musculoskeletal pain . TENS exOur other studies consistently showed that combined treatment of acupuncture and TENS was more effective than separate treatments ,25. TENSThe present study clearly demonstrated that combined acupuncture and TENS treatment is effective for pain relief in terms of VAS and knee function improvement in terms of WOMAC in patients suffering from knee OA. Large scale clinical trials are warranted.ACP: acupuncture group; ANOVA: analysis of variance; OA: osteoarthritis; QOL: quality of life; ROM: range of motion; TENS: transcutaneous electrical nerve stimulation; VAS: visual analogue scale; WOMAC: Western Ontario and McMaster Universities Osteoarthritis IndexThe author(s) declare that they have no competing interests.KI was responsible for study design, acupuncture treatment, manuscript preparation and submission. SH was responsible for patient recruitment. HO was responsible for all statistical design and data analysis. YK was responsible for manuscript review. HK was responsible for study design, critical manuscript review and patient recruitment. All authors read and approved the final manuscript."}
+{"text": "Unique germline mutations in BRCA1 and BRCA2 account for inherited predisposition to breast and ovarian cancer in high-risk families. In Jewish high-risk individuals of Ashkenazi (east European) descent, three predominant mutations, 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations, and two of these mutations (185delAG and 6174delT) are also found at about 1% each in the general Jewish-Ashkenazi population. We identified a novel BRCA1 mutation in two Jewish-non-Ashkenazi families with ovarian cancer: a thymidine to guanidine alteration at position 3053, resulting in substitution of tyrosine at codon 1017 for a stop codon (Tyr1017Ter). The mutation was first detected by protein truncation test (PTT) and confirmed by sequencing and a modified restriction digest assay. Allelotyping of mutation carriers using intragenic BRCA1 markers revealed that the haplotype was identical in these seemingly unrelated families. No mutation carrier was found among 118 unselected Jewish individuals of Iranian origin. Our findings suggest that this novel mutation should be incorporated into the panel of mutations analysed in high-risk families of the appropriate ethnic background, and that the repertoire of BRCA1 mutations in Jewish high-risk families may be limited, regardless of ethnic origin."}
+{"text": "An ascitic form of plasmacytoma (MP-5563) in C3H mice has proved stable on transplantation. A simple linear relationship was demonstrated between the serum level of the paraprotein produced and the total number of plasmacytoma cells within the ascitic fluid."}
+{"text": "The kinetics, specificity and morphology of cytolethal responses have been studied in human glucocorticoid-sensitive and -insensitive lymphoid cell lines (HLCL) and fibroblasts following treatment with high (10(-3)M) and low (10(-6)M) doses of steroid. The high dose cytolethal response appears non-specific occurring in all cell lines with every steroid tested. By contrast, the low dose  cytolethal response requires an active glucocorticoid and a sensitive HLCL. However, both high and low concentrations of steroid induce virtually identical morphological changes in dying cells and similar changes can be induced in cells killed by deliberate feed exhaustion. Although the morphological features in each case resemble apoptosis, the \"programmed\" physiological form of cell death, the intracellular events leading to cytolysis seem likely to differ. The earliest morphological changes presaging cell death comprise rounding up of cells and condensation of nuclear chromatin. Nuclear changes progress rapidly thereafter and appear to result from detachment of chromatin from the nuclear matrix. The low dose cytolethal response requires the continuous presence of glucocorticoid for periods in excess of 24h, prior to which cell growth appears unaffected. The constancy of this latent interval suggests glucocorticoids may influence some replication control mechanism unrelated initially to macromolecular biosynthesis."}
+{"text": "We examined the localization of basic fibroblast growth factor (bFGF) in a series of human breast carcinomas using immunohistochemistry. Staining was observed in tumour cells in 15 out of 54 (28%) tumours and in the adjacent stroma in 34 out of 54 (63%) tumours examined. No correlation was observed between positive staining of these two compartments. The relationship between bFGF staining and expression of the metalloprotease stromelysin-3, and between bFGF and microvessel density, was examined. A statistically significant correlation (P < 0.003) was observed between bFGF staining of the stromal compartment and high expression of stromelysin-3  metalloprotease mRNA by stromal cells. In contrast, no correlation was observed between bFGF and intratumour microvessel density (IMD). These results raise the possibility that bFGF may be involved in the induction of stromelysin-3 mRNA expression in breast cancer stroma."}
+{"text": "Patients treated with tamoxifen (TAM) for primary breast cancer often manifest de novo or acquired resistance, possibly through changes in drug metabolism. Using solid-phase extraction methods and reversed-phase high-performance liquid chromatography separations, levels of TAM and metabolites 4-hydroxytamoxifen (4OH) and desmethyltamoxifen (DMT) have been measured in plasma and tumour tissue from breast cancer patients treated with TAM for at least 3 months. Patients were categorized into those with tumours responding to TAM and those showing de novo or acquired resistance. Levels of TAM, 4OH and DMT in both plasma and tissue samples were correlated with clinical response, length of treatment and patient weight. Interesting results included accumulation of 4OH in tumour tissues over time in all patients, with significance reached in the acquired resistance group. In addition, significantly lower levels of 4OH and DMT were found in plasma taken from responding patients after 3 months of treatment when compared to non-responding patients, and a small group of ER-poor patients showed significantly lower levels of all three species in plasma when compared to other patients. Whilst not explaining TAM resistance in all cases, these differences could account for the development of resistance to TAM treatment in certain subgroups of patients. \u00a9 2000 Cancer Research Campaign"}
+{"text": "A possible variable is the influence of growth conditions on discerning candidates. The present study examined the influence of growth conditions on the expression of chromosome 3 genes in the tumorigenic EOC cell lines, OV-90, TOV-21G and TOV-112D using Affymetrix GeneChipChromosome 3 gene expression profiles  were extracted from U133A expression microarray analyses of the EOC cell lines OV-90, TOV-21G and TOV-112D that were grown as monolayers, spheroids or nude mouse xenografts and monolayers derived from these tumors. Hierarchical cluster analysis was performed to compare chromosome 3 transcriptome patterns of each growth condition. Differentially expressed genes were identified and characterized by two-way comparative analyses of fold-differences in gene expression between monolayer cultures and each of the other growth conditions, and between the maximum and minimum values of expression of all growth conditions for each EOC cell line.An overall high degree of similarity (> 90%) in gene expression was observed when expression values of alternative growth conditions were compared within each EOC cell line group. Two-way comparative analysis of each EOC cell line grown in an alternative condition relative to the monolayer culture showed that overall less than 15% of probe sets exhibited at least a 3-fold difference in expression profile. Less than 23% of probe sets exhibited greater than 3-fold differences in gene expression in comparisons of the maximum and minimum value of expression of all growth conditions within each EOC cell line group. The majority of these differences were less than 5-fold. There were 17 genes in common which were differentially expressed in all EOC cell lines. However, the patterns of expression of these genes were not necessarily the same for each growth condition when one cell line was compared with another.in vivo and in vitro growth conditions of tumorigenic EOC cell lines appeared to modestly influence the global chromosome 3 transcriptome supporting the notion that the in vitro cell line models are a viable option for testing gene candidates.The various alternative  The molecular genetic analysis of ovarian cancer has been facilitated by the establishment and characterization of spontaneously immortalized epithelial ovarian cancer (EOC) cell lines that have been derived from malignant cells by long-term growth in cell culture . In our in vitro EOC cell line models. Recently, our group has reported on global differences in gene expression between EOC cell lines that were cultured as monolayers, spheroids, or nude mouse xenografts suggesting that microenviroment could impact the transcriptome [in vitro model with the potential for identifying and testing chromosome 3 tumor suppressor genes because of extensive loss of heterozygosity of the 3p arm [A possible variable in the application of EOC cell line models is the influence of growth conditions on discerning and then characterizing gene candidates which initially exhibit differential gene expression in criptome . To furtcriptome . We havecriptome ,8,14,15.criptome . Both OVcriptome ,16. Karycriptome ,5. In pae 3p arm  but has The present study was focused on addressing the magnitude and extent of transcriptome modifications for different EOC cell line models that may be influenced by tumor microenvironment. As each cell line exhibits unique molecular genetic characteristics comparisons of chromosome 3 transcriptome modifications were made with respect to gene expression profiles generated with each growth condition within each experimental cell line model.The EOC cell lines were derived from a stage III/grade 3 clear cell carcinoma TOV-21G), a stage IIIc/grade 3 endometrioid carcinoma (TOV-112D), and from the ascites fluid of a stage IIIc/grade 3 adenocarcinoma (OV-90), all from chemotherapy na\u00efve patients, as described [1G, a sta\u00ae HG-U133A microarray analyses of the OV-90, TOV-21G and TOV-112D EOC cell lines that were each grown under different conditions as described previously [. These conditions include monolayer cultures (L), spheroid cultures (S), nude mouse xenografts at subcutaneous (TSC) or intraperitoneal (TIP) sites, and monolayer cultures of subcutaneous (LSC) and intraperitoneal (LIP) xenografts, as described previously [\u00ae experiments, was achieved from the raw expression data using the MAS5 software (Affymetrix Microarray Suite\u00ae) by multiplying the value for an individual probe set by 100 and dividing by the mean of the raw expression values for the given sample data set as described previously [Chromosome 3 gene expression profiles were extracted from normalized Affymetrix GeneChipeviously . The sof and the UniGene Homo sapiens database, based on UniGene Build 198 . Additional mapping information was obtained from the University of California Santa Cruz (UCSC) Human Genome Browser database, March 2006 (NCBI Build 36.1) hg 18 assembly . Based on these databases, 1147 probe sets were identified that mapped to chromosome 3, representing 735 genes and ESTs. Chromosome 3 alignment of probe sets (represented genes) was determined based on the UCSC Human Genome Browser database, where 535 probe sets mapped to genes on the chromosome 3p arm and 612 probe sets mapped to genes on the chromosome 3q arm.The normalized data set was then used to extract the expression profiles associated with probe sets representing chromosome 3 genes. Probe sets corresponding to chromosome 3 genes were identified using the Affymetrix NetAffx Batch Query tool The normalized expression data sets were also rescaled to eliminate systematic biases due to low expression values. Low values with A-calls are considered to be technical noise, which may influence fold-difference comparisons and overestimate expression differences that result from high variability of low expression values. Probe sets containing A-calls may also reflect either absent expression or poorly designed probe sets . To redu. In order to determine the significance of the differential expression, modified t-tests were performed with Bioconductor's limma package, where p-values from the resulting comparison were adjusted for multiple testing as described [genefilter package was used to filter out probe sets with insufficient variation in gene expression across all tested samples for the analysis of each EOC cell line data set. In the remaining expression values, a log base 2 scale of at least 0.5 for the interquartile range was required across all tested samples for each EOC cell line group as described. Hierarchical clustering analysis was performed with R's cluster package, using the Pearson correlation distance.Hierarchical cluster analysis was performed on normalized and rescaled gene expression data analyzed using Bioconductor, an open-source software library for the analyses of genomic data  based onescribed . This meTwo-way comparative analyses based on fold differences of expression values were performed on normalized and rescaled gene expression data derived from each EOC cell line. The expression values with at least one high-reliability score or P call for each EOC cell line sample set  were evaluated in two-way comparative analyses. Differentially expressed genes were defined as those which exhibited at least a 3-fold difference in two-way comparative analyses with expression value for monolayer culture and each growth condition, or between the maximum and minimum value of expression observed within a set of data for each EOC cell line.Hierarchical cluster analysis of chromosome 3 gene expression data from each EOC cell line grown in monolayer cultures (L) and alternative growth conditions such as spheroid cultures (S), nude mouse xenografts at subcutaneous (TSC) or intraperitoneal (TIP) sites, and monolayer cultures of subcutaneous (LSC) and intraperitoneal (LIP) xenografts is shown in Figures To further characterize the gene expression profiles and identify the genes that may be influenced by the growth conditions, we applied a two-way fold-difference comparative analysis approach. As monolayer cultures are often used in molecular genetic assays of cancer derived cell lines, we compared gene expression values of the EOC cell lines grown as monolayer cultures with each of the alternative growth conditions comprised of spheroid cultures (S), nude mouse xenografts at subcutaneous (TSC) or intraperitoneal (TIP) sites, and monolayer cultures of subcutaneous (LSC) and intraperitoneal (LIP) xenografts. We performed two-way comparison analysis based on fold-differences using the expression values which contained at least one high reliability score  per probe set for each EOC cell line. Using this criterion, the expression values of 692 (60.3%), 739 64.4%), and 693 (60.4%) probe sets from the total of 1147 chromosome 3 probe sets for OV-90, TOV-21G and TOV-112D, respectively, were evaluated for fold-differences  of the expression values exhibited by all alternative growth conditions. Two-way comparative analysis was performed between the maximum and minimum values of expression observed for probe sets for each EOC cell line group. A minimum 3-fold cut-off was used to characterize differences in gene expression. Overall less than 23% of probe sets exhibited greater than 3-fold differences in gene expression in this comparative analysis in any EOC cell line group  and both subcutaneous (TSC) and intraperitoneal (TIP) xenografts exhibited the lowest values of expression of this gene  xenograft sample and the lowest value was observed with intraperitoneal (TIP) xenograft  in gene expression in each EOC cell line group tested irrespective of growth condition. It was also reflected in the two-way comparative analyses where a 3-fold cut-off was applied. Although we have previously shown that replicates of Affymetrix GeneChip\u00ae expression data derived from the EOC cell lines grown as monolayer cultures were highly reproducible [\u00ae expression microarrays of the EOC cell lines, we have used a lower threshold level of 15 rather than 50 or 100 depending on the GeneChip\u00ae used [In this study, we described chromosome 3 transcriptome changes for three well characterized EOC cell lines  that each responded differently in relation to various growth conditions such as in three dimensional spheroid culture and nude mouse xenograft models, relative to the conventional monolayer culture. However, the alternative oducible ,6, a lowoducible ,17. Unliip\u00ae used -10. A loip\u00ae used .TP53, whereas TOV-21G harbors a somatic mutation in KRAS and exhibits microsatellite instability. OV-90 also is monoallelic for the 3p arm, however this gross genomic anomaly did not significantly impact on global patterns of gene expression of the chromosome 3p arm as assayed by Affymetrix expression analyses of this cell line and the other EOC cell line used in the present study [The EOC cell line lines exhibited unique patterns of gene expression as shown by the hierarchical cluster analysis. These unique differences are also reflected in a previous global analyses of gene expression from the entire Affymetrix U133A microarray . These Ent study ,15. The ARPC4 and NCK1), cell growth and division (CDC25A and SKIL), and extracellular signaling/cell-cell junctions  (Additional file TMEM158, HEG1, PLOD2 and ATP13A3, were recently found differentially expressed greater than 3-fold in a comparative analysis of primary cultures of normal ovarian surface epithelial cells and malignant serous ovarian tumors [Given the molecular genetic differences in the EOC cell lines, it is not surprising that there were few similarly differentially expressed genes found in common with all of EOC cell lines. Indeed there were only 17 genes in common in all three EOC cell lines which exhibited differential expression greater than 3-fold in all comparative analyses (Additional file in vitro and in vivo growth conditions may all still be significantly different when each is compared with normal cells [S100A6, was found differentially expressed relative to culture conditions and further validated by RT-PCR and immunohistochemistry [in vitro model systems for studying gene candidates, our results in the present study show that a high correlation of gene expression in the transcriptomes generated from ovarian cancer cell lines propagated in different contexts. Overall these results attests to the validity of the EOC cell lines as an in vitro model for studying gene candidates but point out that some genes may be influenced by microenvironment, a factor that should be taken into consideration when investigating the molecular biology of specific genes. As our EOC cell lines are amenable to propagation in alternative growth conditions one could assay and further investigate the magnitude of transcriptional effects for specific candidate genes of interest and their consequences at the protein level to further understand the biological relevance gene expression differences associated with microenvironment.Future experiments are required to determine if the differences observed in the EOC cell lines grown in alternative conditions are biologically relevant or a reflection of experimental design. The magnitude of the differences in gene expression observed in the EOC cell lines grown under the various al cells . The EOChemistry . While tin vivo and in vitro growth conditions affords the opportunity to study gene expression of candidates in contexts that more closely mimic tumor growth in vitro. However, the analyses of chromosome 3 transcriptomes are highly comparable within each EOC cell line context. These observations would argue that gene expression studies using monolayer cultures of ovarian cancer lines is still a viable option for initial studies involving the characterization of gene expression pattern of candidate genes.The ability to culture tumorigenic EOC cells under different The authors declare that they have no competing interests.NALC participated in the study design of expression analysis, performed the data analysis, and drafted the manuscript. MZ performed experiments involving the growth of the EOC cell lines in different conditions. DMP participated in the study design. A-MM-M supervised the growth conditions assays and participated in the study design. PNT conceived the chromosome 3 study and study design, and drafted the manuscript. All authors have read the manuscript and approved the final manuscript.The pre-publication history for this paper can be accessed here:Table S1: Genes exhibiting greater than 3-fold difference in gene expression in common in all EOC cell lines.Click here for file"}
+{"text": "Cytotoxic drug resistance developing after chemotherapy is thought to be the main cause of treatment failure in several human tumours, including small cell lung cancer (SCLC). Cell lines showing drug resistance following prolonged exposure to a single agent frequently acquire resistance to several functionally unrelated drugs, the phenomenon of multi-drug resistance (MDR). Classical MDR is thought to arise from changes effecting a reduction in intracellular availability of cytotoxic drugs. We describe a flow cytometry (FCM) technique to monitor the MDR phenotype in drug resistant variants of SCLC and non-SCLC cell lines. The technique is based on a multiparametric analysis of the nuclear binding of a model chemotherapeutic agent, the fluorescent dye Hoechst 33342 (Ho342), which is capable of supra-vital staining of DNA in intact, viable cells. A laboratory derived drug resistant SCLC cell line, H69/LX4, showed a significant (30%) reduction in nuclear binding compared to the parental line H69/P. Exposure to verapamil (VPL) rapidly increased (within 2 min) nuclear binding of Ho342, and the new equilibrium of nuclear staining, attained within 20 min, remained lower than the level achieved in the parental cell line, suggesting some ability of H69/LX4 to limit the effect of the drug efflux blocker. A drug resistant large cell carcinoma line showed only a small reduction (10%) in nuclear binding when compared to the parent line, and this difference was not altered by VPL. A drug resistant adenocarcinoma line showed less than 10% difference in nuclear binding compared with the parental line and neither line was significantly affected by VPL treatment. Our findings suggest that different mechanisms of resistance may occur in lung tumours of different tissue types. This technique may be extended to the rapid and direct examination of biopsy specimens of human solid tumours for evidence of multi-drug resistance."}
+{"text": "Several cobalt(II), copper(II) and nickel(II) complexes of nicotinoylhydrazine-derived compounds were prepared and characterised by physical, spectral and analytical data. These compounds and their complexes have proven to be antibacterial. The screening data show the metal complexes to be more potential/bactericidal than the uncomplexed compounds against one or more bacterial species."}
+{"text": "From 1980 through 1988, biliary surgery was performed in 197 patients with acute gallstone disease andconcomitant elevation of serum glutamic oxalacetic transaminase (SGOT) or serum glutamic pyruvictransaminase (SGPT) of over 300 Karmen units. In 137 patients, anatomic inspection and liver biopsywere performed during the acute stage of the disease. Impacted and floating bile duct stones were foundin 69 (50%) and in 43 (32%) of the 137 patients, respectively. The main liver histology was necrosis ofliver cells. After surgery, high serum transaminase fell rapidly with immediate recovery in 99% of thepatients. In the remaining 60 patients, their signs and symptoms settled soon after initial conservativetreatment and surgery was performed after an average time of 21 days. At laparotomy, impacted bileduct stones were found in 2 (3%) and liver histology revealed regeneration of liver cells.\t\tThese findings suggest that marked elevation of serum transaminase in patients with acute gallstonedisease might be due to an acute inflammatory liver cell injury caused by impacted bile duct stones ormigrating stones, which would be transient and reversible after early resolution of the bile ductobstruction."}
+{"text": "As these complexes are candidates for a novel class anti-HSV drugs, further studies on their mutagenicity are of particular interest. In the present paper we present data showing that Zn(pic)2 and Zn(asp)2 do not express mutagenic effect in both prokaryotic  and eukaryotic (Saccharomices cerevisiae) test systems.Former studies showed that complexes of Zn(II) with picolinic and with aspartic acids, Zn(pic)"}
+{"text": "Radiotherapy of tumours proximal to normal CNS structures is limited by the sensitivity of the normal tissue. Prior to the development of prophylactic strategies or treatment protocols a detailed understanding of the mechanisms of radiation induced CNS toxicity is mandatory. Histological analysis of irradiated CNS specimens defines possible target structures prior to a delineation of cellular and molecular mechanisms. Several lesions can be distinguished: Demyelination, proliferative and degenerative glial reactions, endothelial cell loss and capillary occlusion. All changes are likely to result from complex alterations within several functional CNS compartments. Thus, a single mechanism responsible cannot be separated. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; (4) generalized alterations of cytokine expression. Several underlying cellular and molecular mechanisms involved in radiation induced CNS toxicity have been identified. The article reviews the currently available data on the cellular and molecular basis of radiation induced CNS side effects. \u2002\u2002http://www.bjcancer.com \u00a9 2001 Cancer Research Campaign"}
+{"text": "To evaluate visual outcome following pars plana vitrectomy (PPV) and intraocular foreign body (IOFB) removal through the sclerocorneal tunnel combined with simultaneous cataract extraction and sulcus-fixated intraocular lens (IOL) implantation as a single procedure in penetrating ocular trauma with IOFB and traumatic cataract.Eighteen cases of penetrating ocular trauma with retained IOFB and traumatic cataract who underwent PPV, IOFB body removal and cataract extraction with posterior chamber IOL (PCIOL) implantation in the same sitting, between June '04 and December '05 were retrospectively analyzed. All the foreign bodies were removed through the sclerocorneal tunnel.All the 18 patients were young males, with an average follow-up period of 12 months. In 12 cases the foreign body was intravitreal and in six cases it was intraretinal but extramacular. Thirteen cases had a best corrected visual acuity ranging from 20/20 to 20/60 at their last follow-up. Five cases developed retinal detachment due to proliferative vitreoretinopathy (PVR) changes postoperatively and were subsequently managed by surgery.Primary IOL implantation with combined cataract and vitreo-retinal surgery is a safe option reducing the need for two separate surgeries in selected patients with retained IOFB and traumatic cataract. This combined procedure provides good visual outcome with early rehabilitation in young working patients. Open globe injury with or without intraocular foreign body (IOFB) often has a poor visual outcome owing to possible endophthalmitis and/or vitreo retinopathy with the varied and unsterile wounds associated with it.\u20133 ManageMethods for removal of the traumatic cataract include lensectomy, conventional extra-capsular cataract extraction (ECCE), manual small-incision cataract surgery (SICS) and phacoemulsification. Unlike lensectomy other methods of cataract extraction offer a better visual rehabilitation because of implanted intraocular lens (IOL).\u20138 Most sTo avoid such complications, in this series we performed cataract extraction by manual SICS , removed the foreign body through the same tunnel and implanted a posterior chamber IOL (PCIOL) over the anterior capsular rim. The aim of the study was to evaluate visual outcome following pars plana vitrectomy (PPV) and IOFB removal through the sclerocorneal tunnel combined with simultaneous cataract extraction and sulcus-fixated IOL implantation as a single procedure in penetrating trauma with IOFB and traumatic cataract.Medical records of patients with penetrating eye injury and IOFB attending the retina clinic between June 2004 and December 2005 were reviewed. Out of 28 consecutive patients, 10 patients were excluded from this study because of absence of cataract, presence of associated endophthalmitis, severely injured lens with vitreous in the anterior chamber and evidence of zonular dehiscence.Eighteen patients with clinically significant lens opacification and IOFB with or without concomitant vitreoretinal pathology were included in the study. Primary repair was done in all cases except three, where the wound was self-sealed and they were taken up for vitreoretinal procedure directly. All patients underwent a complete general ophthalmologic examination prior to the surgical procedure. Preoperative visual acuity, site of entry of foreign body (FB), capsular and zonular integrity was assessed. Ultrasound B-Scan and/or X-ray of orbit were performed in all patients to locate and evaluate the IOFB. Keratometry and biometry of the injured eyes were done. If keratometry and biometry was not possible on the injured eye, fellow eye measurements were used. In all cases manual SICS was performed before the vitreoretinal procedure. A 6 mm frown-shaped sclerocorneal tunnel was made, followed by continuous curvilinear capsulorrexis and hydrodelineation. The lens nucleus was prolapsed into the anterior chamber and removed through the tunnel by sandwich method.\u201311 Rest 12Sclerotomies and conjunctiva were closed with 6-0 vicryl and 2 mg dexamethasone and 2 mg gentamicin sulphate were injected subconjunctivally. Postoperatively all patients received topical antibiotics and steroid for four weeks with gradual tapering. Oral ciprofloxacin 500 mg twice daily along with nonsteroidal anti-inflammatory agents was given in all cases with addition of systemic steroids when necessary. In each case recording of best corrected visual acuity (BCVA), intraocular pressure measurement, slit-lamp biomicroscopy and indirect ophthalmoscopy was done postoperatively. Cause of decreased vision was assessed considering site of entry of FB, site of lodgment of FB and postoperative complications like RD in each case.All our patients were young males with mean age of 24.5 years. The minimum follow-up period was four months, the maximum being 18 months with median follow-up time of 12 months. In 12 out of 18 cases the FB was intravitreal and in six cases it was intraretinal but extramacular. Thirteen out of 18 cases had BCVA between 20/20 and 20/60. Anatomical success was achieved in 13 out of 18 cases with 11 patients having visual acuity 20/30 or better with first vitreoretinal procedure. With the second vitreoretinal procedure four out of five patients had anatomical success .et al.[We reviewed the visual outcome and complications in 18 patients with penetrating intraocular injury, significant cataract and retained IOFB, who underwent manual SICS, PPV, removal of IOFB and implantation of PCIOL. This simultaneous procedure was chosen to get rid of cataract, which diminished the visualization of posterior segment and for prevention of lens-induced uveitis due to a ruptured lens capsule. We found no significant correlation in \u2018duration between injury and vitreoretinal procedure\u2019 which is well supported by other studies.14\u201319 ButSclerocorneal tunnel and sclerotomy have their advantages and disadvantages as a route for removal of IOFB. Enlargement of sclerotomy carries risk of hypotony, vitreous hemorrhage, peripheral vitreous incarceration into the wound intraoperatively, and RD postoperatively. Removal of the FB through sclerocorneal tunnel may damage or sacrifice the integrity of the posterior lens capsule and anterior capsular rim, but large FBs are easily removed through the sclerocorneal tunnel.\u201319et al.[et al.[et al.[et al.[Except few isolated case reports with large IOFBs, so far there is no data on removal of cataract and FB through the same route. In our experience, IOFB can be safely removed through the sclerocorneal tunnel and IOL can easily be implanted into the cilliary sulcus. In our study, the final BCVA was 20/30 or better in seven out of 18 cases, between 20/40 and 20/60 in six cases and counting finger (CF) at 1 meter (1 m) or less in five cases. This was very well comparable with similar studies.\u201381314 Az813et al. reportedl.[et al. reportedLate onset of RD in our series was seen in five out of 18 cases. The incidence of RD in the intraretinal FB group in this series was seen in five out of six cases. The possible causes of this overwhelming incidence of RD in the intraretinal FB group might be increased manipulation of FB and retinal penetration increasing the chance of proliferative vitreoretinopathy (PVR) changes postoperatively. These ch3Combined cataract and vitreous surgery with FB removal and IOL implantation offers not only faster visual rehabilitation but also24According to our clinical experience, the surgery that combines cataract extraction, IOFB removal and IOL implantation is a safe and desirable operation in patients with IOFB and significant lens opacities. The main advantage of this procedure is rapid visual rehabilitation with a single surgery, reducing the cost and patient discomfort. Randomized controlled studies involving larger number of patients with longer follow-up period may be needed to establish these facts."}
+{"text": "A population-based case-control study of oral contraceptive use and breast cancer was carried out among young women (less than 43 years of age) at Group Health Cooperative of Puget Sound, Seattle, Washington. Use of oral contraceptives before first pregnancy did not materially differ between cases or controls. The rate ratio estimate of breast cancer incidence in women who had used oral contraceptives before first pregnancy compared to those who had not was 0.9 . There were no meaningful patterns of association between breast cancer and duration of use or formulation of oral contraceptive used before first pregnancy."}
+{"text": "Connective tissue growth factor (CTGF) is a major chemotactic and mitogenic factor for connective tissue cells. The amino acid sequence shares an overall 28\u201338% identity to IGFBPs and contains critical conserved sequences in the amino terminus. It has been demonstrated that human CTGF specifically binds IGFs with low affinity and is considered to be a member of the IGFBP superfamily (IGFBP-rP2). In the present study, the expression of CTGF (IGFBP-rP2) in human leukaemic lymphoblasts from children with acute lymphoblastic leukaemia (ALL) was investigated. RNA samples from tumour clones enriched by ficoll separation of bone marrow or peripheral blood mononuclear cells (MNC) from 107 patients with childhood ALL at diagnosis and 57 adult patients with chronic myeloid leukaemia (CML) were studied by RT-PCR. In addition MNC samples from children with IDDM and cord blood samples from healthy newborns were investigated as control groups. Sixty-one percent of the patients with ALL (65 of 107) were positive for CTGF (IGFBP-rP2) expression. In the control groups, no expression of CTGF (IGFBP-rP2) in peripheral MNC was detected, and in the group of adult CML patients only 3.5% (2 of 57) were positive for this gene. The role of CTGF (IGFBP-rP2) in lymphoblastic leukaemogenesis requires further evaluation, as does its potential utility as a tumour marker. \u00a9 2000 Cancer Research Campaign"}
+{"text": "The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies."}
+{"text": "Immunohistochemical, cytochemical and ultrastructural data showing vivid angiogenesis and numerous mast cells (MCs) in the bone marrow of 24 patients with active multiple myeloma (MM) compared with 34 patients with non-active MM and 22 patients with monoclonal gammopathy of undetermined significance (MGUS) led us to hypothesize that angiogenesis parallels progression of MM, and that MCs participate in its induction via angiogenic factors in their secretory granules. \u00a9 1999 Cancer Research Campaign"}
+{"text": "The performance of the Lung Imaging Fluorescence Endoscope (LIFE) system was compared with conventional bronchoscopy in 158 patients: 68 patients with invasive cancer, 42 patientswith abnormal sputum cytology findings (12 early cancer and 26 dysplasia), 17 cases withresected lung cancer and 31 smokers with symptoms. The respective results of conventionalbronchoscopy and LIFE for detection of dysplasia were; sensitivity 52% and 90% (biopsybasis), 62% and 92% (patient basis). Fluorescence bronchoscopy may be an importantadjunct to conventional bronchoscopy to improve the localization of subtle lesions ofbronchus."}
+{"text": "Preoperative bronchoscopic findings of thyroid carcinoma with tracheal invasion wereexamined and compared with the histopathological findings. Tracheal sleeve resectionwas performed in 20 cases. The bronchoscopic findings were classified into 5 types:confirmed tumor in the tracheal lumen (5 cases), extramural compression of the tracheaplus mucosal change (9 cases), extramural compression of the trachea (2 cases), mucosalchanges only (3 cases), normal findings (1 case). Pathological findings revealed that theextent of invasion in the tracheal wall varied according to each of the above bronchoscopictypes. The number of tracheal rings with adventitial invasion averaged 0.8 (maximum2) more than preoperative bronchoscopic findings of the number of tracheal ringswith mucosal invasion. This study demonstrated the necessity of resective 2 more trachealrings than is indicated by the bronchoscopic findings."}
+{"text": "Recently trans-dicarboxylato platinum(IV) complexes with mainly acetate,trifluoracetate or short-chain carboxylate groups (<11 carbons) in the axial position have beendescribed in the literature. In this paper we report on the synthesis and characterization of a new class of ethylenediamineplatinum(IV) compounds that have high lipophilic long-chain carboxylate ligands either in the axialor equatorial position. The platinum(IV) compounds with the lipophilic trans-carboxylate ligands inthe axial position were prepared by acylation of the trans-dihydroxo platinum(IV) species using anacyl halide in the presence of pyridine. In contrast to previous publications[1] the yields wereexcellent (up to 94%!).A series of new ethylenediamine (en) platinum(IV) complexes of the type Pt"}
+{"text": "A slowly progressive Heymann nephritis (SPHN) was induced in three groups of rats by weekly injections of a chemically modified renal tubular antigen in an aqueous medium. A control group of rats received the chemically unmodified version of the antigen in an aqueous solution. One group of SPHN rats were pre- and post-treated with weekly injections of IC made up of rKF3 and rarKF3 IgM antibody at antigen excess (MIC) . One group of SPHN rats were post-treated with MIC 3 weeks after the induction of the disease and one group of SPHN animals received no treatment. The control group of rats received pre- and post-treatment with sonicated u/c rKF3.            The incidence of immune-complex glomerulonephritis (ICGN) in the untreated SPHN rats was 87%, in the pre- and post-treated animals 13%, and in the post-treated-only rats 20%. Rats receiving sonicated ultracentrifuged rKF3 antigen did not develop ICGN.            The present experiment demonstrates that the development of SPHN can be not only prevented but also effectively terminated by our newly developed modified vaccination             technique."}
+{"text": "In the present study we describe the effect of Zn(pic)2 and Zn(asp)2 on thereplication of VZV and on the infectivity of free virions. The experiments are done using BHK-21cells, a clinical isolate of VZV and Zn-complexes in concentration of 10 \u03bcM. When Zn-complexesare present during the whole period of infection, the yield of infectious virus progeny decreases upto 98%. The infectivity of VZV is completely restored after the removal of zinc. The virucidal effect ismanifested at the 2nd h of contact, when 90% of the virions are inactivated. The results show thatboth Zn(pic)2 and Zn(asp)2 specifically inactivate free VZV virions with no effect on viral replication.Zn(II) picolinate and aspartate, Zn(pic)"}
+{"text": "In vivo and in vitro antitumour activity of Htbh,Thiiobenzyhdrazide (Htbh) and its Cu(II) complexes,"}
+{"text": "Evidence in the literature suggests that hyperthermia (HT) or inhibitors of calmodulin can increase the sensitivity of rodent cells to bleomycin (BLM) by interfering with DNA repair functions. In an attempt to explore methods of improving the efficacy of thermochemotherapy we have investigated the individual and combined effects of HT (44 degrees C) and the calmodulin inhibitor trifluoperazine  on early plateau phase monolayer cultures of mouse EMT6 tumour cells for simultaneous exposures to BLM. Early plateau phase cultures are relatively resistant both to HT and to BLM. The selected HT and TFP regimens  were non-toxic. Comparing the sensitizing effect (given by the ratio: Do BLM/Do BLM + modifier) of the various regimens on BLM-treated cells, we found that: TFP alone had a marginal effect (ratio 1.3), HT alone showed significant potentiation (ratio 19) and the combination of HT and TFP strongly sensitized (ratio greater than 110) cells to BLM cytotoxicity. We propose that the use of calmodulin inhibitors in thermochemotherapy is worthy of further evaluation."}
+{"text": "To the Editor: Verotoxin-producing Escherichia coli (VTEC) of serogroup O157 causes severe gastrointestinal and renal illness; clinical signs may be mild diarrhea, hemorrhagic colitis, or hemolytic uremic syndrome (HUS). Typically, 10%\u201315% of reported VTEC infections quickly progress to HUS  identified 18 cases of verotoxin-producing SF-O157 infection in Scotland, 13 of which were associated with a nursery. HUS developed in 8 of the 18 patients; those with thrombotic microangiopathy were admitted to the renal unit of a specialist pediatric hospital, which immediately reports cases of HUS to HPS as part of national surveillance (t test showed that nadirs for serum albumin were significantly higher for children with SF-O157 HUS (p = 0.03;  Statistical analysis by  Our study highlights a number of lessons. Medical practitioners rarely have the opportunity to recognize patients at such an appreciable and predictable risk of progressing rapidly to anuric renal failure as they do when they see children with early O157 infection. Failure to appreciate the potential gravity of O157 infection and the possible development of HUS may result in avoidable illness and even death. Our investigation of the prehospital management of SF-O157 and non\u2013SF-O157 in this cohort found no difference in pharmacologic intervention or duration of delay in admission to hospital.Our study has limitations. A number of patients in the cohort were prescribed antimicrobial drugs and/or antimotility drugs or were sent home from the local hospital without hospital admission or further monitoring; such actions potentially exacerbate clinical outcomes (Our data suggest that infection with SF-O157 results in less severe colitis than does the more common non\u2013SF-O157 infection. Less severe colitis could result in a lower risk for renal disease because less verotoxin would be translocated into the bloodstream and bound to the kidneys. However, patients infected with SF-O157 had anuria for longer periods and consequently had longer sessions of peritoneal and hemodialysis. Although unknown bacterial or host inflammatory cytokines may contribute to enhanced disease progression, this observation is surprising and requires further investigation. Additional research is needed to learn more about the virulence of SF-O157 strains and establish other host factors that contribute to disease progression."}
+{"text": "A total of 85 spontaneous rat fibrohistiocytic tumours were evaluated histologically and assessed for the presence or absence of metastases. The overall incidence in controls from 2-year carcinogenicity studies was 2.7%. The tumours occurred principally in the subcutaneous and deep soft tissues, and generally appeared after 18 months of age. Four histological types were recognized: histiocytic (17%), pleomorphic (33%), cellular (17%) and very fibrous (33%). Histiocytic tumours were highly malignant, and most produced metastases. Pleomorphic and cellular neoplasms occasionally produced metastases and must be regarded as potentially malignant. Very fibrous lesions were essentially benign. The close resemblance, both histologically and biologically, between rat and human fibrohistiocytic neoplasms supports the use of the fibrohistiocytic concept in laboratory-animal pathology. Study of these rat tumours may provide insight into the development of human fibrohistiocytic neoplasms."}
+{"text": "Serum carcinoembryonic antigen (CEA) concentrations were found to be raised in 28 of 72 black patients (39%) with hepatocellular cancer (HCC). The degree of elevation was slight or moderate, except in 3 patients in whom values greater than 20 ng/ml were recorded. No significant correlation could be demonstrated in individual patients between the serum CEA concentration and various tests of liver function. The mean CEA value in the patients with cirrhosis in the non-tumorous liver was slightly higher than that in those without cirrhosis, but the difference did not reach statistical significance. There was no correlation between serum CEA and alpha-foetoprotein (AFP) levels."}
+{"text": "The effects of histone deacetylase inhibitor (HDACi) treatment on SV40 transcription and replication were determined by monitoring the levels of early and late expression, the extent of replication, and the percentage of SV40 minichromosomes capable of transcription and replication following treatment with sodium butyrate (NaBu) and trichostatin A (TSA).The HDACi treatment was found to maximally stimulate early transcription at early times and late transcription at late times through increased numbers of minichromosomes which carry RNA polymerase II (RNAPII) transcription complexes and increased occupancy of the transcribing minichromosomes by RNAPII. HDACi treatment also partially relieved the normal down-regulation of early transcription by T-antigen seen later in infection. The increased recruitment of transcribing minichromosomes at late times was correlated to a corresponding reduction in SV40 replication and the percentage of minichromosomes capable of replication.These results suggest that histone deacetylation plays a critical role in the regulation of many aspects of an SV40 lytic infection. Structural and biological changes in chromatin structure are brought about by changes in the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) which add or remove acetyl groups from lysine residues on histone tails respectively. It has been well established that inhibition of HDAC activity is characterized by two important changes within the cell (i) an increase in the amount of hyperacetylated histones  and (ii)Streptomyces and a potent inhibitor of HDAC activity. NaBu has been extensively used as a HDAC inhibitor (HDACi), though it is far less efficient (required in millimolar quantities) in its inhibition capabilities as compared to TSA (required only in nanomolar quantities). DNA micro array studies have shown that almost 7 % to 10% of genes undergo altered gene expression on HDACi using TSA   for one hour. The cells were then washed twice in chilled PBS and extracted using the Hirt method of viral DNA extraction  or RPA 70 [replicating Minichromosomes]). \u0394CT was expressed either as a percentage of minichromosomes containing the epitope for a particular antibody. Statistical analysis was performed using two tailed Student's t test.\u00ae polyacrylamide gel  under denaturing conditions and electroblotted onto PVDF membrane . Antibodies used for western blotting were goat polyclonal anti GAPDH (sc-20357); Santa Cruz Biotechnology; rabbit GST-fusion anti VP1 [Protein extracted from untreated, NaBu treated and TSA treated 48 hour wild type 776 SV40 virus infected cells were harvested and lysed using 1\u00d7 RIPA buffer. Protein levels were determined with the Micro BCA\u2122 Protein Assay kit . The proteins were separated on a 4\u201320% PAGEranti VP1  and antiRNAP II: RNA Polymerase II, NaBu: sodium butyrate; TSA: trichostatin A; HDACi: HDAC inhibitors; ISF: immune selection and fragmentation; ISFIP: ISF followed by a second immunoprecipitation; ReChIP: re-chromatin immunoprecipitation; GAPDH: glyceraldehydes-3-phosphate dehydrogenase; VP1: viral protein 1; P.I.: post-infectionThe author(s) declare that they have no competing interests.LB performed the experiments and wrote the manuscript. BM edited the manuscript and provided input into the experiments. Both authors read and approved the final manuscript."}
+{"text": "To test the role of serotonin in chemotherapy-induced nausea and emesis, ten cancer patients were pretreated with the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA). PCPA (2 g 8 hourly for 2 or 3 days prior to cisplatin) reduced the spontaneous urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), inhibited the increase in urinary 5-HIAA induced by cisplatin and markedly attenuated the acute period of nausea and vomiting associated with the cytotoxic drug. These results indicate that gastrointestinal serotonin mediates cisplatin-induced emesis and that the amount of serotonin released by cisplatin is a major factor in determining the severity of the acute period of emesis experienced by the patient."}
+{"text": "Between January 1981 and December 1985, 122 patients with non-seminomatous germ cell tumours (NSGT) were seen at a regional referral centre. Of these, a total of 98 patients received chemotherapy for metastatic disease. Treatment was given within collaborative EORTC Urology group studies, all of which involved cis-platin-containing schedules. Ninety patients had tumours of testicular origin, and their 2 year actuarial survival rate is 91%; 8 had tumours of extragonadal origin and their 2 year actuarial survival is 25%. Patients with testicular tumours were subdivided by volume of metastatic disease using the recommendations of the Testicular Cancer Subgroup of the MRC Urological Cancer Working Party and survival was significantly worse in the group with very large volume metastatic disease  compared with the groups with large volume metastases  and small volume metastases . There were 31 patients with Stage I disease at presentation; of these 6 were treated by prophylactic abdominal radiotherapy and 25 were managed by a policy of surveillance only. Seven of these Stage I patients (23%) relapsed with metastatic disease (median 8 months); all have been successfully treated with chemotherapy. These data confirm that the majority of patients now presenting with metastatic NSGCT are curable with chemotherapy, but that a small proportion with very large volume metastases or extragonadal tumours require alternative chemotherapy schedules."}
+{"text": "Cytological studies in the light microscope showed that thioacetamide (TAA) depressed the mitotic index in cultures of skin fibroblasts at the lowest concentrations used (100 \u03bcg/ml). At high concentration (1 mg/ml), TAA tended to cause aberration in nuclear morphology. Ethylenethiourea (ETU) had no effect on either mitotic index or nuclear morphology at 1 mg/ml. Fibroblast cultures treated with 1 mg/ml TAA and cultures grown in the presence of 2 mg/ml ETU were studied by electron microscopy. In some TAA-treated cells there was unfolding of the nuclear membrane and enlargement and granulation of the nucleolus, but these effects were not correlated. In all cells, TAA caused severe and characteristic damage to the majority of mitochondria, whether or not there were nuclear aberrations. The organelle showed extensive swelling of the cristae of the inner membrane and an increase in matrix density. Ultrastructure of other cell components appeared to be unaffected by this treatment. In ETU-treated cells some less severe swelling of inner mitochondrial membranes was seen and only in a minority of cells, whilst all other cell structures appeared normal. Similar membrane swelling and increase in matrix density was seen in isolated rat liver mitochondria after incubation with TAA, indicating a direct antimitochondrial effect of the carcinogen.When yeast cells were treated with TAA and ETU, primary antimitochondrial activity of these compounds was apparent from (1) inhibition of growth in non-fermentable medium, (2) selective blockage of mitochondrial protein synthesis and (3) induction of mitochondrial mutations. TAA was much more effective than ETU in all these respects."}
+{"text": "Sir,In a recent letter criticising one of several IARC Interphone studies investigating possible associations between mobile phone use and brain tumour risk, Editors NoteThe Editor-in-Chief of British Journal of Cancer now considers the correspondence published in Volume 94 Issue 9 and above closed."}
+{"text": "Purpose: Soft tissue sarcomas (STS) account for less than 1% of all malignancies and constitute a heterogeneous tumor entity in which malignant fibrous histiocytomas (MFH) represent one-third and are characterized by a lack of type-specific differentiation. A defective mismatch repair (MMR) system cause the familial cancer syndrome hereditary non-polyposis colorectal cancer (HNPCC), and since occasional MFH have been described in HNPCC patients we assessed the contribution of defective MMR to the development of MFH.Methods: MMR status was characterized in a series of 209 histopathologically reviewed MFH. Tissue microarray sections from the tumors were immunohistochemically stained for the MMR proteins MLH1, MSH2 and MSH6, and cases with aberrant staining were further characterized for microsatellite instability.Results and Discussion: Two of the 209 STS\u2013a storiform-pleomorphic MFH and a myxofibrosarcoma\u2013showed concomitant loss of MSH2 and MSH6, but retained staining for MLH1 on both cases. The myxoid tumor also had a microsatellite unstable phenotype. These findings, together with previous observations of defective MMR in pleomorphic STS, indicate that these tumors may be part of the HNPCC-associated tumor spectrum and demonstrate that MMR defects occur in a small subset of STS."}
+{"text": "Girls who engage in strenuous physical activity are often amenorrheic and have recently been reported to be at a reduced risk of breast cancer. To determine whether moderate amounts of exercise affect menstrual cycle patterns and ovulatory frequency in young postmenarcheal girls, the menstrual cycles and physical activity patterns of 168 high school girls were monitored for a 6 month period. Anovulatory cycles were associated with later age at menarche, fewer elapsed years since menarche and greater levels of energy expended per week in physical activity. After adjusting for age at menarche and years since menarche, there was a significant dose-related trend in the risk of anovular menstrual cycles associated with increasing levels of physical activity (1-sided P = 0.03). Major determinants of average cycle length were weekly average energy expenditure , age at menarche (an increase of 0.7 days per year of age) and race (Asians having cycles about 1.9 days longer than Caucasians). Because a major determinant of breast cancer risk may be the cumulative number of ovulatory cycles, these data suggest that regular participation in moderate physical activity, by reducing the frequency of ovulatory cycles in adolescence, may provide an opportunity for the primary prevention of breast cancer."}
+{"text": "The structure of circulating chromogranin A (CgA) of phaeochromocytoma patients was characterised and compared with that of CgA extracted from tumours. Size exclusion chromatography experiments provided evidence that CgA is present in the blood of different patients, as well as in tumour extracts, as multiple forms having different hydrodynamic sizes of 600 kDa (CgA-I), 100 kDa (CgA-II) and 55 kDA (CgA-III). The amount of each CgA form as a proportion of the total antigenic material was different in different patients. Western blot analysis of chromatographic fractions indicated that these forms are made up by polypeptides of similar molecular weight (about 60-70 kDa). All CgA forms express the epitopes recognised by two monoclonal antibodies (A11 and B4E11), directed against residues 68-70 and 81-90 of human CgA. However, their relative immunoreactivity was markedly different. No evidence for the presence of multimeric complexes in the CgA-I fraction was obtained by various immunological and biochemical methods. These results suggest that circulating CgA in phaeochromocytoma patients consists of at least three forms that appear to be made up by polypeptides with similar molecular weight and different hydrodynamic properties and immunoreactivity. We hypothesise that different conformations and shapes contribute to the heterogeneity of circulating CgA."}
+{"text": "After the 1999 West Nile (WN) encephalitis outbreak in New York, 2,300 overwintering adult mosquitoes were tested for WN virus by cell culture and reverse transcriptase-polymerase chain reaction. WN viral RNA and live virus were found in pools of Culex mosquitoes. Persistence in overwintering Cx. pipiens may be important in the maintenance of WN virus in the northeastern United States."}
+{"text": "The prevalence of primary liver cancer (PLC) varies throughout the world. It has been attributed to variations in incidence of the predominant histological type, hepatocellular carcinoma (HCC). The incidence of PLC types other than HCC such as cholangiocellular carcinoma (CCC) is far less known, especially in low-incidence areas. The aetiology of HCC and other PLC types is obscure, with the exception of the association between HCC and cirrhosis as well as chronic viral hepatitis. The present retrospective incidence and aetiology study concerns a well-defined population from a period with a high autopsy frequency. Preserved biopsy specimens were re-evaluated histopathologically and patient records were studied. Among 590 histologically verified cases of PLC, HCC constituted 90%, CCC 8% and a mixed form of these types 1%. At the end of the study period the annual age-standardised incidence rate of HCC was 3.6 cases per 100,000 inhabitants. Other PLC types were hepatoblastoma (n = 3), fibrolamellar carcinoma (n = 2), angiosarcoma (n = 1) and infantile haemangioendothelioma (n = 1), each constituting less than 1% of the PLC cases. Comparing HCC with CCC we found that cirrhosis (70%) and alcoholism (21%) was significantly more frequent in HCC, and cholelithiasis was significantly more common (60%) in patients with CCC. In the majority of the PLC cases with liver cirrhosis this disorder was unknown before diagnosis of the tumour."}
+{"text": "Malignant pericarditis, when associated with massive pericardial effusion, presents a critical condition in lung cancer patients. Because this condition often arises in terminally ill patients, intensive therapy such as multi-drug combination chemotherapy is rarely appropriate. This study evaluated the clinical relevance of intrapericardial administration of carboplatin for controlling malignant pericardial effusions associated with non-small-cell lung carcinoma (NSCLC). The method used for 10 eligible patients consisted of draining the pericardial effusion and infusing 300 mg/body of carboplatin in 50 ml of saline through an in-place catheter into the pericardial space and clamping the catheter for 40 min. Nine of the 10 patients showed satisfactory results, and 8 experienced complete regression of the effusion. No major or minor adverse effects were observed. Pharmacokinetics analysis revealed that the concentration of free platinum in the pericardial fluid was very high while that of total platinum in the circulating plasma was very low, assuring the usefulness of the intrapericardial instillation of carboplatin in terminally ill patients for controlling malignant pericardial effusion when the systemic delivery of cytotoxic agents is inappropriate. \u00a9 2000 Cancer Research Campaign"}
+{"text": "The present study evaluated serial serum measurements of tissue polypeptide-specific antigen (TPS) in comparison with prostate-specific antigen (PSA) for assessment of tumour progression in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS). Twenty-three men were recruited into an IAS trial consisting of an initial 8 months of androgen suppression, followed by cycles of treatment cessation and resumption of therapy upon increases of PSA > 20 ng ml(-1) to prolong the hormone responsiveness of the tumour cells. Periods of androgen suppression resulted in reversible reduction in serum testosterone (< 1.8 nmol I(-1)) and PSA (< 4 ng ml(-1)) and decreases in tumour volume (mean reduction for first cycle 24 +/- 10%), indicating partial growth arrest and apoptotic regression of the tumours. In contrast to PSA values, non-specifically elevated TPS values were found in 8 of 23 patients. In 15 of 23 patients, TPS fell during periods of apoptotic tumour regression and increased simultaneously with testosterone and preceded the increases in PSA by 2 months during the period of treatment cessation. Although TPS represents a highly sensitive marker of tumour proliferation in this IAS clinical model of controlled tumour regression and regrowth, its low specificity compared with PSA limits its usefulness to monitoring of prostate cancer patients with proven absence of non-specific elevations of this marker."}
+{"text": "The presence of tumour cells in the blood circulation may predict disease recurrence and metastasis. We have evaluated the specificity and sensitivity of detecting hepatoma cells in blood using nested polymerase chain reaction with primers specific for the alphafetoprotein (AFP) gene. The nested polymerase chain reaction amplified a 270-base pair AFP DNA fragment from cDNA of Hep 3B hepatoma cells. In a reconstitution experiment, AFP mRNA was detected from peripheral mononuclear cells isolated from 10 ml of blood containing as few as ten Hep 3B cells. Peripheral mononuclear cells from the blood of 20 hepatoma patients were analysed, and 19 patients showed positive AFP mRNA expression. Seven of 13 samples from hepatitis patients also showed positive AFP mRNA expression. All five paired samples of peripheral blood or umbilical cord blood from pregnant mothers and their babies, respectively, showed positive AFP expression. None of 22 control samples was positive. The presence of AFP mRNA in the blood of hepatitis or hepatoma patients suggests the presence of circulating hepatoma cells or hepatocytes in the circulation. The high incidence of AFP mRNA in the blood of hepatoma patients supports the notion of early haematogenous spreading of the disease."}
+{"text": "The cytoreductive effects of anti-transferrin receptor (anti-TfnR) immunotoxins (ITs) and of ricin toxin against tumour micromasses have been evaluated in a multicellular tumour spheroid (MTS) model. More than 600 (656) MTSs obtained with human breast carcinoma (MCF7) or rat glioblastoma (9L) cell lines were treated individually with ITs or toxin and the effects induced by the treatment were measured for each MTS as volume variation vs time by applying the Gompertz growth model. Two dose-dependent patterns of MTS growth were observed in MTSs of both cell lines in response to IT or toxin treatment: (1) complete inhibition of MTS growth ('sterilisation'); and (2) partial/complete inhibition ('heterogeneous response'). Within the range of IT or toxin concentrations resulting in partial inhibition of MTS growth, the sensitivity of treated MTSs was extremely heterogeneous (the cytoreductive effects varying between 0.1 and 4 logs of cells killed for a given IT or toxin concentration). Analysis of the post-treatment regrowth kinetics indicated that treated non-sterilised and control MTSs reached the same final limiting volumes. However, the doubling time estimated for the surviving cells of treated MCF7 and 9L MTSs ranged between 15 and 50 h, indicating that each MTS had individual growing potential. In conclusion, our results indicate that at substerilising IT concentrations individual heterogenicity of MTSs may greatly influence the cytoreductive potential of ITs. An implication of our study is that the efficacy of an IT treatment in eradicating disseminated micrometastases may not be predictable a priori. The MTS model that we describe in this paper may help in dissecting out factors limiting the effect of ITs in three-dimensional tumours."}
+{"text": "Twenty-seven patients with Hodgkin's (n = 19) and non-Hodgkin's (n = 8) lymphomas underwent cytological and colposcopic screening of the uterine cervix. Colposcopically directed cervical punch biopsies were taken from all patients in whom a colposcopic abnormality was detected. Lymphoma patients were compared with 79 controls with normal cervical cytology and no known haematological abnormality. Colposcopically directed punch biopsies were taken from the cervical transformation zone of all controls. Significantly more lymphoma patients (19%) than controls (3%) had CIN II or III (P less than 0.01) and cervical human papillomavirus infection, as judged by the presence of koilocytes . All six lymphoma patients with CIN had Hodgkin's disease (HD), and five had received combination chemotherapy. Half of the cases of CIN in lymphoma patients and all the cases of CIN in control patients were not detected by cervical cytology. This study suggests that female patients with HD are at increased risk of CIN, and that cervical cytology alone may be an inadequate form of screening for these patients."}
+{"text": "Ontogenetic study on the expression of cytokeratin (CK) polypeptides within particularsubsets of rat thymic epithelial cells (TEC) has been performed by a large panel of anti-CKmonoclonal antibodies (mAbs) using the streptavidin-biotin immunoperoxidase method.Simultaneous presence of two or more CK subunits in the same TEC has been demonstratedby double immunoflouorescence labeling. The obtained results showed that the expressionof CK polypeptides in fetal and neonatal thymus differed from the adult patterns. The maindifference was observed in expression of CK10, 18, and 19 polypeptides. During fetalontogeny, CK10 and 18 are markers for most medullary TEC or a subset of medullary TEC,respectively, whereas CK19 is mainly a pan-TEC marker. In the adult animals, they arelocalized in the cortical and a subset of medullary TEC (CK18), subcapsular/perivascular andsome medullary TEC (CK19), or in a subset of medullary TEC and Hasall\u2019s corpuscles (HC)(CK10). The switch in their expression in the cortex was observed during the first two weeksof postnatal life."}
+{"text": "In the present study, we investigated telomerase activation and its implications in plasma cell dyscrasias including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and plasma cell leukaemia (PCL). All 5 patients with MGUS exhibited normal levels of telomerase activity in their plasma cells. Elevated telomerase activity was found in the samples from 21/27 patients with MM and 4/4 with PCL. In addition, 4 myeloma cell lines all expressed high levels of telomerase activity. The expression of telomerase reverse transcriptase (hTERT) and telomerase RNA template (hTER) was positively associated with the levels of telomerase activity in MM/PCL. Tankyrase expression was upregulated, concomitant with the induction of hTERT and activation of telomerase in MM/PCL. The present findings indicate that MGUS cells may not be immortalized and that activation of telomerase plays a role in the malignant transformation from MGUS to MM. \u00a9 2001 Cancer Research Campaign"}
+{"text": "Two P388 cell lines with acquired resistance to daunorubicin have been shown to exhibit cross-resistance to anthrapyrazolone (NSC 357885). The degree of cross-resistance observed in these cell lines (58 and 150 fold) is similar to those observed towards daunorubicin (34 and 142 fold). However the decreased drug accumulation observed for daunorubicin in the resistant cell lines (4-6 fold) is not observed for anthrapyrazolone. Similarly, verapamil can increase daunorubicin accumulation in resistant cells but has no effect on anthrapyrazolone accumulation. It is concluded that in contrast to daunorubicin, decreased anthrapyrazolone accumulation is not the resistance mechanism operative in daunorubicin resistant cell lines towards anthrapyrazolone."}
+{"text": "Directly observed therapy short course (DOTS) is the internationally recommended strategy to ensure cure of tuberculosis; it has become the standard for the diagnosis, treatment and monitoring of tuberculosis worldwide and has been implemented in 182 of 211 countries, covering more than 77% of world's population(The present study included patients with pulmonary tuberculosis (previously treated within RNTCP then included under CAT II) who failed DOTS CAT II treatment at various centers mainly from eastern and north-eastern parts of Uttar Pradesh and some even from surrounding states like Madhya Pradesh, Bihar and Uttarakhand. The study period extended from June 2004 to December 2005. Informed consent was taken from all subjects. All cases were critically evaluated by detailed clinical history including history of antitubercular treatment (ATT) taken before inclusion in DOTS. History regarding their socioeconomic background, smoking, alcohol intake and drug abuse was recorded and cause for their inclusion in CAT II was evaluated. Pretreatment sputum bacillary count was noted from their records. Leading questions were asked regarding non-adherence to CAT II treatment and the causes were sought into. They underwent thorough clinical examination, radiological and bacteriological evaluation. The radiographs were classified based on the report of American Thoracic Society., in CAT III , default in previous DOTS therapy  and relapse  [The reason for inclusion of these 95 cases in CAT II was treatment failure in CAT I  . Thirty-8, 8.4%) . Since tThe pretreatment sputum bacillary load was 1+ in 22 cases (23%), 2+ in 31 (33%) and 3+ in 42 (44%) cases . MaximumThere were 35 cases (37%) who had taken CAT II treatment irregularly and finally became CAT II treatment failure cases (18 cases had interrupted treatment in the intensive phase while 17 in continuation phase and 80% of the non-adherence occurred for more than 1 month). The most important causes of interruption were the lack of relief of symptoms (37%), intolerance/toxicity (17%), inability to come for drug administration during intensive phase due to loss of earning and poor general condition (15%) and migration (14%).The study included 95 cases of failed CAT II (previously treated within RNTCP), who reported to our hospital for further treatment. The majority of patients (80%) were from economically productive age group (15-44 years) and from lower socioeconomic status. There were 32 patients who were initially wrongly categorized in CAT I since they had already received ATT for >1 month from local practitioners before inclusion in CAT I; they should have been categorized in CAT II directly, which could have been one of the important reason for the ultimate CAT II failure.n = 51) belonged to already failed CAT I cases and this could be one of the important reason for CAT II failure., drug intolerance (17%) and migration (14%). Another important factor was non-willingness to come thrice weekly for the drug administration (9%) during the intensive phase and most of the cases were from low socioeconomic strata and to them earning was more important than spending time at DOTS center for treatment. This factor becomes still more important when the symptoms of the disease are alleviated by initial treatment.The average contact of tuberculosis patients was as high up to seven to eight in our study and as nucleus of Indian household is very compact and transmission of disease is easier, presence of a resistant case in such a situation increases chances of primary drug resistance.The above study was prompted by large number of DOTS failure coming to our department and it throws some light on some of the problems of DOTS CAT II. The important causes of CAT II failure were previous CAT I failure, initial wrong categorization in CAT I, initial heavy bacillary load and non-adherence to treatment."}
+{"text": "Mice were injected with tritiated misonidazole (750 mg/kg-1), killed after 24h and the excised tissues prepared for autoradiography (ARG) to identify sites of accumulation. The previously reported high grain count associated with bound misonidazole metabolite(s) was observed in the liver. The ratio of grain count in the emulsion above the centrilobular hepatocytes to the count over connective tissue (stroma) was 12. A higher count ratio for 'target' cells to stroma was observed in the following cells/tissues: meibomian gland , oesophagus (keratinised layer 60), incisor (enamel organ 17), nasal septum . For some of these tissues the explanation might appear to lie with localised hypoxia, but for others which were probably normoxic there is as yet no obvious reason for these findings."}
+{"text": "Serum alpha-foetoprotein (AFP) and serum carcinoembryonic antigen (CEA) levels were measured, serially whenever possible, in 70 patients attending the Institute of Radiotherapy, Rotterdam, on account of testicular (65) or ovarian (4) germ cell tumours or, in one case, an endodermal sinus (yolk sac) tumour in the mediastinum. In 15 patients the disease was active; in the others it was in remission. Patients with active disease had raised serum AFP levels which correlated well with disease activity; no patient without evidence of active disease had raised serum AFP levels. None of the patients with active disease was found to have raised serum CEA levels. There was no correlation between serum AFP and CEA levels in patients with germ cell neoplasms, but good correlation between serum AFP levels and disease activity. Serum CEA levels did not correlate with disease activity, and serial determinations would therefore not be useful in monitoring progress in this group of diseases."}
+{"text": "Serial determinations of serum alpha-foetoprotein (AFP) concentrations are well established in monitoring the response to therapy of malignant germ cell tumours. Using a radioimmunoassay (RIA) with a sensitivity down to 2kul-1 the majority (57%) of 28 patients with non-AFP producing germ cell tumours had measurable immunologically-reactive AFP in their serum while on treatment. Follow-up for 11-43 months (mean 27) without evidence of tumour activity indicated that this immunologically-reactive AFP was unlikely to be produced by tumour. In patients where the initial serum AFP was raised prior to chemotherapy the AFP concentration did not fall to the normal range at the end of the treatment in 16 (32%) of 41 patients. Follow-up of these patients for 9-48 months (mean 27) has resulted in 5 (12%) relapses in this group. Serum AFP greater than 20kul-1 three months after stopping chemotherapy was a good indicator of residual active tumour and 4 (57%) of 7 patients in this group relapsed. The production of detectable serum AFP is probably related to the type of chemotherapy used and only 7 (14%) of 51 patients treated for gestational choriocarcinoma had detectable AFP concentrations while on cytotoxic chemotherapy. The problem of interpretation of serum AFP concentration in patients with malignant germ cell tumour stresses the need to determine whether there are differences between AFP produced by germ cell tumours and that produced at other sites as a basis for a sensitive assay system able to discriminate between them."}
+{"text": "Human dialysable Transfer Factor (TFd) extracted from lymphocytes of patients with transitional cell carcinoma of bladder (TCCB) was replicated in culture by lymphoblastoid cell lines. The effectiveness of two such TFdLs produced in vitro in transferring sensitivity to TCCB was assessed in the lymphocyte migration test (LMT) using formalin-treated TCCB cells as antigen. The results, showed that one TFdL transferred sensitivity in 5/14 cases and the other in 12/15, not only to leucocytes of healthy individuals but also to leucocytes of TCCB patients. Preliminary results showing an in vivo transfer of sensitivity are discussed."}
+{"text": "RNA extracted from the spleens of tumour-bearing (TLRNA) and tumour-immune (ILRNA) mice was shown to transfer to normal lymphocytes (NL) the ability to produce factors that blocked specific tumour-cell cytotoxicity and mediated specific antibody-dependent cell cytotoxicity (ADCC). Aliquots of normal C3H mouse lymphocytes were treated with TLRNA or ILRNA and cultured in vitro in the absence of tumour antigen. Supernatants were collected at 24h intervals and tested in a microcytotoxicity assay for blocking and ADCC activities. Factors that inhibited tumour destruction by specifically sensitized lymphocytes at the level of both the tumour cells and effector cells were demonstrable in culture supernatants of NL pretreated with TLRNA (50 or 100 microgram/4 X 10(6) cells) but not ILRNA. However, treatment of NL with either RNA resulted in the production factors that mediated tumour-specific ADCC. Cytotoxicity testing and absorption studies of the tumour cell and a control cell (LM) indicated that factors mediating ADCC and blocking at the target-cell level were specific for the tumour. Suppressor activity at the effector-cell level was not absorbed by tumour cells and represents a separate and distinct mechanism of immunosuppression. These data indicate that RNA faithfully transfers \"suppressive\" as well as \"positive\" types of immune responses that have been reported previously for lymphocytes obtained directly from tumour-bearing and tumour-immune animals."}
+{"text": "Itis suggested that the lower biological effects of IRIM compared to ICR are a consequence of the larger kineticinertness of the iridium(III) center with respect to ruthenium(III).Some biological aspects of the new complex imidazolium bisimidazole tetrachloro iridate(III)-IRIM- the iridium(III) analogue of ICR, were considered. More in detail the conformational effects produced by IRIM on DNA and the cytotoxic properties of IRIM on some selected human cell lines were measured.Dialysis experiments and DNA thermal denaturation studies are suggestive of poor binding of IRIM to DNA;formation of interstrand crosslinks is not observed. In any case CD measurements suggest that addition ofincreasing amounts of IRIM to calf thymus DNA results into significant spectral changes, that are diagnosticof a direct interaction with DNA. A number of experiments carried out on the A2780 human ovarian carcinoma,B16 murine melanoma, MCF7 and TS mammary adenocarcinoma tumor cell lines strongly point outthat IRIM does not exhibit significant growth inhibition effects within the concentration range 10"}
+{"text": "Local free cell (eosinophils and macrophages) and extracellular (acid mucopolysaccharides) reactions were studied by histochemical techniques in 72 primary lung cancers (Group A), 17 pulmonary metastases and 5 lung tumours of unknown origin (Group B). Strong cellular reactions were more frequent in Group A than in Group B, whereas extracellular reactions were more frequent in Group B than in Group A. In both groups the degrees of eosinophilic infiltration and accumulation of acid mucopolysaccharides tended to be negatively correlated. In contrast, macrophages and eosinophils showed a positive correlation in the primary cancers, but none in the other tumours. The extracellular material had physical and chemical properties  of the sulphated acid mucopolysaccharides. From its distribution it appeared to be derived from fibroblasts and/or tumour cells."}
+{"text": "The occurrence of aberrations involving chromosomes 11 and 17 in malignant tissues of breast cancer patients has not yet been studied systematically. Using fluorescence in situ hybridisation (FISH) with centromere-specific probes, we determined chromosome 11 and 17 status in interphase nuclei from primary and/or metastatic breast cancer cells. In all cancerous specimens obtained from 30 patients, FISH identified cells with clonal chromosomal abnormalities, with aneuploidy rates ranging from 6% to 92% (median 59%). There was a gain of centromeric signals for chromosome 11, most likely corresponding to hyperploidy; aberrations of chromosome 17 in specimens from 26 patients (87%) were hyperploid as well; however, four cases (13%) showed loss of chromosome 17 centromeres. All specimens contained heterogeneous aneuploid cell populations with excessive gain of signals in some cases. The pattern of aneuploidy did not appear to correlate with tumour grade/stage and was comparable in primary tumours and corresponding metastatic axillary lymph nodes, indicative of genetic instability early in tumour development. Screening with a panel of FISH probes may lead to enhanced sensitivity and specificity in detecting malignant cells, as demonstrated in this study with effusions which could not be conclusively interpreted as being malignant by cytological criteria."}
+{"text": "To elucidate the role of ras gene mutations during the early stage of colorectal tumour progression, K-ras gene mutations were analysed in 32 benign adenomas and 36 adenomas with focal carcinoma in the colorectum by microscraping of histologically pure regions from tissue sections, polymerase chain reaction-restriction fragment length polymorphism and in part by direct sequencing. Several regions were scraped out and analysed when an adenoma contained areas with different grades of dysplasia. The frequencies of K-ras gene mutation in mild dysplasia, moderate dysplasia and focal carcinoma were 19% (7/36), 51% (25/49) and 39% (14/36) respectively. The K-ras gene status was heterogeneous in 4 of the 11 benign adenomas from which multiple samples were obtained, and mutations were always found in the regions with more advanced dysplasia in these adenomas. Thirteen of the 36 adenomas with focal carcinoma showed heterogeneity of mutations between the adenoma region and the focal carcinoma. Seven of which had mutations only in the adenoma region. These findings indicated that the K-ras gene mutations occur during the late stage of adenoma progression and may confer a more advanced morphological phenotype of adenoma, but these mutations are not mainly involved in malignant transformation from adenoma to carcinoma."}
+{"text": "Methotrexate (MTX) shows consistent cytotoxicity for melanoma cells in vitro but it is ineffective in clinical use at equivalent concentrations in vivo. This apparent paradox has been investigated by cell culture techniques and results quantified by cell number. In an in vitro model of high dose MTX therapy followed by leucovorin rescue (HD-MTX-LCR) there was survival of both melanoma and choriocarcinoma cell lines but not of an acute lymphocytic leukaemia cell line. The 70H metabolite of MTX was identified by HPLC in plasma samples of melanoma patients treated by HD-MTX-LCR, in which MTX concentrations approximately 10(-5) M were maintained for 24 h. However, metabolism per se is unlikely to account for the lack of response to MTX clinically. In vitro 70H MTX (10(-7) - 10(-6) M) was two orders of magnitude less cytotoxic for melanoma than MTX (10(-9) - 10(-8) M). The cellular accumulation of [3H]-MTX, using a rapid gradient centrifuge technique for separation of melanoma cells from medium, was reduced in the presence of 70H-MTX. The results suggest that reduced cellular uptake of MTX combined with biochemical rescue of tumour cells may partially explain the paradoxical lack of clinical response of melanoma to the drug."}
+{"text": "The extracellular pH (pHe) of solid tumours is often lower than in normal tissues, and this may influence the uptake and/or activity of anti-cancer drugs. The cytotoxicity of mitoxantrone, paclitaxel and topotecan was therefore assessed at low pHe and after manipulation of intracellular pH (pHi) in murine EMT6 and in human MGH-U1 cells. The cytotoxic efficacy of all three agents was reduced at pHe 6.5 as compared with pHe 7.4. The ionophore nigericin and inhibitors of membrane-based ion exchange mechanisms that regulate pHi  were used to cause intracellular acidification. Combined use of the cytostatic drugs with pHi modifiers reduced their cytotoxicity under both physiological and low-pHe conditions. The uptake into cells of mitoxantrone (a weak base) was inhibited at pHe 6.5 as compared with pHe 7.4, and smaller effects of low pHe to inhibit uptake of topotecan were also observed. DNA analysis of cell cycle distribution revealed that intracellular acidification, as observed during incubation at low pHe and/or using pHi modifiers, resulted in accumulation of cells in G1 phase, where they may be more resistant to these drugs. Reduced uptake of weak bases (mitoxantrone) at low pHe and altered cell cycle kinetics upon acidification are the postulated causes of reduced cytotoxicity of the agents investigated."}
+{"text": "Nuclear and cytoplasmic oestrogen receptors (REN and REC) were sought in 5 normal cervices and in 43 specimens of squamous carcinoma of the cervix. All 3 tissues components of the 5 normal cervices contained both REN and REC. Thirty-five (81%) of the tumours contained receptors, but in only 9 (21%) were they found in both subcellular compartments. Twenty-four tumours (56%) had only REC and 2 had only REN. The potential therapeutic significance of these findings is not yet known, but it seems possible that tumours with an intact receptor mechanism might benefit from oestrogen therapy and have a more favourable prognosis."}
+{"text": "We evaluated West Nile (WN) virus seroprevalence in healthy horses, dogs, and cats in New York City after an outbreak of human WN virus encephalitis in 1999. Two (3%) of 73 horses, 10 (5%) of 189 dogs, and none of 12 cats tested positive for WN virus-neutralizing antibodies. Domestic mammals should be evaluated as sentinels for local WN virus activity and predictors of the infection in humans."}
+{"text": "In order to identify the possible role of the DCC gene in neoplasms of the human female reproductive tract, messenger RNA expression of the DCC gene was examined by reverse transcriptase-polymerase chain reaction, and expression of the DCC gene product was detected immunohistochemically. While histologically normal endometrium, cervical epithelium and ovary expressed detectable mRNA of the DCC gene, three of eight (37%) endometrial carcinomas, one of two (50%) cervical carcinomas and 9 of 22 (41%) ovarian malignant tumours had significantly reduced or negligible DCC expression, and another endometrial carcinoma and two other ovarian tumors underexpressed DCC when compared with histologically normal endometrial or ovarian tissues. Impaired DCC mRNA expression was detected more frequently in grade 3 ovarian epithelial tumours than in grade 1 tumours (P = 0.002). Loss of expression of the DCC gene product detected by immunohistochemistry significantly correlated with the loss of mRNA expression in ovarian carcinomas (P = 0.01 by chi-square test) or in both endometrial and ovarian carcinomas combined (P = 0.001). Loss of heterozygosity of the DCC gene was also evaluated by restriction fragment polymorphism analysis of the polymerase chain reaction-amplified DNA fragment. Loss of heterozygosity of the DCC gene was detected in one of seven (14%) informative cases of endometrial carcinomas, 1 of 11 (9%) informative cases of cervical carcinomas and two of six (33%) informative cases of ovarian tumours. These results demonstrate that inactivation of the DCC gene, especially by the loss of expression, plays a significant role in the aetiology of neoplasms of the human reproductive tract."}
+{"text": "Signal transduction pathways activated by injury play a central role in coordinating the cellular responses that determine whether a cell survives or dies. GADD153 expression increases markedly in response to some types of cellular injury and the product of this gene causes cell cycle arrest. Using induction of GADD153 as a model, we have investigated the activation of the cellular injury response after treatment with taxol and cisplatin (cDDP). Activation of the GADD153 promoter coupled to the luciferase gene and transfected into human ovarian carcinoma 2008 cells correlated well with the increase in endogenous GADD153 mRNA after treatment with taxol but not after treatment with cDDP. Following treatment with cDDP, the increase in endogenous GADD153 mRNA was 10-fold greater than the increase in GADD153 promoter activity. Likewise, at equitoxic levels of exposure (IC80), cDDP produced a 5-fold greater increase in endogenous GADD153 mRNA than taxol. The tyrosine kinase inhibitor tyrophostin B46 had no significant effect on the ability of taxol to activate the GADD153 promoter, but inhibited activation of the GADD153 promoter by cDDP in a concentration-dependent manner. Tyrphostin B46 synergistically enhanced the cytotoxicity of cisplatin; however, the same exposure had no significant effect on the cytotoxicity of taxol. We conclude that (1) taxol and cDDP activate GADD153 promoter activity through different mechanisms; (2) the signal transduction pathway mediating induction by cDDP involves a tyrosine kinase inhibitable by tyrphostin B46; and (3) that inhibition of this signal transduction pathway by tyrphostin synergistically enhances cDDP toxicity."}
+{"text": "In 104 patients with gastric cancer the serum proteins carcinoembryonic antigen (CEA), C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP) (orosomucoid) and alpha 1-antichymotrypsin (ACT) were measured pre-operatively. The estimated median survival of patients with both raised CEA and ACT was only 5 weeks in contrast to 64 weeks for those with both proteins normal. An intermediary group with one of these proteins raised and the other normal had an estimated median survival of 15 weeks. Similar results were obtained by considering a combination of CEA with either AGP or CRP. For these data the results were not explicable in terms of associations between survival time and patient's age, stage, operative procedure, histological classification or site of primary tumour."}
+{"text": "The expression of complex carbohydrates recognised by Helix pomatia lectin  has been shown to predict unfavourable prognosis in breast and other cancers. It has been suggested that the prognostic significance of HPA binding may be through recognition of either Tn epitope  or blood group A antigen  GlcNAc-->R). In this study, the expression of glycoproteins terminating in alpha-GalNAc residues was investigated immunohistochemically using HPA and two monoclonal antibodies--BRIC 66  and BRIC 111 (anti-Tn). In paraffin sections, 74/87 (85%) of breast cancers expressed HPA-binding ligands, while 28/87 (32%) were positive for BRIC 66 binding and 25/87 (29%) expressed Tn. Distribution of staining patterns were distinctive and different with the three markers. BRIC 66, BRIC 111 and HPA binding to glycoproteins derived from breast cancer homogenates and to blood group A and Tn positive glycoproteins in Western blots confirmed the immunohistochemistry data. The results suggest that the prognostic significance of HPA binding in breast cancer is unlikely to be simply through recognition of blood group A antigen or Tn epitope on cancer cells. Breast cancers may express a complex profile of related but distinct glycans sharing similar terminal immunodominant sugar GalNAc, which may be implicated in aggressive biological behaviour."}
+{"text": "The transformation of Wistar rat embryo cells in vitro has been studied in passaged cultures using two criteria for transformation: (1) the ability of cells to form colonies in soft agar and (2) the ability of cells to form tumours in young syngeneic animals. In general there was good correlation between the two criteria. Spontaneous transformation was observed in all untreated cultures by 44 weeks although, by not allowing the cells to become confluent, the tendency was for cultures to transform earlier (i.e. 15-21 weeks). It was noticeable that despite untreated cultures having been in vitro for different lengths of time, most cultures transformed after a similar number of passages (42-50). Treatment of the embryo cells with the alkylating agent nitrosomethylurea (NMU) or benzopyrene (BP) sometimes resulted in transformation after a shorter period in vitro than the controls (minimum 12 weeks) although some treated cultures took longer. Transformed cells produced transplantable fibrosarcomata in syngeneic hosts and those arising from NMU transformed cells were histologically different from those arising from spontaneously transformed cells. The significant of spontaneous transformation in in vitro rat cell transformation systems is discussed."}
+{"text": "P < 0.0001). However, TIMP-1 expression was not increased in NPA and SW579 cells, both of which are derived from poorly differentiated thyroid tumours. Immunohistochemical study showed strong TIMP-1 staining in the stroma cells of advanced stages of carcinomas. Overexpression of TIMP-1 by gene transfer resulted in a significant suppression of the malignant phenotype of NPA cells as judged by an in vitro tumour invasion assay. These results suggest that high levels of TIMP-1 transcripts in advanced stages of thyroid carcinoma likely come from stroma rather than thyroid cancer cells, and TIMP-1 may function as a thyroid tumour invasion/metastasis suppressor. \u00a9 1999 Cancer Research CampaignTumour cell invasion and metastasis is a multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs). Tissue inhibitors of metalloproteinases (TIMPs) act as negative regulators of MMPs and thus prevent tumour cell invasion and metastasis by preserving extracellular matrix (ECM) integrity. In the present study we examined the expression of one member of TIMPs, TIMP-1, in 39 thyroid tumour specimens and two thyroid carcinoma cell lines (NPA and SW579). We also investigated the effect of high TIMP-1 expression on the invasive potential of NPA cells. Northern blot analysis showed that TIMP-1 mRNA levels correlated directly with tumour aggressiveness: the highest number of TIMP-1 transcripts was found in stages III and IV vs benign goitre ("}
+{"text": "Rh2(tfacam)4 was tested both in vitro (U937 and K562 human leukemia cells and Ehrlich ascitic tumor cells) and in vivo for cytostatic activity and lethal dose determination, respectively. This is the first rhodium tetra-amidate to have its biological activity evaluated. The LD50 value for Rh2(tfacam)4 is of the same order as that of cisplatin, and it was verified that the rhodium complex usually needs lower doses than cisplatin to promote the same inhibitory effects.The rhodium (II) complexes Rh"}
+{"text": "Equimolar concentrations of cysteamine and reduced glutathione protected against the cytotoxicity of 5 mM misonidazole (MISO), whereas 5mM ascorbate enhanced its toxicity to hypoxic CHO and HeLa cells in vitro. Protection (reappearance of a shoulder region) could also be seen when cysteamine was added at later incubation times. These changes in toxicity were accompanied by changes in drug metabolism, as evidenced by radiochromatograms of cell extracts obtained after treatment with 14C-labelled MISO. In contrast, radiochromatograms obtained from cells treated with toxic levels of MISO (75 mM) under aerobic conditions indicated no drug metabolism. Both toxicity and drug metabolism could be immediately halted by introducing O2 during hypoxic exposure to MISO. These observations are discussed in terms of a possible model for the metabolism-mediated toxicity of MISO and the roles which sulphydryls and O2 may play."}
+{"text": "Optimized functional results are difficult to achieve following hand injuries. This prospective study was undertaken to evaluate the functional outcome after surgical stabilization of metacarpal and phalangeal fractures.Forty-five fractures of digits of hand in 31 patients were managed by surgical stabilization. Five fractures were fixed with closed reduction and percutaneous Kirschner wire fixation; 10 with external fixator; 26 with open reduction and Kirschner wire fixation; and four with open reduction and plate and screw or screw fixation.Final evaluation of the patients was done at the end of three months. It was based on total active range of motion for digital functional assessment as suggested by the American Society for surgery of hand. Overall results were excellent to good in 87%. Better total active range of motion (excellent grade) was observed in metacarpal fractures (47%) versus phalanx fractures (31%); closed fractures (57%) versus open fractures (27%); and single digit involvement (55%) versus multiple digits (29%). Excellent total active range of motion was observed with all four plate and screw/ screw fixation technique (100%) and closed reduction and percutaneous kirschner wire fixation (60%). Twenty-two complications were observed in 10 patients with finger stiffness being the most common.Surgical stabilization of metacarpal and phalangeal fractures of hand seems to give good functional outcome. Closed fractures and fractures with single digit involvement have shown a better grade of total active range of motion. Fractures of metacarpals and phalanges constitute between 14-28% of all visits to the emergency department.Forty-five metacarpal and phalangeal fractures of the hand in 31 patients aged 14 yrs or more were included in the prospective study conducted during the period 2004-2005. Unstable metacarpal and phalangeal fractures, intraarticular fractures, avulsion fractures, fracture dislocations and open fractures with sharp and clean wounds were included in the study. An unstable fracture was defined as one in which the patient was able to move the adjacent joints by less than 30% of the expected normal range of motion.The fractures were reduced and fixed using various implants including Kirschner wires, external fixators, plates or screws depending on fracture site, configuration and associated soft tissue damage. The fractures were divided into four groups depending on the type of internal fixation.Group I (n=5): The closed reduction and percutaneous Kirschner wire fixation was done in patients with fractures of the middle phalanx, proximal phalanx and metacarpal when closed reduction was possible.Group II (n=10): Open/closed reduction and external fixation was performed for open fractures with sharp and clean wounds.Group III (n=26): Open reduction and Kirschner wire fixation was done in fractures where closed reduction was not possible Figures \u20134. RetroGroup IV (n=4): Here open reduction with plate and/or screw fixation was performed for long oblique or spiral fractures of both metacarpals and phalanges Figures \u20138. The aThe hand was kept elevated and patients were encouraged to perform movements of the fingers and hand to prevent edema and stiffness. Antibiotics were given for 48h and prolonged in cases of open fractures. The Kirschner wires and external fixation devices were removed between 3 to 6 weeks. Active assisted mobilization was started after removal of Kirschner wire / external fixator usually at three to six weeks. Wax bath and contrast bath were given. Continuous passive motion (CPM) was not used. Patients were followed weekly for the first month and fortnightly for the next two months before final evaluation at three months.The mean age of the patients was 35.6 years (range 14-74 years). The most common mode of trauma was assault and roadside accidents (60%). In all, 43 digits were involved and there were a total of 45 fractures. Twenty-two patients had only a single digit involvement while two digits were involved in six patients and three digits in three patients. Fracture site and configuration in metacarpal and phalanges is shown in The functional outcome after fracture treatment was assessed by calculating total active range of motion (TAM).Metacarpal fractures (n=32) had an excellent n=15, 47%); and good  TAM in 94% of fractures [Figures 5, 47%; aOverall end results of hand fractures in 31 patients managed by surgical stabilization were excellent in 14 (45.16%); good in 13 (41.93%); fair in three (9.68%); and poor in one(3.23%).A total of 22 complications were observed  in 10 paResults in various groups according to TAM are tabulated in Many factors, such as delicate handling of tissues, preservation of gliding planes for tendons, prevention of infection and early and appropriate physiotherapy other than accurate reduction and fixation affect recovery of good mobility.5et al.et al.A higher incidence of excellent TAM n=13, 57%) was observed in closed fractures as compared to open fractures n=6, 27%). Pun , 27%. Pu% was obset al.Closed reduction and percutaneous Kirschner wire fixation was done where fracture could be reduced and maintained by closed means. Of the five fractures treated, three achieved excellent TAM (60%). Belskey et al.et al.External fixator was used for surgical stabilization of 10 open fractures. Advantage of external fixation is that no joint transfixation is required and hence patient does not develop any stiffness of the adjacent joints. Sixty per cent (n=6) of the fractures treated by this technique achieved excellent to good TAM. The results are comparable to those reported by FreelandOpen reduction with Kirschner wire fixation was done for stabilization of 26 fractures using three different techniques. (a) Retrograde insertion of Kirschner wire (n=16) with transfixation of joint was first advocated by Vomsaal.Open reduction and plate fixation was done in two fractures and two patients were treated with screw fixation. Excellent TAM was obtained in all four fractures treated by these techniques. Bosscha and SnellenFinger stiffness was the most commonly observed complication in the present series. Only one case of open fracture developed superficial infection. None of the cases developed osteomyelitis. Two patients with multiple fractures developed angulation at fracture site as the Kirschner wire was removed four weeks postoperatively before any radiological union. The movements, however, were almost full at all joints. Two cases of multiple fractures developed hypertrophic nonunion after Kirschner wire fixation. The cause was thought to be inadequacy of Kirschner wire fixation, which cannot check movements at fracture site completely. Ikuta and Tsugeet al.The results of the present study following surgical stabilization of fractures of metacarpals (94% excellent to good) and phalanges (54% excellent to good) were observed to be superior to those reported by Duncan Limitation of the study: The sample size is very small in some groups for statistical comparison.Surgical stabilization of metacarpal and phalangeal fractures of the hand seems to give good functional outcome. Closed fractures and fractures with single digit involvement are important determinants to achieve a better grade of total active range of motion."}
+{"text": "The concentration of bound sialic acid in the sera of 56 normal subjects and 65 subjects with breast cancer was measured, in order to determine (1) whether serum sialic acid concentrations are raised in breast cancer and (2) whether the concentration of sialic acid in serum reflects tumour stage. The amount of sialic acid in serum was compared to serum carcinoembryonic antigen (CEA) values. Urinary hydroxyproline and serum alkaline phosphatase concentrations were used as indicators of bone and liver involvement. Erythrocyte sedimentation rate (ESR) was also measured. Significantly elevated serum sialic acid concentrations were found in breast cancer, and showed correlation with tumour stage. Serum sialic acid values did not correlate with CEA values. The results suggest that measurement of serum sialic acid concentrations may be of adjunctive value in assessing tumour stage."}
+{"text": "We have studied the incidence of microsatellite instability at three trinucleotide repeats and seven dinucleotide repeats from five chromosomal regions, in a group of 30 mammographically detected 'early' invasive breast cancers and correlated its occurrence with clinicopathological parameters. The myotonic dystrophy (DM-1) trinucleotide repeat was analysed in 48 additional cases. In 4 out of 78 (5%) paired tumour-normal DNA samples we found evidence of somatic microsatellite instability at DM-1: a novel allele of a different size was seen in the tumour DNA which was not present in the normal DNA sample. All four tumours that showed evidence of instability were from the core group of 30 cases (13%) and were well or moderately differentiated, oestrogen receptor-positive, infiltrating ductal carcinomas. Two of these tumours were unstable at nine of ten loci studied, both trinucleotide and dinucleotide repeats. DNA prepared from different normal tissues showed no evidence of instability, for all four instability cases. These data indicate that microsatellite instability is specific to the tumour DNA and is an early event in the genesis of some sporadic breast cancers."}
+{"text": "To date, cytogenetic studies on pancreatic carcinoma are rare, and little is known about the frequency of cytogenetic aberrations in primary carcinomas compared with metastatic tumour cells. We therefore evaluated the frequency of chromosomal aberrations in 12 primary pancreatic carcinomas and in effusion specimens from 25 patients with pancreatic cancer by using interphase fluorescence in situ hybridization (FISH) and a panel of four centromeric probes. Hyperdiploidy and chromosomal imbalances, predominantly affecting chromosome 8, were a constant finding in metastatic effusion cells, whereas concordant gain of chromosomes or relative loss of chromosome 18 characterized primary pancreatic carcinomas. The potential role of oncogenes located on chromosome 8 for pancreatic cancer progression was further investigated by double-hybridization studies of aneuploid effusion cells with a probe to 8q24 (MYC) and a centromeric probe to chromosome 8, which demonstrated amplification of the MYC oncogene in two of ten cases (20%). Finally, a potential application of basic findings in the clinical setting was tested by searching for micrometastatic cells in effusions from pancreatic cancer patients primarily negative by FISH. Two-colour FISH in combination with extensive screening  seems to be a useful tool to unequivocally identify micrometastatic cells by demonstrating hyperdiploidy and intranuclear chromosomal heterogeneity."}
+{"text": "Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes.A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans.In this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema. The incidence of diabetes world-wide, is expected to reach epidemic proportions by 2025. Progression of diabetic retinopathy often results in diabetic macular edema, which is a consequence of the breakdown of the blood-retinal barrier, increased retinal vascular permeability and leakage of plasma from small blood vessels in the macula leading to loss of central vision. While epidemiological studies have suggested that glycemic control plays a major role in the development of vascular complications of diabetesBetacellulin (BTC) is a 32 kD member of the epidermal growth factor (EGF) family that was originally isolated from the conditioned medium of a mouse pancreatic \u03b2-cell tumor lineRecombinant human VEGF was a kind gift from Genentech, CA and recombinant betacellulin was purchased from R&D. Antibodies: polyclonal anti-mouse and anti-human betacellulin antibody (R&D), monoclonal anti-ADAM-10  and HRP-conjugated anti-rabbit, anti-mouse IgG antibodies (Amersham Pharmacia Biotech) and anti-goat IgG (Santa Cruz). Post mortem human eyes were obtained from he National Disease Research Interchange (NDRI), Philadelphia. Postmortem time ranged from 3\u201310 hours.Lysates from mouse or human retina prepared using sonication on ice with RIPA buffer (Boston Bioproducts) containing EDTA free protease inhibitors (Roche) were subjected to SDS-PAGE. Proteins were probed with antibody and detected with either a HRP-conjugated anti-rabbit or anti mouse IgG antibody  followed by ECL. The blots were restripped with Restore\u2122 solution (Thermo Scientific) for 30 minutes and reprobed as indicated.6\u20138 week old C57BL6 mice  were used in this study. The animals were cared for in accordance with the ARVO statement for the Use of Animals in Ophthalmic and Vision research. All experimental procedures used aseptic sterile techniques and were approved by the Animal Care and Use Committee of the Cleveland Clinic (ARC08792).6\u20138 week old mice were rendered diabetic with 3 consecutive daily intraperitoneal injections of STZ (55 mg/Kg) freshly dissolved in citrate buffer (pH 4.5). Control mice were given injections of buffer alone. Development of diabetes (defined by blood glucose greater than 250 mg/dl) was confirmed 1 week after the initial injection (One Touch\u00aeltra\u00aeTest Strips and One Touch\u00aeUltraMini\u2122glucometer).Vascular permeability in the retina was quantitated after 3\u20134 weeks of diabetes using an Evans blue quantitation technique as described previously Steptozotocin-induced diabetic mice with hyperglycemia (fasting blood sugar \u2265200 mg/ml) were examined for increases in retinal vascular permeability using an Evans Blue leakage assay. As described previously To determine if the increase in soluble active betacellulin seen in diabetic mice could contribute to increased vascular permeability we examined whether increased concentration of betacellulin in the retina could induce retinal vascular leakage in normal mice. Intravitreal injections of increasing doses of recombinant soluble betacellulin (0\u2013300 ng) resulted in increased retinal hemorrhage  and diabetic macular edema (DME), we wanted to determine if the effect of betacellulin was VEGF-dependent. No increase in VEGF was observed in mouse retinas injected with betacellulin  indicatiBetacellulin is expressed as a membrane anchored precursor protein (pro-betacellulin) containing an extracellular N-terminal ectodomain, a transmembrane domain and a cytoplasmic domainadisintegrin and metalloproteinase-10) can mediate the constitutive and activated shedding of pro-betacellulinRecent studies have determined that ADAM-10 , characterized by an absolute insulin deficiency as a consequence of destruction of the insulin secretory pancreatic \u03b2 cells of the islets of Langerhans; and type II diabetes  and type II (30% incidence)ADAMs and ADAM-10 in particular have been recently reported to be novel regulators of vascular permeabilityWe have examined betacellulin levels in the plasma and found no significant increase in betacellulin in the circulating plasma of patients with PDR (n\u200a=\u200a23) . While tNeurod-Btc gene therapy to be a promising approach to induce islet regeneration for the treatment of insulin-dependent diabetesRecent studies have suggested Figure S1Betacellulin induces retinal vascular leakage independent of VEGF. Retinas from mice injected intravitreally with PBS or betacellulin (200 ng) or no injection (control) were evaluated for VEGF protein 24 hours post injection.(0.74 MB TIF)Click here for additional data file.Figure S2No significant increase in circulating plasma betacellulin in patients with proliferative diabetic retinopathy. Plasma was prepared from whole blood from patients with no diabetes, diabetes with no evidence of retinopathy and proliferative diabetic retinopathy and analyzed by ELISA for betacellulin.(0.54 MB TIF)Click here for additional data file."}
+{"text": "It is universally acknowledged that if cancer is to be controlled, prevention and down staging are essential. In the year 2000 about 10 million new cases were registered, while 6.3 million people died from cancer worldwide. Stamps are regarded as a very useful and educative tool in fighting cancer by creating awareness and raising money for treatment and research. This year (2003) is the seventy-fifth anniversary of the issue of the first anticancer stamps in 1928, so an up-to-date review of the field of oncophilately is timely. Cancer is posing a serious social and economic problem globally since it was estimated by various organisations including It is necessary to take effective preventive measures and cancer awareness among the general population is essential. It is universally recognised that the anticancer stamps can play an excellent role in various ways as to create awareness and to collect money for treatment and research. This is because philately or stamp collection is still one of the most popular hobbies. Due to their universal circulation and appeal, stamps are powerful and effective messengers. It is also possible to use stamps issued for some other purposes in describing various aspects of cancer as will be exemplified later on. Only one report  and two Five Swedish stamps on King Gustaf V issued in 1928 are regarded as the first anticancer stamps because the entire amount collected from sales was donated for cancer control (stamp 2). This was followed by a set of three Danish stamps issued in 1929 (stamp 3). Norway is the third country with a semipostal issue in 1931 (stamp 4) in the aid of Norwegian Radium Hospital. Since then, numerous countries have published several regular or semipostal stamps (stamps 5\u20138). Record shows that by the year 1964, 46 countries had issued 110 stamps  and by tStamps are available on lung cancer (stamp 13), which is the most common cancer in terms of both incidence  and mortality  in 2000 . It is tBreast cancer is the most prevalent cancer in the world among females  in 2000 . Many stFigure 1is stamp .Stamps have also been published on other cancers like prostate cancer . Passive smoking is also very dangerous. Evidence suggests that nonsmoking women married to smokers experience an excess risk of developing lung cancer in the order of 20%. A Japanese stamp may be used to illustrate this aspect (stamp 24).Excessive drinking causes liver, oral, pharynx, larynx and oesophageal cancers, and may increase the risks of colorectal and breast cancers. Simultaneous drinking and smoking habits are much more dangerous. Alcoholic beverages consumption potentiates the effects of tobacco smoking on cancers of the mouth, pharynx, oesophagus and larynx and has been estimated to account for about 3% of all cancer deaths. Stamps issued by many countries warn people about the use of alcohol (stamps 25 and 26).The British Surgeon Dr Percivall Pott demonstrated the earliest example of occupational cancer in 1775, showing a greater incidence of scrotal cancer among young chimneysweepers who were exposed to tar. Lord Shaftesbury, the great social reformer, worked for the well-being of these poor lads. A British stamp is available in his memory, depicting the hand of a chimneysweeper holding the brush (stamp 27). The stamp showing a picture of aniline (stamp 28) illustrates the need for care to be taken to minimise exposure to this chemical, because as early as in 1895, Rehn was the first to observe increased rate of bladder cancers among aniline dye workers. The stamp 29 describing the structure of benzene may be similarly used to show the need to take care in handling benzene, since it is proved to be a potent human carcinogen causing leukaemia with a latency period of about 15\u201320 years. It is widely used as a solvent in leather, petroleum and other industries. Polyaromatic hydrocarbons (PAH) are found in exhaust gases from automobiles run by petrol and diesel, from railway locomotives and in smoke, dust and exhaust gases from various factories. It is advisable to use protection to prevent inhaling of exhaust gases from automobiles as described in a Swedish stamp (stamp 30).92235U (stamp 31) and development of cancer dates from early observations on survivors of the atomic bombs in Japan.The relation between ionising radiation from various sources including radioactive substances such as Ultraviolet radiation from sunlight is the major risk factor for skin cancers and that of lip. Stamps showing sunrays and flares (stamp 32) may be used to make people aware of the dangers of overexposure to sunrays.Figure 3Links have already been established between some viral infections and the development of cancers such as Epstein\u2013Barr virus and Burkitt lymphoma, hepatitis B and C and hepatocellular (liver) carcinoma, human papilloma virus (HPV) and cervical cancer in females, human immunodeficiency virus (HIV). AIDS patients infected with HIV have higher incidence and death rates from malignancies like Kaposi's sarcoma, non-Hodgkin's lymphoma, etc. Hence awareness regarding HIV infection is very important from a cancer preventive perspective also. So far about 65 countries have issued over 120 anti-AIDS stamps (e.g. stamps 33\u201336).Catharanthus rosea) may be used to point out that some important alkaloidal drugs like vincristine and vinblastine have been isolated from the plant (stamp 40). Taxol has been isolated from Taxus brevifolia (Pacific Yew tree) and Taxus baccata  (stamp 41).Figure 4Nowadays, three chief treatment modalities \u2013 surgery, radiotherapy and chemotherapy \u2013 are used in all sorts of combinations. Bangladesh has issued a beautiful stamp depicting the picture of a crab attacked with these three modes of treatment (stamp 37). One can find individual stamps on surgery (stamp 38), radiotherapy (stamp 39) and chemotherapy. Anticancer drugs are obtained by chemical synthesis or from natural sources such as plants. A French stamp on the Madagascar periwinkle plant  and using \u2018smokeless\u2019 tobacco products like crude leaves, snuff, etc.Limit alcohol consumption to a minimum, if at all (stamps 26 and 43).\u03b2-Carotene present in various yellow, green or orange fruits and vegetables is converted to vitamin A in the liver. Hence it is recommended to eat fresh vegetables and fruits rich in these substances and vitamins like carrot, beans, gourd, broccoli, cauliflower, tomato, etc. (stamp 47) and a variety of fruits (stamp 48).Both vitamin A (stamp 45) and vitamin C (stamp 46) are considered as antioxidants and possess potential cancer chemopreventive properties by inhibiting precancerous changes and damages of DNA leading to cancer. The protective effects of dietary fibre present in vegetables against a number of cancers like colorectal, oesophageal and stomach have been demonstrated. Hence it is advisable to eat vegetables rich in roughage like jackfruit (stamp 49), beans (stamp 47), ladies finger, etc.Curcuma longa (stamp 50) is the source of turmeric, which contains the yellow natural colouring agent namely curcumin which may have chemopreventive properties  have been shown in lab studies to have antitumour as well as tumour promotion inhibitory activities. Onions and ginger have also been shown to possess similar properties.Constituents of Camellia sinensis (stamp 52). Tea is one of the most ancient and next to water the most widely consumed liquid in the world. Many phytochemicals including polyphenols catechin compounds like epigallocatechin gallate (EGCG), etc. present in tea leaves have shown potential chemopreventive and antioxidant properties.Tea is a beverage made from the leaves of the plant species Figure 5Diet has a vital role in the prevention of about 30\u201340% of all cancers (Being very underweight or overweight increases the risk of cancer. Obesity (stamp 53) is associated with the endometrium, breast, kidney, colorectal and gallbladder cancers. Thus it is advisable to maintain a healthy body weight.An active lifestyle is recommended. Physical activity decreases the risk of colon and breast cancers. Walking, cycling, gardening, household chores, climbing the stairs, practising yoga (stamp 54), etc. are recommended.Early detection of cancer is very important to save lives (stamp 55). Annual check-up (stamp 56) of oral cavity, skin, lymph nodes, routine examinations of blood for detection of any abnormalities in its constituents (stamp 57) and chest X-ray (stamp 58) are internationally accepted tests  for earlFor women: Breast awareness is important (Indian stamp 59) and clinical breast examination by a physician may be helpful where there is no national screening programme. It is also suggested to carry out mammography (stamp 60). Cervical PAP test (stamps 61 and 62) should be carried out in adult females at regular intervals.For men: Population-based prostate-specific antigen (PSA) testing can reduce mortality in countries where urological follow-up and treatment are available. US Postal Service issued a semifiscal stamp in 1998 on this aspect , electron microscope (stamp 64), X-ray instruments (stamp 65), radiotherapy instruments (stamps 66 and 67), ultrasonography (USG) (stamp 68), computed topographic (CT) scanning (stamp 69), magnetic resonance imaging (MRI) (stamp 70), nuclear medicine imaging (scintigraphy) (stamp 71), mammography, etc. In 1992, Macedonia had brought out a set of four stamps with the message of early cancer detection in one of them and with the picture of diagnostic equipment in the other three (stamps 72\u201375).Many scientists and physicians appear on stamps for their outstanding contribution in the fight against cancer. WC Roentgen (1845\u20131923) \u2013 discoverer of X-rays in 1895 and the first recipient of the Nobel prize in 1901 (stamp 76). Henri Becquerel (1852\u20131908) (stamp 77) \u2013 discoverer of the phenomenon of spontaneous emanations later termed radioactivity by Madame Marie Curie. Radiotherapy has originated from this discovery. Madame Marie Curie (1867\u20131934) and Pierre Curie (1859\u20131906) \u2013 world-renowned French scientists who discovered radium in 1898, which was the first radioactive substance used for the treatment. Madame Curie appeared in about 100 stamps either alone  or with her husband Pierre Curie (stamps 81 and 82). In 1938, France and its 21 colonies issued the latter stamps (81 and 82) as a tribute to the 40th anniversary of this discovery. The surtax of these stamps was given to the International Union Against Cancer. Pierre Curie was also remembered alone in some stamps. Irene Joliot Curie (1897\u20131956), elder daughter of Madame Curie, and Frederic Joliot (1900\u20131958) son-in-law of Madame. Curie \u2013 joint discoverers of artificial radioactivity (stamp 83). Based on their discovery, a number of artificial radioisotopes have been prepared some of which find use in cancer. George N Papanikolaou (1883\u20131962) (stamps 62 and 84) \u2013 discoverer of PAP test for early diagnosis of cervical cancer that has saved the lives of millions of women worldwide. Moritz Kaposi (1837\u20131902) (stamp 85) \u2013 famous physician who identified in 1872 a special type of sarcoma that was named after him as Kaposi's sarcoma. Rudlof Virchow (1821\u20131902) (stamp 86) \u2013 founder of cellular pathology. He discovered and named gliomas and giant cells. He had also named many common tumours.Postage stamps and cancellations are available on world-famous organisations like International Union Against Cancer (UICC) (stamps 81 and 82), World Health Organization (WHO) (stamp 87), etc.Starting from 1933, UICC organises International Cancer Congress every fourth year where scientists, clinicians, nurses, etc. from all over the world meet. Special commemorative stamps have been issued on these occasions by various countries: 8th held in Russia in 1962 (stamp 88), 9th held in Japan in 1966 (stamps 39 and 89), 12th held in Argentina in 1978 (stamp 90), 14th held in Hungary in 1986 (stamp 85) and 16th held in India in 1994 (stamp 91).Thus our fight against cancer will continue till we achieve success (stamp 92). Research is ongoing globally, and newer concepts, improvements in therapeutic modalities and new drugs are being added continuously. Recent global efforts in DNA decoding (stamp 93) and human genome mapping leading to genome genetic engineering (stamps 94 and 95) will help to identify and repair the defective genes (gene therapy of cancer). The message that should reach everybody is that cancer will be defeated \u2013 sooner or later \u2013 as is beautifully demonstrated in a French stamp issued in 1970 picturing a smiling lady cured of cancer overcoming the threat of death displayed underneath (stamp 96).It is therefore convincingly demonstrated that, in addition to specific anticancer stamps, various other stamps can be used to describe different aspects of cancer. The significant role of stamps in raising awareness among people regarding this dreadful disease has been highlighted."}
+{"text": "The ultrastructure of 16 tumours derived from spontaneously transformed cell lines established from young and old C57 and C3H mouse organs is described. Three types of tumour were found: myxoid (fibrosarcomatous), consisting of cells with long processes and much interstitial material; leiomyomatous, consisting of a bundle of smooth muscle-like cells with less interstitial material; or epithelial-like consisting of closely packed round cells with little interstitial material. The cell types in the tumours were similar to those found in the tissue culture cell lines from which they were derived."}
+{"text": "The Src family kinases possess two sites of tyrosine phosphorylation that are critical to the regulation of kinase activity. Autophosphorylation on an activation loop tyrosine residue (Tyr 416 in commonly used chicken c-Src numbering) increases catalytic activity, while phosphorylation of a C-terminal tyrosine (Tyr 527 in c-Src) inhibits activity. The latter modification is achieved by the tyrosine kinase Csk , but the complete inactivation of the Src family kinases also requires the dephosphorylation of the activation loop tyrosine. The SH3 domain of Csk recruits the tyrosine phosphatase PEP, allowing for the coordinated inhibition of Src family kinase activity. We have discovered that Csk forms homodimers through interactions mediated by the SH3 domain in a manner that buries the recognition surface for SH3 ligands. The formation of this dimer would therefore block the recruitment of tyrosine phosphatases and may have important implications for the regulation of Src kinase activity. Members of the Src family of protein tyrosine kinases, such as c-Src, Lck, Fyn and Hck, are key players in many signalling pathways that regulate cell growth, proliferation and motility The kinase domain of Csk is responsible for the recognition of the Src family kinases as its specific substrates, resulting in phosphorylation of the C-terminal tail The SH3 domain of Csk interacts with several tyrosine phosphatases Pursuing the observation that Csk is dimeric at high protein concentration  in vitro FL) migrates as a dimer by size exclusion, the removal of the SH3 domain (CskSH2KD) or the SH3 and SH2 domains (CskKD) resulted in proteins that no longer appear to dimerize and instead elute as apparent monomers by gel filtration , CskSH2KD (residues 68\u2013450) and CskKD (residues 187\u2013450) were expressed in bacteria and purified as described The constructs of human Csk, CskPurified Csk proteins were subjected to analytical gel filtration using a Superdex S200 column  or SMART S200 column . Column calibration was performed using molecular weight standards ."}
+{"text": "We analysed oestrogen receptor (ER) and progesterone receptor (PR) expression in a retrospective series of 21 low-grade endometrial stromal sarcomas (LGSSs). Archival formalin-fixed and paraffin-embedded material was analysed by immunohistochemistry. ER and PR were measured with monoclonal antibodies and the peroxidase-antiperoxidase method and a score was calculated as for breast carcinoma based on both the percentage of positive tumour cell nuclei and the staining intensity. ER were seen in 15 (71%) and PR in 20 (95%) of tumours respectively. ER expression was scored as high in three (14%), moderate in four (19%), and low in eight (38%) tumours. Six (29%) tumours did not stain for ER and all of these were positive for PR. PR expression was scored as high in eight (38%), moderate in ten (47%) and weak in two (10%) LGSSs. Only one (5%) LGSS did not stain for PR (this tumour was positive for ER). ER and PR expression in LGSS is heterogeneous. This may have implications for hormone therapy in the management of these tumours. These results suggest that ER and PR should be routinely quantified in LGSSs by immunohistochemical methods. \u00a9 2000 Cancer Research Campaign"}
+{"text": "The objective of the study was to review the natural history of patients with a malignant pleural effusion but without obvious evidence of a primary, to assess the value of investigations used to look for a primary and to assess the response to palliative chemotherapy. This was done by a retrospective study of patients' notes at the Lung Unit, Royal Marsden Hospital, Sutton, Surrey. Improvement in tumour-related symptoms (and duration) on chemotherapy was assessed by the patient before the first course of chemotherapy and following each course using simple descriptive criteria as follows: (1) complete disappearance of symptoms (CR); (2) good improvement in symptoms (PR); (3) minor or no change in symptoms (NC); (4) worse symptoms (PD). Pleural effusion objective response (and duration) according to Hamed definition: success defined as a continued absence of reaccumulation of pleural fluid on all follow-up radiographs; any reaccumulation was regarded as a treatment failure. Overall survival was measured from the date of histological/cytological diagnosis to death. The study included 42 patients, 27 males and 15 females with a median age of 55 years. A primary was found in 15 patients (36%), and considered to be lung cancer. A total of 11/32 (34%) had a thoracic computed tomography (CT) scan with abnormalities compatible with a diagnosis of lung primary. When thoracic CT scan was negative, fibre optic bronchoscopy was always negative (0/13). Abdominal and pelvic CT scan, abdominal ultrasound, pelvic ultrasound and mammograms failed to reveal the primary. Twenty-three patients underwent local treatment and 37 received systemic chemotherapy. A total of 29/37 (78%) patients achieved symptomatic improvement  and 32/37 (86%) an objective response of their pleural effusion on chemotherapy . The median survival of the whole group was 12 months (3-60+ months). In this series the thoracic CT led to a diagnosis of lung primary in 34% of the cases. Other radiological examinations and bronchoscopy were unhelpful. Chemotherapy achieved symptom relief in 78% of patients."}
+{"text": "Analysis of human tumour-derived cell lines has previously resulted in the identification of novel transformation-related elements and provided a useful tool for functional studies of different genes. To establish the utility of such cell lines as indicators of change relevant to urothelial cancer, we have characterised the expression of five genes  within a panel of human bladder carcinoma cell lines. Using single-strand conformation polymorphism (SSCP) and direct sequencing, p53 mutations were identified in 7/15 (47%) cell lines reflecting events reported in bladder tumours. Immunohistochemical analysis of p53 in cultured cells and in paraffin-embedded sections of xenografts from the cell line panel revealed discordant results. An absence of p53 nuclear staining was associated with an exon 5 mutation in EJ and with multiple p53 mutations found in J82. Two cell lines positive for p53 staining in the absence of detectable mutation displayed overexpression of MDM2  in Western blot analysis. Loss or aberrant Rb expression was recorded in 5/15  cell lines. Absence of E-cadherin was recorded in 5/15 cell lines  with loss of alpha-catenin in immunoprecipitated E-cadherin complexes of CUBIII. Western blot analysis of APC revealed a truncated protein in 1/15 (CUBIII) cell lines. The characterisation of oncogenic events within this panel of human bladder carcinoma cell lines establishes a representation of change observed in bladder tumours and better defines the genotypic background in these experimental human cell models of neoplastic progression."}
+{"text": "Two human deaths caused by Australian bat lyssavirus (ABL) infection have been reported since 1996. Information was obtained from 205 persons (mostly adults from south Brisbane and the South Coast of Queensland), who reported potential ABL exposure to the Brisbane Southside Public Health Unit from November 1,1996, to January 31, 1999. Volunteer animal handlers accounted for 39% of potential exposures, their family members for 12%, professional animal handlers for 14%, community members who intentionally handled bats for 31%, and community members with contacts initiated by bats for 4%. The prevalence of Lyssavirus detected by fluorescent antibody test in 366 sick, injured, or orphaned bats from the area was 6%. Sequelae of exposure, including the requirement for expensive postexposure prophylaxis, may be reduced by educating bat handlers and the public of the risks involved in handling Australian bats."}
+{"text": "Furthermore, strong correlations were found between the levels of both uPA  and PAI-1  in the cytosols and their levels previously measured with ELISAs based on commercial reagents. In both Cox univariate and multivariate analysis, high cytosolic levels of uPA or PAI-1 were significantly associated with increased rates of relapse and death. The levels of uPA and PAI-1 in the pellet extracts also provided prognostic information, although to a lesser extent compared with the cytosolic extracts. The prediction of prognosis on the basis of uPA and PAI-1 assessed by an alternative ELISA once again emphasizes the established prognostic role and usefulness of these parameters in selection of breast cancer patients at high or low risk of recurrence. \u00a9 1999 Cancer Research CampaignTo evaluate the clinical relevance of urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) measured by a recently developed enzyme-linked immunosorbent assay (ELISA), we analysed both components in samples derived from 892 patients with primary breast cancer (median follow-up 99 months). The assays were performed in cytosolic extracts as well as in corresponding detergent extracts of pellets obtained after ultracentrifugation, which was carried out when preparing the cytosolic fractions for routine steroid hormone receptor determination. Statistically significant correlations were found between the cytosolic levels and those determined in the pellet extracts (Spearman correlation coefficient"}
+{"text": "Recent studies have shown that various gastrointestinal tumours express substantial amounts of vasoactive intestinal peptide (VIP) receptors. Based on these observations, we have developed a receptor scintigraphy using [123I]VIP as a radioligand. An initial series performed at our institution showed promising potential for visualization of various gastrointestinal adenocarcinomas by means of [123I]VIP. In this article, we now report the results obtained in 80 consecutive patients with colorectal adenocarcinoma. Eighty consecutive patients with histologically verified colorectal cancer underwent scanning by means of [123I]VIP . Thirteen patients were free of tumour after complete resection of Dukes' C cancer, eight patients presented with primary and 14 with locally recurrent tumours but were free of metastases. Ten patients had locally recurrent disease and liver, lung or lymph node metastases. Disease confined to organ metastases  was present in 35 patients. The size of the primary or recurrent tumours ranged between 3 and 6 cm, and the size of metastases was between 1 and 13 cm in diameter. Scan results were evaluated independently by two nuclear medicine physicians in a blinded way, and results were then compared with computerized tomography (CT)scans not older than 4 weeks. Seven out of eight primary (87%) and 21 out of 24 (82%) locally relapsing cancers were imaged with [123I]VIP. Negative VIP scans were obtained in all 13 patients in whom the cancers had been curatively resected. All patients with lymph node metastases showed positive VIP scans (four out of four), and positive scans were obtained in 25 out of 28 (89%) patients with liver metastases and in two out of three cases with lung metastases. In four patients with relapsing cancer, the VIP scan indicated the presence of disease before CT, and in two patients the diagnosis of scar tissue instead of a local recurrence of rectal cancer as suggested by CT could be established. We conclude that [123I]VIP receptor scanning is a sensitive method for radioimaging of colorectal cancer with the potential to provide valuable additional information to conventional radiological methods."}
+{"text": "To study pathophysiological roles of mesothelial barrier functions in protection against cancer cell invasion, we isolated mesothelial cells from the rat abdominal cavity and then cultured them with 10(-6)M all-trans-retinoic acid (RA) for 10 days. Mesothelial barrier function assessed by measuring transcellular electrical resistance (TER) and the expression of 7H6 tight junction-associated antigen at the cell border were induced by the treatment . Then we quantified the attachment and penetration of rat mammary cancer cells (SST-2 cells) into the mesothelial cell monolayer by prelabelling of the cancer cells with fluorescent dye and by observing optical sections at different heights using a laser confocal scanning microscope. When SST-2 cells were overlaid onto the mesothelial cell monolayer treated with RA, the number of cancer cells found at the basal level of the monolayer was significantly reduced. These results showed that enhanced mesothelial barrier function at least partially prevents the penetration of cancer cells into mesothelial cells and suggested that 7H6 antigen serves as a reliable immunocytochemical marker for monitoring mesothelial barrier function."}
+{"text": "Anthracenyl-amino acid conjugates represent a novel chemical class of topoisomerase (topo) inhibitor. NU/ICRF 505 is a lead compound that stabilises topo I cleavable complexes and is actively cytotoxic at low microM concentrations. In this study, endonucleolytic DNA cleavage was used as a marker of apoptosis to investigate mechanisms of cell death produced by this compound. NU/ICRF 505 (5 microM) induced a substantial increase in the level of DNA fragmentation in HL60 cells  but only after a 48 and 72 h drug exposure (compared with 6 h after treatment with camptothecin), as determined qualitatively by conventional gel electrophoresis and quantitatively by spectrofluorimetry. This effect was substantially reversed by co-treatment with zinc (1 mM). Subsequent studies with the human lung (NX002), ovarian (A2780) and colon (HT29) cancer cell lines yielded evidence of formation of higher molecular weight DNA fragments in NX002 and A2780 cells in response to NU/ICRF 505 (5 microM). Co-treatment with zinc (1 mM) caused a small decrease in DNA fragmentation. These data suggest that the induction of apoptosis may play an important role in the mechanism of cytotoxicity of NU/ICRF 505 in HL60 cells and that other pathways of cell death may also be operative in NX002 and A2780 in conjunction with apoptosis."}
+{"text": "The relationship between the bioenergetic status of human glioma xenografts in nude mice and morphometric parameters of the perfused vascular architecture was studied using (31)P magnetic resonance spectroscopy (MRS), fluorescence microscopy and two-dimensional digital image analysis. Two tumour lines with a different vascular architecture were used for this study. Intervascular distances and non-perfused area fractions varied greatly between tumours of the same line and tumours of different lines. The inorganic phosphate-nucleoside triphosphate (P(i)/NTP) ratio increased rapidly as mean intervascular distances increased from 100 microm to 300 microm. Two morphometric parameters - the percentage of intervascular distances larger than 200 microm (ivd200) and the non-perfused area fraction at a distance larger than 100 microm from a nearest perfused vessel (area100), - were deduced from these experiments and related to the P(i)/NTP ratio of the whole tumour. It is assumed that an aerobic to anaerobic transition influences the bioenergetic status, i.e. the P(i)/NTP ratio increased linearly with the percentage of ivd200 and the area100."}
+{"text": "The characteristics of lung cancers induced by inhaled chromate were studied in 13 consecutive autopsies on male ex-chromate workers. In addition to histopathology, we examined: (1) the relationship between the occurrence of lung cancer and the amount of chromium (Cr) deposited in the lung as determined by atomic absorptiometry and (2) the chronological changes in five precancerous lung lesions followed by bronchoscopy till death. Twenty-one cancers were identified, including 16 lung tumours observed either during follow-up or at autopsy. Of these 16 tumours, 13 were found in six subjects, implying a high frequency of multiple cancers. Eleven (69%) out of the 16 tumours were of squamous cell type (including carcinoma in situ), this being twice as frequent as in age-matched controls. A further characteristic was predominance in the central part of lung (69%). The lung Cr burden was very much higher  in patients with lung tumours than in those without (8-28 micrograms g-1). Five of the precancerous lesions followed by bronchoscopy originated at bronchial bifurcations. Four of these cases showed a return to normal histology at autopsy even without therapy, and the other did not progress."}
+{"text": "Background: Morbidity and mortality after surgical treatment of bileduct stones increase with age and associated diseases. A proposed alternative therapy is endoscopic sphincterotomy (ES) with the gallbladder left in situ, and we elected to compare this option with standard open surgery in high-risk patients.Methods: 98 patients (mean age 80 years) with symptoms likely to be due to bileduct stones or a recent episode of biliary parcreatitis were randomised to be treated either by open cholecystectomy with operative cholangiography and (if necessary) bileduct exploration (n=48) or by endoscopic sphincterotomy alone (n=50).Findings: The procedure was accomplished successfully in 94% of the surgery group and 88% of the ES group, and there were no significant differences in immediate morbidity (23% vs 16%) or mortality (4% vs 6%). During mean follow-up of 17 months biliary symptoms recurred in three surgical patients, none of whom underwent repeat surgery, and in 10 ES patients, seven of whom had biliary surgery. By multivariate regression analysis endoscopic sphincterotomy was an independent predictor of recurrent biliary symptoms .Interpretation: In elderly or high-risk patients, surgery is preferably to endoscopic sphincterotomy with the gallbladder left in situ as a definitive treatment for bileduct stones or non-severe biliary pancreatitis."}
+{"text": "Microsatellite instability (MSI) was examined at 36 loci, and found in 9 (43%) of the 21 prostatic cancers. A loss of heterozygosity had occurred in five cases (24%). MSI did not correlate with clinical stage, but might play a role in the development of a subset of prostate cancers."}
+{"text": "Development of incisional hernia after open abdominal surgery remains a major cause of post-operative morbidity. The aim of this study was to determine the current practice of surgeons in terms of access to and closure of the abdominal cavity in elective open surgery.Twelve surgical departments of the INSECT-Trial group documented the following variables for 50 consecutive patients undergoing abdominal surgery: fascial closure techniques, applied suture materials, application of subcutaneous sutures, subcutaneous drains, methods for skin closure. Descriptive analysis was performed and consensus of treatment variables was categorized into four levels: Strong consensus >95%, consensus 75\u201395%, overall agreement 50\u201375%, no consensus <50%.157 out of 599 patients were eligible for analysis (85 (54%) midline, 54 (35%) transverse incisions). After midline incisions the fascia was closed continuously in 55 patients (65%), using slowly absorbable , braided  sutures with a strength of 1 . In the transverse setting the fascia was closed continuously in 39 patients (72%) with slowly absorbable  braided sutures  with a strength of 1 .In the present evaluation midline incision was the most frequently applied access in elective open abdominal surgery. None of the treatments for abdominal wall closure (except skin closure in the midline group) is performed on a consensus level. Approximately 700.000 open abdominal procedures are performed annually in Germany and 4.000.000 in the United States . DevelopThere is still controversy about the best strategy for abdominal wall closure due to inconsistent and incomplete evidence provided by several randomized controlled trials (RCT) -8 as wel1. Is midline incision still the most frequently applied access to the abdominal cavity in elective situations?2. Has consensus for abdominal wall closure already been established in surgical routine?The primary objective of this cross sectional study was therefore to identify current practice of abdominal cavity access and closure in elective surgery.Twelve of the 25 participating centres of the INSECT-Trial group agreed in contribution to data acquisition (see acknowledgment). The local ethics committees of participating centres granted ethical approval for the study These include hospitals of all levels of health care , thus ensuring representative study results. Surgeons at these hospitals were asked to assess surgical access and closure methods of 50 consecutive patients who underwent surgery at their service. Patients who underwent more than one operation during the study period were excluded.The study was designed as a cross-sectional cohort study and performed between July and August 2005. A standardized data entry form was designed in order to collect the following information: patient's gender and age, setting of surgery (elective vs. emergency surgery), surgical approach (open vs. laparoscopic surgery), history of previous abdominal surgery, type of applied abdominal incision (transverse vs. midline), suture material used for fascia closure , the technique used for fascia closure , the use of subcutaneous suture and subcutaneous drainage, and the method of skin closure. Classification of suture strengths was reported according to the United States Pharmacopeia XXII (1990).All data entry forms were sent in an anonymous fashion to the Study Centre of the German Surgical Society and analyzed accordingly using Statistical Analysis System (SAS) version 9.1. Descriptive statistics were used in univariate analyses.The treatment of patients were categorized into four levels of consensus according to a classification of Hoffmann et al. :1. Strong consensus: treatment applied in >95% of cases2. Consensus: treatment applied in 75\u201395% of cases3. Overall agreement: treatment applied in 50\u201375% of cases4. No consensus: treatment applied in <50% of casesA total of 599 patient data entry forms out of 600 with an equal distribution of genders  and a mean age of 57 years (SD 19 years) were available for analysis. An open approach was chosen in 375 patients (63%), a laparoscopic in 224 patients (37%). After exclusion of patients with previous open abdominal surgery, an emergency procedure, and laparoscopic procedures, a total of 157 patients with primary elective laparotomy were available for further analysis , midline incisions were performed in 85 patients (54%), transverse incisions (crossing the midline) in 54 patients (35%) and miscellaneous incisions  in 13 patients (8%).Fascia closure for midline incisions was performed with a continuous suture in 55 patients (65%) and interrupted sutures in 16 patients (19%), respectively. In 13 (15%) of these patients a combination of both techniques was applied. Monofilament sutures were applied for fascia closure in 51 patients (60%), braided sutures in 32 patients (38%). Non-absorbable sutures were chosen in four cases (5%), slowly absorbable sutures in 47 patients (55%), and moderately rapid absorbable sutures in 33 patients (39%). Sutures with the strength of 0 were used in two patients (2%), with strength of 1 in 48 patients (57%), and with strength of 2 in 31 patients (36%).Subcutaneous suture was performed in 48 patients (57%) and a subcutaneous drain was placed in 19 patients (22%). Skin closure of patients who received midline incisions was performed with staples in 67 cases (79%).In terms of consensus levels all technical features for closure of midline incisions met the level of \"overall agreement\", except the item of skin closure for which the level of \"consensus\" was reached Table .Abdominal fascia of patients who had a transverse incision (n = 54) was sutured continuously in 39 patients (72%), interruptedly in eleven patients (20%), and with a combination of both techniques in two patients (4%). Suture material with the strength was 0 were chosen in 6 patients (11%), with a strength of 1 in 30 patients (56%) and with a strength of 2 in 17 patients (31%). Monofilament sutures were applied for fascia closure of 25 patients (46%) and braided sutures for 27 patients (50%). In two patients (4%) non-absorbable sutures, in 22 patients (41%) slowly absorbable sutures, in 29 patients (54%) moderately rapid absorbable sutures, and in one patient (2%) rapidly absorbable sutures were applied.Thirty-nine patients (72%) received a subcutaneous suture; a subcutaneous drain was placed in 12 patients (22%). Skin closure of patients who received midline incisions was performed with staples in 39 cases (72%).All technical features for closure of transverse incisions reached the level of \"overall agreement\" Table .In the present analysis midline incision is still the most frequent access to the abdominal cavity in elective surgery. No consensus for fascia closure either for midline or transverse incisions in daily practice of abdominal surgery was detected (>75% of surgeons acting similarly). Use of staples for skin closure after midline incisions was the only item that reached the level of consensus.Our finding that midline incisions are the most frequently applied access in open abdominal surgery is in accordance with previous reports . While tThe lack of consensus for abdominal wall closure strategies after midline incisions demonstrates persistent uncertainty within the surgical community. Several RCTs -8 and meAccording to our data, there is no consensus in closure of transverse incisions either. Closure technique of the abdominal fascia with a continuous suture and skin closure with staples were the only items that almost reached the level of consensus (both performed in 72%). In contrast to midline incisions, however, so far no randomized trial has been solely conducted in order to investigate closure techniques in this setting. Hence, the ideal closure strategy is still to be determined. From some trials comparing closure techniques in midline incisions ,18,19 paThe results of our study might be affected due to bias. The participating hospitals of the INSECT-Trial who agreed to contribute to this study may be a subgroup of hospitals dedicated to clinical research and therefore act differently to other hospitals (e.g. surgeons agree to randomize their patients). However, it is unlikely that such an effect might have systematically shifted the results in favour of consensus.A cross-sectional consecutive data collection of real patient data seems to be the optimal design to answer our initial study questions. Selection bias within the hospitals is prevented due to a consecutive recruitment and measurement bias due to standardized data collection. Furthermore, surgeons of the INSECT-Trial group were trained in data collection during specific preparatory INSECT-Trial meetings . Other sCurrently, no clinical guidelines are available for abdominal wall closure after any type of incision. Further well designed pragmatic randomized controlled trials are necessary to support a development of such evidence-based guidelines and to change the current practice. Otherwise a reduction of incisional hernias seems unfeasible and treatment remains on the level of \"overall agreement\". The results of the recently published INSECT-Trial certainly contribute to the body of evidence on abdominal fascia closure techniques. FurtherIn conclusion, midline incisions were the predominant type of abdominal access in the present study of participating centers of the INSECT-Trial. There is no consensus regarding the strategy for closure of the abdominal fascia after midline and transverse incisions.The authors declare that they have no competing interests.NNR: Study design, data analysis and interpretation, drafting of the manuscript PK: Study design, data acquisition, data analysis, revsion of the manuscript. MKD: Data acquisition, analysis and interpretation, revsion of the manuscript. CS: Study design, data acquisition, data interpretation, revision of the manuscript. KR: Study design, data acquisition, data interpretation, revision of the manuscript. HS: Study design, data acquisition, data interpretation, revision of the manuscript. CMS: Study design, data acquisition, data analysis and interpretation, drafting of the manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "In the recent past, compliance with 21CFR11 has become a major buzzword within the pharmaceutical and biotechnology industries. While commercial solutions exist, implementation and validation are expensive and cumbersome. Frequent implementation of new features via point releases further complicates purchasing decisions by making it difficult to weigh the risk of non-compliance against the costs of too frequent upgrades. This presentation discusses a low-cost interim solution to the problem. While this solution does not address 100% of the issues raised by 21CFR11, it does implement and validate: (1) computer system security; (2) backup and restore ability on the electronic records store; and (3) an automated audit trail mechanism that captures the date, time and user identification whenever electronic records are created, modified or deleted. When coupled with enhanced procedural controls, this solution provides an acceptable level of compliance at extremely low cost."}
+{"text": "The transcription factor, milk protein binding factor (MPBF/Stat5), is a member of the STAT family of signalling molecules which mediates prolactin signal transduction in lactating mammary gland by binding to GAS (gamma-interferon activation site) DNA elements. We have determined the levels of STAT factors in nuclear extracts from a variety of human breast tissues including carcinoma and normal 'resting' breast by electrophoretic mobility-shift assay. The results show that the level of STAT binding activity is low in normal 'resting' breast and benign lesions while carcinoma samples have significantly higher (P < 0.01) amounts of STAT binding activity. Supershift analysis suggests that Stat1 and possibly other members of the STAT family of signalling factors, including Stat3, are activated in breast cancer tissues."}
+{"text": "The main results of these studies can besummarized as follows: (1) exogenous or endogenous catecholamines suppress PBL functions through alpha-2-receptor-mediatedmechanisms, lymphocytes of the spleen are resistant to adrenergic in vivo stimulation,(2) direct or indirect cholinergic treatment leads to enhanced ex vivo functions of splenic and thymic lymphocytesleaving PBL unaffected, (3) cholinergic pathways play a critical role in the \u201ctalking back\u201d of the immune system to the brain,(4) acetylcholine inhibits apoptosis of thymocytes possibly via direct effects on thymic epithelial cells, and maythereby influence T-cell maturation, (5) lymphocytes of the various immunological compartments were found to beequipped with the key enzymes for the synthesis of both acetylcholine and norepinephrine, and to secrete theseneurotransmitters in culture supernatantsFor several years, our group has been studying the"}
+{"text": "Autoimmunity and inflammation are associated with marked changes in lipid and lipoprotein metabolism in SLE. Autoantibodies and cytokines are able to modulate lipoprotein lipase (LPL) activity, a key enzyme in lipid metabolism, with a consequent \u201clupus pattern\u201d of dyslipoproteinemia characterized by elevated levels of very low-density lipoprotein cholesterol (VLDL) and triglycerides (TG) and lower high-density lipoprotein cholesterol (HDL) levels. This pattern favors an enhanced LDL oxidation with a subsequent deleterious foam cell formation. Autoantibodies and immunocomplexes may aggravate this oxidative injury by inducing accumulation and deposition of oxLDL in endothelial cells. Drugs and associated diseases usually magnify the close interaction of these factors and further promote the proatherogenic environment of this disease."}
+{"text": "The isoenzyme Mu of glutathione S-transferase (GSTM1) is dominantly inherited, and the prevalence of this isoenzyme in the population is about 60%. The lack of GSTM1 has been linked with cancer risk. The frequency of the phenotypes of this isoenzyme in melanoma (MM) patients (n = 197) is reported here. A significantly higher proportion of individuals in the control group (n = 147) had measurable GSTM1 than MM patients ; there was a higher proportion of positive phenotypes in general among women than among men. Odds ratio analysis indicated that individuals with this polymorphic variant have an approximately 2-fold risk of developing these cancers. GSTM1 phenotype distribution depends on age, smoking habit and tumour pathology. A group of MM patients with dysplastic naevi was also studied."}
+{"text": "A study was made of the relationship between the intrinsic radiosensitivity of human cervical tumours and the expression of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (HAP1). The radiosensitivity of clonogenic cells in tumour biopsies was measured as surviving fraction at 2 Gy (SF2) using a soft agar assay. HAP1 expression levels were determined after staining of formalin-fixed paraffin-embedded tumour sections with a rabbit antiserum raised against recombinant HAP1. Both measurements were obtained on pretreatment biopsy material. All 25 tumours examined showed positive staining for HAP1, but there was heterogeneity in the level of expression both within and between tumours. The average coefficients of variation for intra- and intertumour heterogeneity were 62% and 82% respectively. There was a moderate but significant positive correlation between the levels of HAP1 expression and SF2 . Hence, this study shows that there is some relationship between intrinsic radiosensitivity and expression of a DNA repair enzyme in cervical carcinomas. The results suggest that this type of approach may be useful in the development of rapid predictive tests of tumour radiosensitivity."}
+{"text": "Between January 1977 and January 1988, 19 patients with non-Hodgkin's lymphoma (NHL) involving the ileocaecal region were cared for by the CRC Wessex Medical Oncology Unit. Fifteen of these patients had primary ileocaecal NHL (stages IE or IIE) and four had secondary involvement of this region (stage IV). The commonest clinical presentation was with abdominal pain and a palpable mass in the right iliac fossa. Bulky (greater than 10 cm) disease was a particularly common feature, and complete surgical removal was possible in only seven patients. All patients had intermediate (18) or high grade (one) NHL using the Working Formulation. The commonest histological subtype was diffuse large cell. Seventeen patients received postoperative therapy, comprising local radiotherapy in one and combination chemotherapy in the remaining 16. Eleven of the 19 patients remain disease-free 6-60 months from diagnosis. Because of the high incidence of bulky disease at this site, postoperative therapy may be indicated, even for patients with apparently completely excised stage I disease."}
+{"text": "Sir,We read with great interest the article by The diagnosis of chronic pancreatitis was based on the radiologic data obtained by means of either endoscopic retrograde cholangiopancreatography or computed tomography.DNA was extracted from 20\u2009ml of the serum by using the QIAmp Blood Kit (Qiagen) and the mutations in codon 12 of the K-ras gene were searched as described previously (BstNl restriction enzyme (PCR-RFLP).As positive controls, we used DNA from neoplastic tissues of 10 patients with pancreatic carcinoma by using the DNeasy Tissue Kit (Qiagen). For molecular analysis, DNA was amplified in the codon 12 region introducing a restriction site (GACCT) for digestion with DNA from peripheral blood resulted not mutated in the 40 patients with chronic pancreatitis and in the 30 with pancreatic carcinoma, while DNA from pancreatic neoplastic tissue resulted mutated in 70% of the samples.To verify our results, all the samples were analysed by direct sequencing using Big Dye terminator v 1.1 cycle sequencing Kit and performing runs on ABI Prism 310 genetic analyzer (Applied Biosystem)Despite what was mentioned in Maire's article, we failed to find any mutations in all patients analysed, as well as we failed to correlate K-ras mutations with the levels of tumour markers such as Ca 19.9, CA242, CA50, CEA.The results of the present investigation lead us to these conclusions: (1) the eventual presence of cancer cells in peripheral blood may be a rare event, even if numerous reports support the detection of K-ras abnormalities in the serum, (2) neoplastic cells are supposed to circulate in clusters, and consequently their cognition could be hampered by a single blood sample extraction. (3) Large amounts of nonmutated DNA, coming from leucocytes held in the buffy coat layer, might also mask some vestiges of the mutant type of K-ras gene."}
+{"text": "Saccharomyces cerevisiae, has been established as part of our new drug discovery programme. Use of this assay has provided the first direct evidence that TOP1 and RAD52 proteins are involved in the mode of action of bisdioxopiperazine ICRF compounds, which thus express a mode of action quite distinctive from the other known TOP2 inhibitors evaluated. The functional assay is based on a comparison of pairs of yeast differing in their phenotypes by specific traits: the expression or lack of expression of ectopic human DNA topoisomerase I, with or without that of the RAD52 gene. Amongst a series of anticancer agents, inhibitors of topoisomerase I (camptothecin) were identified as such in yeast expressing human topoisomerase I, whilst the presence or absence of RAD52 protein permitted the discrimination of compounds generating double-stranded DNA breaks, either directly (bleomycin) or involving DNA adduct formation (cisplatin), or indirectly with DNA damage mediated via inhibition of the topoisomerase II enzyme (etoposide). Notably, however, both the RAD52 protein and the lack of TOP1 enzyme appeared implicated in the cytotoxic activities of the series of bisdioxopiperazine ICRF compounds tested. This functional assay in a living organism therefore appears to provide a valuable tool for probing distinctive and specific mode(s) of action of diverse anticancer agents. \u00a9 1999 Cancer Research CampaignA screening procedure which permits identification of compounds based on their activities against specific biological targets directly in a living organism,"}
+{"text": "The uptake, retention and effects of aluminium chloro sulphonated phthalocyanine (AlSPc) were measured in two cell lines, UV-2237 a murine fibrosarcoma and the non-tumorigenic NIH/3T3 fibroblast line. The behaviour of cells treated with AlSPc was compared with that of those treated with haematoporphyrin derivative (HpD), a photosensitizer often used in photodynamic therapy (PDT) of cancer. AlSPc absorbs light strongly in the red region, is taken up by cells in a dose dependent fashion and is retained in vitro over a period of days (5 days after exposure greater than 40% remains cell-associated versus less than 25% of HpD). Additionally AlSPc was less cytotoxic to cells, maintained in darkness or exposed to room light, compared to HpD (100% viability versus 0% viability 3 days after 60 min exposure to room light). However red light (approximately 600-700 nm) caused greater toxicity in AlSPc-treated cells (100%) than in similarly exposed HpD-treated cells (less than 60%). No significant differences were detected between the responses of the fibrosarcoma and the fibroblast cell lines. These characteristics of AlSPc suggest that it may prove to be a useful photosensitizer for PDT of cancer and this possibility is discussed."}
+{"text": "This investigation first set out to analyse which cellular proliferative and apoptotic factors, in addition to the clinical prognostic factors, are most predictive in patients with non-small-cell lung carcinomas (NSCLC). To this purpose, we related the proliferative factors proliferating cell nuclear antigen (PCNA), cyclin A, cyclin D1, cyclin-dependent kinase 2 (cdk2), cdk4 and the proportion of cell cycle phases in NSCLC to the survival times of 150 patients. Additionally, we associated the expressions of Fas, Fas ligand and caspase-3 in NSCLC to patient survival. Immunohistochemistry was used to determine the proteins and flow cytometry to assess the proportion of cell cycle phases. Patients with PCNA-positive carcinomas had significantly shorter survival times than patients with PCNA-negative carcinomas . Corresponding results were obtained with the factor cyclin A (64 vs 92 weeks), with the factor cdk2 (76 vs 89 weeks), with the factor cdk4 (62 vs 102 weeks) and with the proportion of S phases (86 vs 121 weeks). Patients with an expression of the apoptotic factors had a more favourable prognosis than patients with negative carcinomas. The median survival times of cancer patients with Fas expression was 86 weeks and of those without Fas expression only 69 weeks. Corresponding results were obtained with the Fas ligand (87 vs 41 weeks) and caspase 3 (87 vs 34 weeks). In order to determine whether a combination of factors can yield improved prognostic information, we investigated all possible combinations of the proliferative and apoptotic factors. Patients with tumours having a high proliferative activity, but which did not express apoptotic factors had the shortest survival times while patients with a low proliferative activity and a high expression of apoptotic factors had the most favourable outcome. A multivariate analysis (Cox model) of the cellular and clinical prognostic factors indicated that stage, lymph node involvement, Fas, PCNA and cyclin A are the most important prognostic factors for the clinical outcome of patients with non-small-cell lung carcinomas. \u00a9 2000 Cancer Research Campaign"}
+{"text": "Epidemiological evidence has implicated Chinese salted fish as a human nasopharyngeal carcinogen. In the present study, 221 Wistar-Kyoto rats aged 21 days were randomly assigned to one of three experimental groups. Rats in group 1 (high dose group) were fed a powder diet of one part Chinese salted fish to three parts certified rat chow during the first 18 months. Similarly, rats in group 2 (low dose group) were fed a powder diet of one part salted fish to five parts rat chow for 18 months. Rats in group 3 were given rat chow only throughout the 3-year experiment. Four malignant tumours of the nasal cavity were observed among rats fed the experimental diets (three and one respectively in the high and low dose groups). No comparable tumours were observed in controls, compatible with the historical control rate of zero. Our results, therefore, further strengthen the hypothesis that Chinese salted fish is a human nasopharyngeal carcinogen; they also establish Wistar rats as a viable animal model for carcinogenicity studies of this food in the laboratory."}
+{"text": "From 1996 through 1999, 35 deer mice (Peromyscus maniculatus) were captured in 25 urban and suburban homes in southwestern Montana. Mice were captured throughout the year except for January; seven mice (20%) from seven (28%) of the homes were seropositive for Sin Nombre virus. The infected mice were mostly adult males captured in the spring and fall."}
+{"text": "A new autofluorescence (AF) system for bronchoscopy that operates as compact as aconventional white light bronchoscopy system is described. The system is also capable of whitelight illumination and excitation of aminolevulinic acid (ALA) induced fluorescence. Changing between white light and (auto-) fluorescence mode is easy and always possible. Broad band excitation with blue light  delivers highintensity illumination at the distal end of the bronchoscope . A specialoptical observation technique makes the AF directly visible to the eye instead of indirecttechniques used in other AF systems. A compact (160 g)and sensitive camera can be used for documentation."}
+{"text": "No numerical aberration of chromosomes that might be specific for prostate cancer has so far been established. We used fluorescence in situ hybridisation (FISH) with centromere-specific probes for chromosomes 7, 8, 17, X and Y to establish the distribution of centromere copy numbers in frozen-stored or freshly prepared samples of benign prostate hypertrophy (BPH) and to detect numerical aberrations of these chromosomes in 28 prostate cancers from Japanese men. There was no significant difference in the data of centromere copy numbers between fresh and frozen-stored tissue. The most common aberration in prostate cancers was a gain of chromosome 8 (57%), with numerical aberration of chromosome 7 being the second most frequent anomaly (50%). Numerical aberration of chromosome 7 is most significantly associated with a higher Gleason score (GS) (P < 0.005) or with lymph node metastasis (P < 0.001). Numerical aberration of several chromosomes, including chromosomes 7 and/or 8, was common in aggressive prostate cancers. Loss of chromosome Y was detected in only 4% of cases. FISH analysis thus proved to be a useful method for detecting numerical aberrations of individual chromosomes, with application to touch preparations of frozen-stored tissue having the advantage of exact sampling of cancer foci. The results suggest that numerical aberration of chromosome 7 is associated with aggressive tumour behaviour and poor prognosis of patients with prostate cancer. The association between genetic change and chromosomal abnormality should be studied in detail."}
+{"text": "Idiopathic juxtafoveolar retinal telangiectasis (IJRT) group 1A usually affects one eye of young and middle aged male patients.1 TelangieA 40-year-old healthy male was referred to us for visual distortion and inability to see in the upper left field of vision in the right eye (OD) for six weeks. Medical work-up and laboratory tests excluded the presence of any systemic ailment including hypertension and diabetes mellitus. The best-corrected visual acuity was 20/30 OD and 20/20 in the left eye (OS). Anterior segment examination showed no cell or flare in the anterior chamber or in the anterior vitreous in both eyes (OU). Intraocular pressure (IOP) was 15 mmHg OU. Dilated fundus examination OD showed abnormal telangiectatic blood vessels and hard exudates temporal to the fovea as well as cystic appearance in the foveal area . The funOver the next one year the patient was followed closely without improvement in vision (following laser treatment) or change in the fundus appearance. However, 15 months after the initial examination, his vision dropped to 20/50 OD with significant increase in macular edema clinically and on OCT . The cenOn the basis of biomicroscopic and fluorescein angiographic patterns, Gass and Blodi have classified IJRT into three groups: Group 1 Laser photocoagulation and photodynamic therapy of the telangiectatic capillaries in IJRT group 1A are reported to be effective in reducing the foveolar edema and exudation.\u20134 Howeveet al. and Maia et al. successfully treated their patients of group 1 IJRT with intravitreal injection of triamcinolone acetonide.[There was dramatic improvement in vision two weeks following intravitreal triamcinolone injection in the present case. The vision improved along with resolution of macular edema that was confirmed on clinical examination and on OCT. Li cetonide.6 Both thOur experience with this patient demonstrates that intravitreal triamcinolone acetonide may be considered an additional therapeutic option besides photocoagulation in the management of IJRT group 1A, especially when the latter treatment is ineffective. Moreover, OCT is a useful non-invasive tool that helps in diagnosing the disease and following it over the years. Further long-term case controlled prospective studies evaluating the safety and efficacy of this treatment modality for patients with IJRT group 1A are warranted."}
+{"text": "In vivo growth characteristics of myeloid leukaemia induced by whole-body irradiation of CBA/H male mice were examined in the strain of origin by procedures expected to enhance or depress immunological responses. Syngeneic growth in vivo  was not modified by attempted active immunization with radiation-inactivated cells or by sublethal whole-body irradiation of recipients before inoculation of small numbers of clonogenic cells. Since the growth stimuli involved in in vivo repair of severely damaged normal haemopoietic tissue also did not modify the growth of the radiation-induced leukaemia cells in syngeneic passage, their growth in vivo in the irradiated primary hosts can be regarded as autonomous by the stage at which leukaemia was diagnosed. Challenge inocula in the \"immunization\" experiments were 1-9 clonogenic cells from 4 different passaged lines and in the whole-body radiation experiments, 1-10(3) clonogenic cells derived from 11 different primary hosts and 4 different passaged lines."}
+{"text": "Introduction and aim. Management of complicated wounds after tumor extipiration of pelvic and proximal lower limb musculoskeletal sarcoma represents an essential component in the outcome of these patients. The authors present modified vertical rectus abdominis musculocutaneous (VRAM) flap techniques to reconstruct extensive defects after debridment of these complicated wounds. Material and Methods. Over a period of 4 years (2002\u20132005), 5 men and 2 women were managed. Median age was 21 years (range 15\u201349). The patients were managed for complicated lower trunk, groin, and upper thigh wounds after resection of three pelvic chondrosarcomas as well as two pelvic and two proximal femur osteosarcomas. The modifications included a VRAM flap with lateral and tongue-like extension design of the skin paddle (5 cases) or a delayed extended VRAM flap (2 cases). Results. All flaps showed complete survival and healing with no ischemic events providing stable coverage. All patients were ambulant with good limb functions in terms of walking and gait after adequate rehabilitation, 2 needed support with crutches. Conclusion. The modified VRAM flaps offer reliable reconstructive tools for coverage of complex groin and thigh defects by providing larger well-vascularized soft tissue with acceptable donor site. Limb salvage remains a major objective in contemporary management ofbony and soft tissue sarcomas of the pelvis and lower extremities , 2. RadiSeven consecutive patients with complicated wounds secondary to resection of pelvicand proximal lower extremity musculoskeletal sarcoma were managed with modified VRAM flaps between2002\u20132005. The medianage of the patients in this series at the time of surgery was 21 years (range15\u201349) and included 5 men and 2 women. The modifications included VRAM flapwith lateral and tongue-like extension design of the skin paddle (5 cases) or adelayed extended VRAM flap (2 cases). All the patients have been treated with amultidisciplinary approach; the management of osteosarcoma patients  included a 4-month course of neoadjavant chemotherapyfollowed by resection of the primary tumor and postoperative 3-month course of chemotherapy;while chondrosarcoma patients (3 pelvic) were offered surgical resection only.The complications, which necessitated management by the plastic andreconstructive surgeons, included infection and wound dehiscence with ultimateexposure of metal prosthesis (4 patients) and necrosis of thigh flaps (3patients). The median interval duration between the primary operation and thereconstructive procedure for the complicated wounds was 16 days (range: 13\u201336).All patients underwent thorough clinical assessment, adequate debridment andirrigation of the wounds, followed by immediate coverage of the resultantdefects (median size 7 \u00d7 17\u2009cm) usingmodified VRAM flaps.This technique was used to cover exposed metal plates dueto wound breakdown after osteosarcomas resection of proximal femur where lengthof the flap was predominantly required than its width. An ipsilateralparasternal skin paddle was designed 10\u2009cm cephalic to the costal margin and 2\u2009cm from the lateral sternal edge. The pinch test, originally described byTaylor et al. , was useThis technique was used in cases after resection ofchondrosarcomas and osteosarcomas of the pelvis, which necessitated thedevelopment of large subcutaneous thigh flap to allow adequate exposure andvascular exploration to achieve adequate oncological resection. Extensive full-thicknessthigh flap necrosis occurred in these patients which necessitated adequatedebridement and coverage of the resultant defect utilizing a contralateral,laterally oriented VRAM with a tongue-like skin extension. The contralateralmuscle was selected due to the sacrifice of the ipsilateral inferior epigastricpedicle as part of the radicality of the primary tumor resection. The lateralorientation of the skin paddle was designed to be oblique (45\u00b0) tothe longitudinal axis of the rectus muscle to provide an average extra lengthof 5\u2009cm. The tongue-like extension ofthe skin paddle was designed throughout the whole length of the muscle taperingtowards the pivot point of the flap at the entry of the inferior epigastricpedicle. The fasciomusculocutaneous component of the VRAM flap was harvestedutilizing the standard technique with elevation of the laterally oriented partof the flap in the fascial plane. Theorigin and insertion of rectus muscle were transacted leaving the vascular pedicle asthe sole tether point; this significantly increased the arc of rotationallowing more muscle mass to be transposed to the wound. Incising the skinbridge between the donor and recipient defect to lay open the tunnel connectingthe recipient and the donor site followed this. The tongue-like skin extension provided the roof foropened tunnel after rotation of the flap to settle to the defect; allowing moreroom for the pedicle and providing coverage for the medial part of the defect.In all patients, the donor site was closed primarilyafter reinforcement of the abdominal wall using an onlay prolene mesh, suctiondrains were used both at the recipient and donor sites. All patients weremobilized within 2 weeks postoperatively under supervision of the orthopaedicand physical therapy team. The mean duration to postoperative chemotherapy was3 weeks. The mean follow-up period was 26 months at which patients were followed up with assessment of the oncological outcome, durability of soft tissue reconstruction, and finally assessing the functional outcome using Enneking system,All flaps showed complete survival and healing withno ischemic events, hence providing stable coverage. Mild infection wasobserved in 1 patient; no haematomas were detected. All patients were ambulantwith good limb functions in terms of walking and gait after adequaterehabilitation; 2 needed additional support with crutches. All patients showedgood emotional acceptance; and no pain has been observed during ambulation inall patients. One patient developed incisional hernia at the donor site that requiredrepair 1 year later; otherwise, no other donor site morbidity was noted.Another patient died of haematogenous metastatic spread after completeresection 15 months later. There was no hypertrophic scar formation or flapbreakdown experienced on long-term follow-up in any of the patients.Limb preservation has become a more realistic andnecessary goal in the management of patients with musculoskeletal sarcoma ofextremities . RadiatiThe reconstructive options to provide coveragefollowing debridment of these complicated wounds would be local, distant flaps,or free-tissue transfer. VRAM flaps havebeen used successfully in coverage of defects of the chest wall, groin, hip,perineal, vaginal, and gluteal regions with good functional outcomes \u201317. The The delayed phenomenon has been used for many yearsto enhance functional blood flow through vasodilatation of the arterial networkand avoidance of complete vasoconstriction caused by catecholamine release, andhence it increases the flap reliability especially in high-risk patients , 24. TheThe authors believe that these modifications willprovide reliable extralength of soft tissue, which is tension free with a widerarc of rotation, better filling of dead space with well-vascularized tissue soas to resist infection, and stable coverage with good functional outcome.Other modalities described for management ofcomplicated infected wounds as skin grafting or vacuum-assisted closure wouldnot be suitable due to the presence of dead space and exposed hardwareprosthesis after debridement , 4, 27. The use of free-tissue transfer is rare in theseclinical scenarios; on the other, hand-free osteocutaneous fibular flaps wereperformed for primary skeletal reconstruction after tumor extipiration ofsarcoma of the lower extremities  rather tIn conclusion, the modified VRAM flaps would offerreliable reconstructive tools for coverage of complicated primary wound withnecrosis and breakdown after radical resection of pelvic and proximal lowerlimb musculoskeletal sarcoma. They offer larger well-vascularized soft tissuewith acceptable donor site, more durable coverage with no delay in thepostoperative adjuvant therapy, good functional outcome, together with overallimprovement in the survival."}
+{"text": "A method was developed for delineating the structure ofparamagnetic metal complexes. The selective disappearanceof cross-peaks in proton-carbon shift correlated 2D NMRmaps was shown to uniquely depend upon the scalar and/ordipolar interaction between ligand nuclei and the unpairedelectron(s), thus providing a means of identifying bindingsites. Copper(II) was shown to form metal complexes withboth Penicillin (PNC) and Pilocarpine (PLC) and the structureof the two 1:2 complexes in water solution at physiologicalpH were determined."}
+{"text": "Solid tumours develop an acidic extracellular environment with high concentration of lactic acid, and lactic acid produced by glycolysis has been assumed to be the major cause of tumour acidity. Experiments using lactate dehydrogenase (LDH)-deficient ras-transfected Chinese hamster ovarian cells have been undertaken to address directly the hypothesis that lactic acid production is responsible for tumour acidification. The variant cells produce negligible quantities of lactic acid and consume minimal amounts of glucose compared with parental cells. Lactate-producing parental cells acidified lightly-buffered medium but variant cells did not. Tumours derived from parental and variant cells implanted into nude mice were found to have mean values of extracellular pH (pHe) of 7.03 +/- 0.03 and 7.03 +/- 0.05, respectively, both of which were significantly lower than that of normal muscle . Lactic acid concentration in variant tumours (450 +/- 90 microg g(-1) wet weight) was much lower than that in parental tumours (1880 +/- 140 microg/g(-1)) and similar to that in serum (400 +/- 35 microg/g(-1)). These data show discordance between mean levels of pHe and lactate content in tumours; the results support those of Newell et al (1993) and suggest that the production of lactic acid via glycolysis causes acidification of culture medium, but is not the only mechanism, and is probably not the major mechanism responsible for the development of an acidic environment within solid tumours."}
+{"text": "Automated Flow Injection Gas Diffusion (FIGD) promotes theselective transmembrane diffusion of MAs and NH3 from aqueoussample under strongly alkaline , chelated (EDTA) conditions into a recycled acidic acceptor stream. The acceptor is then injected onto an ion chromatograph where NH3 and the MAs are fully resolved as their cations and detectedconductimetrically. A versatile PC interfaced control unit and data capture unit (DCU) are employed in series to direct the selonoid valve switching sequence, IC operation and collection of data. Automation, together with other modifications improved bothlinearily  andprecision (<8%) of FIGD-IC at nanomolar concentrations, compared with the manual procedure. The system was successfully applied to the determination of MAs and NH3 in seawater and in trapped particulate and gaseous atmospheric samples during anoceanographic research cruise.The automation and improved design and performance of FlowInjection Gas Diffusion-Ion Chromatography (FIGD-IC), a novel technique for the simultaneous analysis of trace ammonia (NH"}
+{"text": "A simple, rapid histone agglutination test (HAT) is described. It consists of incubation in microplates or in microtubes of blood lymphocytes isolated from cancer patients and patients with non-malignant diseases with microquantities of histone fraction F2A1. Positive reaction is shown by massive agglutination of lymphocytes of the patients tested (126 subjects): this test was positive in 76% of cases. All controls (59 subjects) were negative."}
+{"text": "By analogy with the case of [Pt(en)2]Cl2 it is suggested that Auen acts as a minor groove binder.Reactions of the complexes bisethylendiammine gold(III) and bisethylendiammine platinum(II) with calfthymus DNA were comparatively analysed. Both complexes bind DNA non-covalently most probably on the basis of electrostatic interactions. Binding of either complex at low ratios results into modest modifications of B-type DNA conformations, as detected by CD. Far larger CD alterations are observed at high ratios. The gold(III) chromophore is scarcely perturbed by DNA addition Binding of [Au(en)"}
+{"text": "During a 15-month period, we used in vivo bromodeoxyuridine (BUDR) infusion to study cell kinetics in 112 consecutive patients with various types of malignant tumours: acute leukaemia (50 patients), gastric cancer (42) and brain gliomas (20). The in vivo BUDR method requires that a single tumour sample be taken 4-6 h after infusion and that bivariate flow cytometry (FCM) be employed to measure simultaneously the percentage of BUDR-labelled cells  and their mean DNA content (following propidium iodide staining). This technique rapidly furnishes the labelling index (LI) and the DNA synthesis time (TS), from which the tumour potential doubling time (Tpot) and production rate  are calculated. The procedure took 6-9 h to complete and there was no immediate toxicity from BUDR administration. Successful LI and TS determinations were obtained in 89 (80%) and 80 (72%) of the 112 patients, respectively. Correlations were sought between kinetic parameters and a number of pathological and clinical ones. In 34 patients with acute non-lymphoblastic leukaemias who were uniformly treated for remission (CR) induction and maintenance, proliferative activity, as measured by Tpot and FTR, was greater in responsive than in non-responsive patients, and in those who experienced CR for over 8 months than in those who had a shorter CR. Proliferative activity was also greater in patients with advanced gastric cancers than in those with more limited disease. No correlations between kinetic and clinical and pathological parameters were found in gliomas. These data indicate the in vivo BUDR infusion coupled with FCM measurements can be performed in clinical settings to obtain kinetic data rapidly in quite large patient series. This will probably allow the inclusion of kinetic data in clinical trials aimed at evaluating the prognostic relevance of these data."}
+{"text": "Long-term cognitive and educational sequelae have been inconsistently reported in children who received cranial irradiation (CRT) to prevent central nervous system (CNS) disease in acute lymphoblastic leukaemia (ALL). This study investigates a large and representative sample of survivors of ALL and compares them with non-irradiated survivors of cancer and healthy control children to determine the effect of CRT on cognitive and educational ability. Three groups of children were studied: Group 1 (n=100) survivors of ALL treated with chemotherapy and CRT, group 2 (n=50) children with a variety of malignancies treated with chemotherapy alone, group 3(n=100) healthy children. Cognitive and educational abilities of these groups were evaluated using standardised psychometric techniques. Significant differences in cognitive and educational abilities were found between the children in group 1 (chemotherapy + CRT) and the two control groups, with the children receiving CRT performing less well in a range of tests. Greatest differences were detected for tasks dependent on language function including verbal IQ, reading and spelling. Within group 1 a younger age at treatment (less than 5 years) and a higher dose of CRT (24 Gy vs 18 Gy) were predictive of poor long-term outcome for cognitive and education ability. In contrast, children who received chemotherapy alone, with or without intrathecal methotrexate, performed similarly to healthy controls. No gender differences were detected for these measures."}
+{"text": "Alterations in DNA ploidy accompany hepatocellular carcinoma (HCC). However, changes in DNA content are also seen in regenerating liver and with increasing age. Thus, to investigate the role of DNA ploidy changes in development of HCC, flow cytometric DNA content determinations were done in a rat model system of peroxisome proliferator-induced HCC. Paraffin blocks of liver isolated from 18 Fisher 344 male rats fed ciprofibrate for 20 weeks (4), 40 weeks (4) or 20 months (10) were examined. Livers from age-matched control rats were also examined. From the 20 month ciprofibrate group, nine neoplastic nodules (NNs), 27 HCCs and four non-tumorous surrounding tissue controls (NTCs) were examined. Significant DNA tetraploid populations were seen in both the NNs and NTCs. A significant increase in the percentage of DNA diploid cells was observed in the NN samples. No significant difference in the percentage S-phase cells was seen. Emergence of cell populations with new DNA ploidy classes (8c or DNA aneuploid) as compared with NTCs was only seen in HCCs (7 of 27), and five of these seven were DNA aneuploid, as distinct from DNA tetraploid, populations. A total of 16 of 24 HCC samples that were adequate for cell cycle analysis had average percent S-phase greater than the mean of the NTCs plus three standard deviations. Although a direct role cannot be inferred, these results support the hypothesis that increases in the fraction of diploid cells is an important early event in the development of rat HCC and that further alterations in DNA ploidy and increased proliferative fraction accompany the development of HCC."}
+{"text": "Copper(II) complexes of several hydroxyflavones were prepared and characterised through their physico-chemical properties. The nuclease activity of three synthesised complexes is reported. These copper(II) complexes present more nuclease activity than the ligands and the copper(II) ion."}
+{"text": "We examined hepatic artery ligation combined with an angiogenesis inhibitor, TNP-470, in the treatment of VX2 tumour inoculated into the liver of rabbits. Effects on tumour growth were correlated with arterial collateral development in this system. Three treatment methods were compared: (1) the left hepatic artery was ligated at the liver hilum (ligation group); (2) TNP-470 (40 mg per body) was infused continuously for 7 days via the common hepatic artery (TNP group); (3) the left hepatic artery was ligated and TNP-470 was infused continuously for 7 days via the common hepatic artery (ligation + TNP group). These treatments were started 12-14 days after tumour inoculation. The day of initiating treatment was defined as day 0. Although there were no significant differences in tumour volume among the three treated groups on day 7 after treatment, tumour volumes in the ligation + TNP group were significantly smaller than in the ligation group and the TNP group on day 14 after treatment. The vasculature and arterial collaterals around the tumour were demonstrated by the perfusion of a silicon rubber solution, Microfil. In the ligation + TNP group, the new microvasculature around the tumour decreased compared with the ligation group. The TNP-470 inhibition of microvascular proliferation may limit the development of collaterals that communicate with new feeding arteries. These results suggest that transarterial embolization combined with TNP-470 may enhance the anti-tumour effect of transarterial embolization alone in the treatment of liver tumours."}
+{"text": "The hormonal mechanisms involved in the development of gynaecomastia accompanying the treatment of multiple myeloma in adult men have been investigated by studying levels of circulating testosterone (T), oestrone (EI), oestradiol (E2), sex-hormone binding globulin (SHBG), prolactin (PRL) and the gonadotrophins LH and FSH, before, during and after development of gynaecomastia in 4 men. These have been compared with 5 closely matched men who did not develop gynaecomastia during similar treatment for myeloma. Levels of circulating T fell, and levels of E1 and E2 rose during treatment periods in all subjects, and the changes were statistically significant in subjects developing gynaecomastia, which resolved as levels of sex steroid returned towards normal following cessation of treatment. We conclude that treatment of adult men for myeloma results in testicular dysfunction with a reduction in circulating T and a rise in circulating oestrogens. These changes are most marked in subjects developing gynaecomastia in whom the normal breast tissue is stimulated by a subtle, transient oestrogen:androgen imbalance in favour of oestrogens."}
+{"text": "Twenty-four symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with cisplatin-based chemotherapy . Patients were assessed for symptom relief as well as for objective response. Although only five patients achieved an objective response (21%), 18 patients (75%) reported a complete disappearance or good improvement in at least one of their tumour-related symptoms. The overall symptomatic response rate was 67% with 16 patients feeling better or much better on treatment. The toxicity of treatment (primarily myelosuppression and nausea and vomiting) was mild and hair loss was minimal. The high incidence of symptomatic relief seen in this study, even in the absence of objective response, suggests that moderate dose chemotherapy may have a role in the palliation of NSCLC."}
+{"text": "Activation of the RET tyrosine kinase domain occurs in a proportion of thyroid papillary carcinomas. Three chromosomal rearrangements have been described, of which PTC1 is the commonest. Wide differences (2.5-25%) in frequency of PTC1 in different populations have been reported; it is not clear whether these are due to environmental factors, racial differences or technical reasons. We have developed a simple and rapid reverse transcriptase nested polymerase chain reaction (RT-nPCR) method enabling the detection of gene expression from single 5 microns sections of formalin-fixed paraffin wax-embedded archival material. We have applied this approach to detect expression of the RET tyrosine kinase domain, allowing identification of RET activation resulting from any rearrangement, whether characterised or not, or from overexpression. A retrospective study was performed on 22 adult and 21 childhood papillary carcinomas. Thirteen of 22 (59%) adult and 10 of 21 (48%) childhood carcinomas showed evidence of RET activation, demonstrating a major role for the RET oncogene in UK thyroid papillary carcinogenesis. This study also shows a similar frequency of RET activation in both children and adults. The use of a technique that allows reliable amplification of RNA from archival material, using primers chosen in different exons so that amplified products are readily distinguished from genomic DNA, will allow correlation of translocations and chromosomal rearrangements with a variety of specific tumour types."}
+{"text": "A lymphocyte stimulation assay is described which detects immune reactivity to antigens derived from the CaSki cervical carcinoma cell line. Taking a stimulation index of greater than 4.1 as positive, the peripheral blood lymphocytes of 14/20 patients (70%) with untreated dysplasia or carcinoma-in-situ, 8/19 patients (42%) with untreated macroinvasive squamous cell carcinoma of the uterine cervix and 8/38 controls (21%) showed positive reactions. Statistical analysis revealed a significant difference between the group of patients with dysplasia or carcinoma-in-situ and the controls. The sera of patients and controls were simultaneously tested for the presence of tumour-directed antibody. There was no correlation between the occurrence of cellular immune reactivity and of serum antibody, both directed to cervical carcinoma antigens. Cellular immune reactivity tended to occur more frequently in patients with preinvasive stages of cervical carcinoma, and serum antibody in patients with macroinvasive carcinoma."}
+{"text": "These data stimulate further epidemiological and functional studies focusing on the role of homocysteine and folate metabolism in lymphoma tumorigenesis.Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. We analysed different functional genetic variants affecting the folate and homocysteine metabolism important for DNA integrity in 31 PCNSL patients and 142 controls. We found significantly less carriers of the methionine synthase c.2756A>G (D919G) missense polymorphism among the patients (0.16  S-adenosylmethionine (SAM) as a cosubstrate in DNA methylation.Primary central nervous system lymphomas (PCNSL) are highly malignant non-Hodgkin's lymphomas (NHL). The vast majority of them are of the diffuse large B-cell type . GeneticFigure 1We performed a case\u2013control study using DNA samples of 31 German patients with PCNSL of the DLBCL-subtype .The Hardy\u2013Weinberg equilibrium was confirmed for all polymorphisms. Allele frequencies of the control group did not significantly differ from those reported in the literature  or \u03c72-analysis . Further, we did not find any significant association of the other polymorphisms  or combinations with PCNSL.The CBS 844ins68 polymorphism was detected more frequently in patients (26%) than in controls (14%). However, the difference did not reach statistical significance in regression analysis  is associated with a lower risk of developing colorectal cancer and types of systemic NHL  against PCNSL and encourage future studies investigating the influence of genetic and dietary conditions of homocysteine and folate metabolism on cancerogenesis."}
+{"text": "Serologic and molecular evidence indicates that peste des petits ruminants virus (PPRV) infection has emerged in goats and sheep in the Ngari region of southwestern Tibet, People\u2019s Republic of China. Phylogenetic analysis confirms that the PPRV strain from Tibet is classified as lineage 4 and is closely related to viruses currently circulating in neighboring countries of southern Asia. Peste des petits ruminants (PPR) is an acute and highly contagious viral disease contracted by small ruminants such as goats and sheep and causing high rates of illness and death. The disease is endemic in parts of sub-Saharan Africa, the Middle East, and Asia. The PPR virus (PPRV) genogroup consists of 4 lineages  in the Ngari region, where animals having clinical signs of PPRV infection had been reported by local authorities. The second group included 298 animals in Gar and Bulang counties in the same region and in 2 counties bordering the Ngari region (Nyima in Nagqu region and Zhongba in Shigatse region). The third group contained 520 animals in 5 counties within 3 separate regions . We examined 1,536 animals (771 goats and 765 sheep) and collected serum samples from each. A competitive ELISA that used a monoclonal antibody to the N protein . Rates oField samples, including organ  and swab specimens, were obtained from 49 goats and sheep suspected of being infected with PPRV. These animals inhabited 4 counties in the Ngari region . Two reverse transcription\u2013PCRs (RT-PCR) and 1 newly developed and validated real-time quantitative RT-PCR (qRT-PCR) were conducted to determine whether the animals had viral RNA .The study confirmed 11 outbreaks in 4 counties in the southwest Ngari region in Tibet. Nine of the 11 occurred in southern Rutog County, northern Ge\u2019gyai County, and Gerze County, and samples from these 9 were seropositive for PPRV , panel AThe nucleic acid sequences obtained from the PCR products were aligned with sequences from PPRV strains available in GenBank. Partial sequencing (448 bp) of the F gene showed that 20 of 21 samples were identical over the portion of the genome that was characterized (GenBank accession no. EU816772). One (GenBank accession no. EU815053) differed from other Ngari sequences by 1 nt. The Ngari sequences showed a level of nucleotide identity with other PPRV strains of 88.8%\u201398.8%. Strains of PPRV from Tibet were classified as lineage 4 and were closely related to the India/Bsk/Guj/05 strain isolated in India in 2005 , panel AIn this study, PPRV was found by collecting samples from animals in the field and detecting infection by using competitive ELISA and RT-PCR. Our research provides valuable data on PPRV infection in small ruminants in Tibet. Infection was observed in 4 counties in the Ngari region of southwestern Tibet. Most outbreaks occurred in Rutog and Ge\u2019gyai counties; 1 outbreak was confirmed in Gerze County and another in Zada County. Epidemiologic and serologic evidence suggests that the infection first emerged in Rejiao village in southwestern Rutog from November 2005 through March 2006. PPR likely existed for several years without being recognized in Tibet because veterinarians, animal health workers, and livestock owners in the area are unfamiliar with its clinical and pathologic features. Also, this disease is frequently confused with other diseases that cause respiratory problems and death in small ruminants (The molecular epidemiologic techniques provided data suggesting cross-border transmission of PPRV infection into Tibet. PPR infection has been recognized in many Asian countries bordering southwestern China, including India ("}
+{"text": "Single cell suspensions of two allogeneic tumours (W-256 and Y-P388) injected intravenously produced macrocolonies in the lungs of rats. Colony forming efficiency  was low in 6-week or older rats but was markedly increased by 1000-1500 rad local thoracic irradiation (LTI) given 7-14 days before the tumour cell injection, or by antilymphocytic serum (ALS) but not by sublethal whole body irradiation (WBI). Similarly, LTI increased the incidence of pulmonary metastases produced by a solid tumour growing in the leg muscle. Stimulation of CFE by LTI was a strictly local phenomenon and not due to effects of irradiation on thymus, spleen or other tissues of the rat. LTI failed to increase CFE in immunized rats. It is concluded that (1) LTI stimulates clonogenic growth of tumour cells arrested in the lungs, by causing inflammatory reactions accompanied by regenerative cellular proliferation of lung tissue, which increases the \u201cplating\u201d efficiency of tumour cells, (2) the increase in CFE in lungs is not due to suppression of immunity to tumour growth by LTI."}
+{"text": "The full spectrum technique in the fourier domain was studied forsimultaneous determination of Cu(II), Pb(II) and Cd(II) with 4-(2-pyridylazo) resorcinol (PAR). A program called SPGRFSQ. was designed to perform the calculations. Seven error functions were calculated for deducing the number of factors. Data reduction was performed using principal component analysis (PCA) algorithm. Experimental results showed the method to be successful even where there was severe overlap of spectra."}
+{"text": "Knowledge and awareness about childhood autism is low among health workers and the general community in Nigeria and other Sub-Saharan African countries. Poor knowledge and awareness about childhood autism, especially among health workers can compromise early recognition and interventions which had been known to improve prognosis in children with autism. In formulating policy and designing interventions for these children, there is need to develop a reliable tool that can be used in assessing baseline knowledge about childhood autism among health workers and the impact that future continued education and awareness campaign may have on such baseline knowledge. Knowledge about childhood autism among health workers (KCAHW) questionnaire was designed for this purpose.The KCAHW questionnaire is a nineteen (19) item self-administered questionnaire that is divided into four domains. KCAHW questionnaires were distributed to fifty (50) psychiatric nurses involved in community mental health services in South-Eastern Nigeria to complete. After two weeks period, the KCAHW questionnaires were re-administered to the same fifty (50) psychiatric nurses to assess their knowledge about childhood autism and to assess the test-retest reliability and internal consistency of this questionnaire.KCAHW questionnaire showed good test-retest reliability when the mean domain and total scores at first and second time administration were compared. The four mean domain scores and the mean total scores at first and second time administration were significantly correlated. The questionnaire also had a good overall internal consistency when the mean scores of the four domains were correlated with mean total scores .The KCAHW questionnaire is a reliable tool for assessing knowledge of health workers about childhood autism. It would be a useful tool in improving early recognition of features of autism among affected children in Sub-Saharan African and other developing countries of the world where knowledge and awareness about childhood autism is low. Since Leo Kanner's paper titled, \"Autistic disturbances of affective contact\" about seven decades ago , awareneEarlier survey on knowledge about childhood autism among health care workers had been by Stone . The stuRhoades et al  exploredThe above surveys coming from the United States of America (USA), an environment where knowledge and research about childhood autism are more widely spread than what obtains in sub-Saharan Africa point to the need to assess knowledge and awareness in this environment and put in place programs to increase such knowledge and awareness with the ultimate aim of helping children with ASD.It had been presumed that in view of the rarity of presentation of childhood autism cases in pediatric health facilities in developing countries especially Sub-Saharan Africa, health care workers especially the nurses who are often in charge of various Primary Health Care (PHC) facilities in rural communities in Africa might not be well versed with the condition. Subsequently, early identification at the community level and intervention which have been shown to improve the prognosis of these cases ,21,22 maThis presumption was put into test in May 2007, when African Network for the Prevention and Protection Against Child Abuse and Neglect (ANPPCAN), Nigeria Chapter in collaboration with the World Bank carried out a survey to ascertain the level of knowledge and awareness of health care workers and the general public in Enugu State, South Eastern Nigeria on autism and implemented a project aimed at increasing the level of awareness on autism.The results of the survey showed that there is a very low level of awareness on autism among the general public and a low to average level of awareness among various categories of health care workers, with highest level of awareness noted among those health workers working in psychiatric facilities. Attempt was made then, to increase the level of awareness on autism through a workshop organized for the stakeholders and a radio phone \u2013 in program for the general public. However, one of the problems encountered during the survey was the unavailability of easily understandable and reliable questionnaire for measurement of the health care workers baseline knowledge of autism, aimed at early identification of cases in the community . The KCAIt had therefore been established that knowledge and awareness on autism and ASD is low in south-eastern Nigeria and there had been recent outcry in Nigeria to promote knowledge and awareness about childhood autism among the health care workers and the general community .In doing this, there is need for baseline assessment of present knowledge, facilities in place for intervention among other things. This would ensure proper planning. Promoting awareness at the community level should begin with various health workers who are involved in community health services. They can be trained to become trainers of other category of people in the community towards early recognition of children with childhood autism.For proper design of community campaign and continued education needed for these health workers, the need arises to design a reliable tool that can be used in measuring their baseline knowledge about childhood autism and the possible impact that future continued education and campaign may have on the knowledge of these health workers about childhood autism.Knowledge and awareness about childhood autism may vary from one geographical region to another. The same tool can be used to assess variation in knowledge of the disease condition over different geographical regions, given an index of geographical locations where immediate attention need to be focused as regards health workers and community education.\"Knowledge about Childhood Autism among Health Workers (KCAHW) Questionnaire\" for use in various communities of developing countries where knowledge about childhood autism is limited among the health workers working at the community level.The above reasons inform the design of This article is aimed at describing the content of KCAHW questionnaire and reporting the test-retest reliability and internal consistency of the questionnaire.Location of the study was at Federal Neuro-Psychiatric Hospital, New Haven, Enugu (FNHE), Nigeria. FNHE is a specialist Psychiatric Hospital located in the South-Eastern region of Nigeria. The hospital is involved in community mental health service collaboration with various PHC facilities located in the rural communities of South-Eastern Nigeria. This community mental health care service in various PHC facilities in this region of the country is overseeing by the psychiatric nurses employed by the hospital.Ethical approval for this study was obtained from the ethical committee of FNHE, Nigeria.A total of fifty (50) psychiatric nurses employed by FNHE, Nigeria and who are involved in the community mental health services of the hospital participated in the study. There were 12 males and 38 females. The fifty nurses included in the study had had a minimum of five years of practice in general psychiatry nursing and possessed diploma qualification in general nursing and psychiatry nursing. It should be noted that only psychiatric nurses were used as the sample for this study because in the context of our environment in Nigeria and other sub-Saharan African countries, they are supposed to be the most likely health care workers who attend to cases such as autism and ASD and still supervise health care services at primary care level.In addition to the socio-demographic questionnaire, KCAHW questionnaire was distributed to consented fifty (50) psychiatric nurses to complete. After a period of two (2) weeks, the KCAHW questionnaire was re-distributed to the same fifty (50) psychiatric nurses to complete. The questionnaires were completed by the respondents and collected from them there and then at each point of administration to prevent them from consulting any study material or discussing with their colleagues before filling in their responses.This is a self administered questionnaire that contained a total of nineteen (19) \u2013 item questions. Each of the item questions has three (3) options to choose from with only one of these three options being correct. The correct option on each item question attracts a score of one (1), while the other two options that are incorrect attract a score of zero (0) each.The KCAHW questionnaire is further divided into four (4) domains:Contained eight (8) item questions that addressed the impairments in social interaction usually found in children with childhood autism. A maximum and minimum score of 8 and 0 respectively are possible in this domain.Contained only one (1) item question that addressed impairment in area of communication and language development, which is part of symptom presentation in children with childhood autism. A maximum and minimum score of 1 and 0 respectively are possible in this domain.Contained four (4) item questions that addressed area of obsession and compulsive pattern of behavior found in children with childhood autism, a pattern of behavior which had been described as restricted, repetitive and stereotyped. A maximum and minimum score of four (4) and zero (0) respectively are possible in this domain.Contained six (6) item questions that addressed information on what type of disorder is childhood autism, possible co-morbid conditions and onset of childhood autism in affected children. A maximum and minimum score of six (6) and zero (0) respectively are possible in this domain.Therefore, a maximum and minimum total score of nineteen (19) and zero (0) respectively are possible when the four domain scores are added together.The content of the questionnaire and the scoring system are shown in Appendices 1 and 2.The mean total score on KCAHW questionnaire among a particular sample population or community is a measure of level of knowledge about childhood autism among that particular sample population or community.The mean scores in each domain and the mean total scores generated when KCAHW questionnaires were administered the first and second time were compared with paired t-test statistical analysis to assess the test-retest reliability of the KCAHW questionnaire.Then, the mean inter-domain scores during the first and second time administration of the questionnaire were correlated with the mean total scores and cronbach's alpha  was calcA total of fifty (50) psychiatric nurses employed by FNHE, Nigeria and who are involved in the community mental health services of the hospital participated in the study. There were 12 males and 38 females with mean age of 32.6 years. The mean scores in the four domains of KCAHW questionnaire and mean total scores of 9.6 and 9.8 on first and second time administration of KCAHW questionnaire respectively which gave indices of level of knowledge on childhood autism in that particular sample population are shown in Table The paired t-test analysis comparing these mean scores and the 95% Confidence Interval (95% C.I) for the differences in the mean scores are shown in Table The correlation co-efficient for the four mean domain scores and mean total scores at first and second time administration of KCAHW questionnaire are shown in Table The internal consistency of KCAHW questionnaire was assessed by correlating different mean domain scores with the mean total scores at first and second time administration of the questionnaire and calculating the cronbach's alpha. The cronbach's alpha value of 0.97 obtained following the correlation is acceptable based on Nunnaly's recommendation .The ten by ten correlation matrix table of the four mean domain scores and mean total scores at first and second time administration of the KCAHW questionnaire is shown in Table The content of KCAHW questionnaire had been described. The test-retest reliability of the questionnaire is good based on the significant correlations in the mean domain and mean total scores at first and second time of administration. The KCAHW questionnaire also showed a good internal consistency as revealed in the cronbach's alpha value obtained for mean domain scores correlation with the mean total scores both at first and second time of administration.The imperative need to increase the level of knowledge and awareness among health workers and of the general community in Sub-Saharan African and other developing countries of the world about childhood autism necessitated the design of a reliable measuring tool that can be used to assess baseline knowledge of health workers on childhood autism and also subsequently the impact the future campaign and continuous education may have on the knowledge of these health workers about childhood autism, especially those group of health workers at primary health care facilities who are closer to the communities.KCAHW questionnaire could also be used to compare knowledge about childhood autism among different categories of health workers, if there is an indication for such. The variation in knowledge about childhood autism among health workers that could exist in various geographical regions of Sub-Saharan African and other developing countries where awareness about autism and ASD is low could also be assessed with KCAHW questionnaire.The limitation of administering the KCAHW questionnaire is that it could only be completed and collected immediately from the respondents upon administration. This is to prevent consultation of study materials or discussion with colleagues which can influence the respondents' response to the questions contained in the questionnaire. The KCAHW questionnaire would therefore serve the purpose only of a point time assessment of knowledge.KCAHW questionnaire is a reliable tool for assessing knowledge of health workers about childhood autism, aimed at early recognition of the condition in the primary care settings. It would be a valuable tool in assessing baseline knowledge of health workers about childhood autism in Sub-Saharan African communities and other developing countries where public awareness about childhood autism is low and policy and interventions are being planned for children affected by childhood autism. The level of knowledge of health workers about childhood autism, especially those working in the rural communities in this environment and other developing countries is an essential ingredient for early recognition and intervention which had been noted to improve prognosis in the affected children ,17,18. KPOE is affiliated with African Network for the Prevention and Protection against Child Abuse and Neglect (ANPPCAN), Nigeria Chapter and ANPPCAN, Nigeria Chapter received sponsorship from the World Bank in May 2007 for a survey on level of awareness of autism and implementation of program to raise awareness on autism in Enugu State, South Eastern Nigeria.All authors contributed to the conception of the study. MOB, POE and AOA are involved in writing and revision of the manuscript. All authors approved the final draft of the manuscript.Please do not consult formal text books to answer these questions.Thank you for your time.The following behaviors best describe a child with Childhood Autism:i. Marked impairment in use of multiple non-verbal behaviors such as eye to eye contact, facial expression, body postures and gestures during social interaction?(A) Don't Know, (B) Yes, (C) Noii. Failure to develop peer relationship appropriate for developmental age?(A) Don't Know, (B) Yes, (C) Noiii. Lack of spontaneous will to share enjoyment, interest or activities with other people? (A) Don't Know, (B) Yes, (C) Noiv. Lack of social or emotional reciprocity? (A) Don't Know, (B) Yes, (C) Nov. Staring into open space and not focusing on any thing specific?(A) Don't Know, (B) Yes, (C) Novi. The child can appear as if deaf or dumb? (A) Don't Know, (B) Yes, (C) Novii. Loss of interest in the environment and surroundings?(A) Don't Know, (B) Yes, (C) Noviii. Social smile is usually absent in a child with Autism?(A) Don't Know, (B) Yes (C) Noi. Delay or total lack of development of spoken language?(A) Don't Know (B) Yes (C) Noi. Stereotyped and repetitive movement (e.g. Hand or finger flapping or twisting)?(A) Don't Know (B) Yes, (C) Noii. May be associated with abnormal eating habit?(A) Don't Know, (B) Yes, (C) Noiii. Persistent preoccupation with parts of objects?(A) Don't Know, (B) Yes, (C) Noiv. Love for regimented routine activities? (A) Don't Know, (B) Yes, (C) Noi. Autism is Childhood Schizophrenia? (A) Don't Know, (B) Yes, (C) Noii. Autism is an auto-immune condition? (A) Don't Know, (B) Yes, (C) Noiii. Autism is a neuro-developmental disorder? (A) Don't Know, (B) Yes, (C) Noiv. Autism could be associated with Mental Retardation?(A) Don't Know, (B) Yes, (C) Nov. Autism could be associated with Epilepsy? (A) Don't Know, (B) Yes, (C) Novi. Onset of Autism is usually in, (A) Neonatal age, (B) Infancy, (C) Childhoodi Marked impairment in use of multiple non-verbal behaviors such as eye to eye contact, facial expression, body postures and gestures during social interaction?(A) 0 (B) 1 (C) 0ii Failure to develop peer relationship appropriate for developmental age?(A) 0 (B) 1 (C) 0iii. Lack of spontaneous will to share enjoyment, interest or activities with other people? (A) 0 (B) 1 (C) 0iv Lack of social or emotional reciprocity? (A) 0 (B) 1 (C) 0v Starring into open space and not focusing on any thing specific?(A) 0 (B) 1 (C) 0vi. The child can appear as if deaf or dumb? (A) 0 (B) 1 (C) 0vii. Loss of interest in the environment and surroundings?(A) 0 (B) 1 (C) 0viii. Social smile is usually absent in a child with Autism?(A) 0 (B) 1 (C) 0i. Delay or total lack of development of spoken language?(A) 0 (B) 1 (C) 0i. Stereotyped and repetitive movement (e.g. Hand or finger flapping or twisting)?(A) 0 (B) 1 (C) 0ii. May be associated with abnormal eating habit?(A) 0 (B) 1 (C) 0iii. Persistent preoccupation with parts of objects?(A) 0 (B) 1 (C) 0iv. Love for regimented routine activities? (A) 0 (B) 1 (C) 0i. Autism is Childhood Schizophrenia? (A) 0 (B) 0 (C) 1ii. Autism is an auto-immune condition? (A) 0 (B) 0 (C) 1iii Autism is a neuro-developmental disorder? (A) 0 (B) 1 (C) 0iv. Autism could be associated with Mental Retardation?(A) 0 (B) 1 (C) 0v. Autism could be associated with Epilepsy? (A) 0 (B) 1 (C) 0vi Onset of Autism is usually in (A) 0 (B) 0 (C) 1A total maximum score of 19 and a minimum score of 0 are possible. The average score on the KCAHW questionnaire among a particular sample population give an index level of knowledge about childhood autism in that particular population."}
+{"text": "Elevated serum levels of the beta-subunit of human chorionic gonadotrophin (hCG) were measured in 50% of patients with locoregional recurrences or progressive vulvar carcinoma (n = 14). At diagnosis of vulvar cancer, however, the incidence of elevated serum levels was low (5%) in 104 patients. The rising serum levels during progression of disease indicate that the synthesis of the beta-subunit hCG can be increased in vulvar carcinoma."}
+{"text": "In the northern hemisphere winter of 2003\u201304 antigenic variant strains (A/Fujian/411/02 \u2013like) of influenza A H3N2 emerged. Circulation of these strains in the UK was accompanied by an unusually high number of laboratory confirmed influenza associated fatalities in children. This study was carried out to better understand risk factors associated with fatal cases of influenza in children.Case histories, autopsy reports and death registration certificates for seventeen fatal cases of laboratory confirmed influenza in children were analyzed. None had a recognized pre-existing risk factor for severe influenza and none had been vaccinated. Three cases had evidence of significant bacterial co-infection. Influenza strains recovered from fatal cases were antigenically similar to those circulating in the community. A comparison of protective antibody titres in age stratified cohort sera taken before and after winter 2003\u201304 showed that young children had the highest attack rate during this season . Clinical incidences of influenza-like illness (ILI) in young age groups were shown to be highest only in the years when novel antigenic drift variants emerged.This work presents a rare insight into fatal influenza H3N2 in healthy children. It confirms that circulating seasonal influenza A H3N2 strains can cause severe disease and death in children in the apparent absence of associated bacterial infection or predisposing risk factors. This adds to the body of evidence demonstrating the burden of severe illness due to seasonal influenza A in childhood. Influenza A virus is a cause of severe morbidity and mortality worldwide Human seasonal influenza A viruses evolve rapidly through genetic mutation, allowing them to escape previously acquired immunity This study investigated fatal cases of influenza H3N2 in children during the emergence of A/Fujian/411/02 in the UK in winter 2003\u201304. The goals of the study were: to investigate whether any of the case fatalities had underlying disease or risk factors; to evaluate how laboratory confirmed infections were recorded in death certification; to describe the clinical and pathological findings in relation to circulating virus strains; and to investigate whether the high number of laboratory confirmed fatalities was reflected in measures of morbidity in primary care, age specific attack rates and age specific all-cause mortality. We reviewed the antecedent illness history, underlying risk factors, clinical findings and observed pathology at autopsy. Age-stratified serological data were combined with community based clinical morbidity data to provide an assessment of the overall population immune susceptibility, attack rates and impact of A/Fujian/411/02-like influenza in comparison with other winter seasons in which new H3N2 antigenic variants emerged.This study was conducted as part of a public health inquiry by the Health Protection Agency and Health Protection Scotland into paediatric deaths, where it was agreed that ethical approval for linking personal clinical outcome information to virus strains was not required. Nationally representative, anonymised, age stratified residual sera were obtained from the HPA serum bank held in Preston NHS hospital. Ethical approval was given by the HPA for the collection of these samples.st September 2003 to 30th May 2004) with laboratory confirmation of influenza virus infection reported to HPA. Most specimens were initially tested at referring hospitals, and all were subsequently tested at the national influenza laboratory, HPA Centre for Infection, Colindale (HPA CfI). Microbiological findings deemed significant are included.A case was defined as a death in child less than eighteen years of age during the 2003\u201304 influenza season . The activity took place within the context of a national public health enquiry into influenza associated childhood deaths in winter 2003. Children without risk factors recognized by UK Joint Committee on Vaccination and Immunisation to increase the risk of influenza related complications were classified as \u201cpreviously healthy\u201d. U.K. risk factors for severe influenza from 2003\u201304 are given in reference 12. Verification of the certified cause of death in each fatal case was performed by matching cases to Office of National Statistics (ONS) death registration records held at HPA.http://www.hpa.nhs.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1195733836222.The Weekly Returns Service (WRS) of the Royal College of General Practitioners is a clinical information system based upon a network of sentinel general practices located throughout England and Wales Viruses were grown in either MDCK or MDCK-SIAT1 cells and subtyping was performed by RT-PCR, if no virus isolate was available Nationally representative, anonymised, age stratified residual sera were obtained with ethical approval from the HPA serum bank held in Preston NHS hospital. The number of sera tested from 2003 was 88 (ages 0\u20134), 196 (ages 5\u201317), 293 (ages 18\u201344), 185 (ages 45\u201364) and 101 (ages 65+). The number of sera from 2004 for each age group was 70 (ages 0\u20134), 160 (ages 5\u201317), 273 (ages 18\u201344), 199 (ages 45\u201364) and 98 (ages 65+).Haemagglutination inhibition (HI) assays to assess protective antibody titres in human sera were performed using standard protocols and antigenically representative viruses. A titre of >1/40 was taken as protective.Seventeen fatal cases of laboratory-confirmed influenza A in children under eighteen years were reported to HPA between September and December 2003. This period corresponded with peak circulation of influenza during the winter 2003\u201304. The median age of fatal cases was two years, with a range from four months to seventeen years; the majority (64%) were under five years. Ten (58%) deaths were in females. The duration of illness prior to death varied, with a median duration of three days (range 0\u201314 days). Four (24%) deaths were sudden with either no recognized antecedent illness or illness of less than 6 hours duration. A further four (24%) occurred within forty-eight hours of onset of symptoms, five (29%) were ill for three to four days prior to death, three (18%) were ill for a week prior to death, and one individual was unwell for over ten days. Eight (47%) children died following hospitalization and nine (53%) died in the community. In the cases with recognized antecedent illness, eight (57%) had fever, eleven (79%) had respiratory symptoms (cough/chest infection/croup), three (21%) had vomiting and/or diarrhea, two (14%) had clinically recognized sepsis. Two (14%) children were markedly confused prior to collapse .Among the sixteen cases for whom underlying health status information was available none was recorded as having a known risk factor for severe influenza, although two cases (both over two years) had a history of febrile convulsions In nine cases (53%) influenza A detection occurred by more than one method , either in respiratory clinical samples or from post-mortem tissues. In eleven (64%) cases influenza A virus isolates were recovered. The cultured viruses were analyzed for their antigenic characteristics; all isolates were found to be antigenically similar to each other and to virus isolates recovered from non-fatal cases matched for age, week of infection and geographical location (controls) as well as to other circulating strains from the same locality (data not shown). Influenza AH3N2 was detected by RT-PCR only in five (29%) cases.Staphylococcus aureus and Streptococcus pneumoniae in blood were identified in the two cases of clinical sepsis and one case had Streptococcus pneumonia bacterial pneumonia. No other significant bacteriological findings were described. Enterovirus and norovirus were also detected by RT-PCR in two cases.Staphylococcus aureus or Streptococcus pneumoniae and myocarditis in two cases (12%). Eight cases (47%) showed abnormalities of the lymphoid system, including seven (41%) with enlargement of the lymph nodes (LN), thymus or spleen, six (35%) with hemorrhagic LN, thymus or spleen and two (12%) with \u201cstarry sky\u201d LN indicating an infiltration of macrophages in the lymphoid tissue. No metabolic disorders were recognized ante or post mortem, although one case showed unusual large fiber laryngeal musculature of uncertain significance.Autopsy reports were available for all cases . All casDeath registration information was not available for one case. By routine death registration only nine of sixteen fatal cases (56%) were coded with influenza (ICD10 J10\u2013J11). Seven of these specifically mentioned influenza A on the death certificate and a further certificate mentioned \u201cinfluenza\u201d when text was searched manually. Two (13%) of the deaths were registered as pneumonia (J18); two (13%) as other respiratory disorders (J98); two (13%) were registered as sudden infant death (SIDS) and one as acute myocarditis, without mention of influenza (I40). Septicemia (A41) and myocarditis  were identified as contributing causes to death on three certificates. No death certificate indicated any chronic medical conditions known to increase the risk of severe disease from influenza infection.We sought to establish whether young children showed particular susceptibility to A/Fujian/411/02-like virus infection during this winter season by analyzing sera from summers 2003 and 2004, prior and subsequent to the emergence of this antigenic drift variant. Serum samples in a nationally representative age-stratified serum cohort were analyzed for the presence of protective antibodies . The numTo assess the morbidity of influenza in different age groups we analysed observational clinical data from primary care recorded by GPs of the Weekly Returns Service (WRS). This is a national sentinel network which has been recording influenza-like illness (ILI) for over 40 years, and for which linked clinical-virological surveillance has been operational since 1994. The all-age incidences of ILI in England and Wales over a ten year period from 1994\u20132004, together with incidence rates in children ages 0\u20134 and 5\u201314 years is shown in Winter 2003\u201304 was marked by an unusually high number of severe and fatal cases of influenza in the young, following the emergence of the influenza A H3N2 antigenic drift variant A/Fujian/411/02 The range of clinical complications in UK fatal cases can be grouped into categories including (1) fulminant progression to death after an initially mild illness, (2) invasive bacterial infection, (3) respiratory tract complications and (4) non respiratory complications including myocarditis and encephalopathy. Extrapulmonary complications of myocarditis and encephalopathy were not accompanied by the detection of viral RNA from brain or heart tissue by RT-PCR, although virus was recovered from the nasopharynx. The pathological conclusions rest on histology findings, which suggests that tissue damage may occur through mechanisms other than direct viral replication, as has been previously suggested Staphylococcus aureusThe clinical microbiological findings add to the debate about the importance of bacterial co-pathogens in influenza associated fatality. Only three (18%) of the fatal cases showed evidence of significant bacterial co-infection. This is similar to findings from fatal cases in the US 2003\u201304 and also to preliminary information from the current outbreak of swine-origin influenza A H1N1, where a minority of paediatric hospital admissions had possible or probable bacterial infection In this case series over 40% of death certificates had no mention of influenza as a direct or indirect cause of death, and in over 70% of cases the diagnosis of influenza was not made until post mortem tissue was examined. The burden of influenza in young children is therefore under recognized, precisely because few influenza infections are recognized clinically A risk-factor based influenza vaccination program for children would not prevent these fatal cases as the reasons underlying susceptibility to severe disease remain cryptic. Further studies on the outcome of seasonal influenza in children will help us to predict the impact of future epidemics and will assist understanding of the outcome of infections in the immune na\u00efve host during influenza pandemics."}
+{"text": "The differential p53 overexpression in different subtypes of intestinal metaplasia and gastric cancer suggests that type III intestinal metaplasia is the commonest lesion in dysplasia-carcinoma transition, particularly in the intestinal type of gastric cancer."}
+{"text": "Higher concentrations of PSA and hK2 were found in tumours expressing steroid hormone receptors , and both PSA  and hK2  correlated directly with PR levels. A negative correlation between patient age and PSA  was also found. Both proteins were present in nipple aspirate fluid at relatively high concentrations which were positively correlated . The molecular weights of the immunoreactive species quantified by the hK2 and PSA assays were established by high-performance liquid chromatography (HPLC) and were consistent with the known molecular weights of hK2 and PSA. Together these data provide the first evidence, to our knowledge, that both malignant breast tissue and normal breast secretion contain measurable quantities of hK2, and that the degree of hK2 expression or secretion is directly proportional to the expression of PSA and steroid hormone receptors. hK2 expression may therefore be a marker of steroid hormone action in breast tissue. \u00a9 2000 Cancer Research CampaignThe recent demonstration of human glandular kallikrein (hK2) expression in a breast carcinoma cell line has suggested that this putatively prostate-restricted, steroid hormone-regulated protease may also be expressed in breast epithelium in vivo and secreted into the mammary duct system. Given that the only substrate yet identified for hK2 activity is the precursor of prostate-specific antigen (PSA), the expression of which in breast carcinomas may be associated with favourable prognosis, our purpose was to examine the expression pattern of both hK2 and PSA in breast tumour tissues. Cytosolic extracts of 336 primary breast carcinomas prepared for routine oestrogen receptor (ER) and progesterone receptor (PR) analysis, as well as 31 nipple aspirates from six women with non-diseased mammary glands, were assayed for hK2 and PSA using immunofluorometric assays developed by the authors. In the tumour extracts, measurable hK2 and PSA concentrations were detected in 53% and 73% of cases respectively, and were positively correlated to each other ("}
+{"text": "DCC is the most likely target of LOH because loss or reduction of DCC expression has been found in many types of cancers. However, few reports have focused on sequence mutations of this gene. We investigated sequence mutations and expression of DCC in primary gastric cancers. We studied mutations in 25 of the 29 DCC exons by PCR-SSCP in 17 primary gastric cancers exhibiting LOH on 18q21. No mutations of DCC were found in any of the tumours, although 78% (47/60) of the primary tumours showed apparent loss or reduction of DCC expression by immunohistochemistry. Analysis of methylation status of DCC revealed that methylation frequently occurred in both primary tumours  and corresponding non-cancerous gastric mucosae . Methylated status of DCC was significantly correlated with the loss of DCC expression in primary tumours (P< 0.01). These results indicate that DCC is frequently silenced, probably by epigenetic mechanisms instead of sequence mutations in gastric cancer. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comLoss of heterozygosity (LOH) on chromosome 18q21 is frequently found in various human cancers, suggesting the presence of tumour suppressor gene(s) in this chromosomal region."}
+{"text": "To identify and implement strategies that help meet safety monitoring requirements in the context of an observational study for artemether-lumefantrine (AL) administered as first-line treatment for uncomplicated malaria in rural Tanzania.Pharmacovigilance procedures were developed through collaboration between the investigating bodies , the relevant regulatory authority (Tanzania Food and Drugs Authority) and the manufacturer of AL (Novartis Pharma AG). Training and refresher sessions on the pharmacovigilance system were provided for healthcare workers from local health facilities and field recorders of the Ifakara Health Demographic Surveillance System (IHDSS). Three distinct channels for identification of adverse events (AEs) and serious adverse events (SAEs) were identified and implemented.st September 2007 to 31st March 2010, 57 AEs were reported . The remaining seven were due to anti-pyretic or anti-parasite medications. Twenty patients experienced SAEs; in 16 cases, a relation to AL was suspected. Six of the 20 cases were reported within 24 hours of occurrence. In all cases reported after AL, 5 cases (vomiting), 16 cases (itching and/or rash) and others were difficult breathing, convulsion and headache (10 cases). The four AEs that occurred after SP were mild erythematic skin lesions that did not progress to Stevens-Johnson syndrome. The AEs seen following treatment with penicillin and amoxicillin were both rashes.Training was provided for 40 healthcare providers (with refresher training 18 months later) and for six field recorders. During the period 1Safety monitoring and reporting is possible even in settings with weak health infrastructure. Reporting can be enhanced by regular and appropriate training of healthcare providers. SMS text alerts provide a practical solution to communication challenges.Experience gained in this setting could help to improve spontaneous reporting of AEs and SAEs to health authorities or marketing authorization holders."}
+{"text": "Fibreoptic bronchoscopy in previously untreated patients with malignant lymphoma provided diagnostic information in 8 of 25 cases with radiological evidence of intrathoracic involvement. There was a marked difference in the pattern of endobronchial involvement between Hodgkin's Disease (HD) and Non Hodgkin's Lymphoma (NHL) which specifically infiltrated the bronchus-associated lymphoid tissue. Bronchoalveolar lavage was abnormal in only one patient with Hodgkin's Disease in whom the presence of many Sternberg-Reed cells suggested occult dissemination of otherwise localised disease."}
+{"text": "One hundred and seven patients with biliary pancreatitis undergoing operation from 1976 to 1989 werereviewed. To clarify the reason for failure to respond to conventional supportive therapy, 73 patients (68%) who underwent emergency surgery were retrospectively divided into two groups according to the severity of the pancreatitis evaluated at laparotomy and compared. Sixty-two had minimal or mild pancreatitis (Group I), among whom 44 (71%) had life-threatening acute biliary tract disease. All underwent biliary surgery and 4 (6%) subsequently died, 2 due to acute obstructive suppurative cholangitis. Eleven had hemorrhagic necrotizing pancreatitis (Group II), among whom 7 had complications of acute pancreatitis such as pancreatic ascites or abscess. These underwent pancreatic and/orbiliary surgery and 3 (27%) died of multi-organ failure.\t\tThere appears to be two types of biliary pancreatitis refractory to conventional supportive therapy, which differ in the extent of surgery required and in mortality: (1) minimal or mild pancreatitis with persistent life-threatening acute biliary tract disease (biliary type), and (2) more severe pancreatitis (pancreas type) early in the course of the disease."}
+{"text": "The analyses were carried out with the aid of ion-exchange chromatography. The molar proportions of 5 bases detected in acid hydrolysates of tumour tRNA (N"}
+{"text": "The measurement of carcinoembryonic antigen (CEA) in serum and endoscopic brush specimens was evaluated for the differential diagnosis of malignant and nonmalignant gastric disease. Brush specimens were studied from 33 patients with gastric cancer and 36 patients with benign gastric lesions or apparently normal gastric mucosa. Demonstrable CEA immunoreactivity was found by radioimmunoassay in brush specimens from 24/33 cancer patients (73%) and from 23/36 patients with benign lesions (64%). Patients with CEA+ tissue in the immunoperoxidase test had somewhat higher CEA concentrations in the brush specimens than cases with CEA- biopsy tissue, although overlap was considerable. Thirty-five per cent of cancer patients had both a positive tissue CEA reaction and a CEA/DNA ratio greater than 10 ng/micrograms, whilst patients with benign lesions had only 15% of positives by these criteria (0.01 greater than P greater than 0.001). The serum CEA concentration was above the upper normal level of 5 ng/ml in 2/39 patients, both of whom had gastric cancer. The CEA immunoreactive material from benign and malignant lesions eluted in gel filtration on Sephadex G-200 in the same volume as CEA purified from liver metastases of cancer of the colon, showing that a glycoprotein sharing immunological and physicochemical properties with CEA is present both in malignant and nonmalignant lesions of the gastric mucosa, and that there is considerable overlapping in the amount of CEA. The estimation of CEA in gastric-brush specimens is therefore of limited value in the differential diagnosis of benign and malignant gastric lesions."}
+{"text": "Peripheral blood leucocytes from chronic myeloid leukaemia patients in remission were tested for inhibition of migration in presence of solubilized membrane antigens from leukaemic cells in 15 cases. Eight out of 9 autochthonous combinations (88-8%) and 35/49 allogenic combinations (71-4%) showed inhibition of migration. Antigens prepared from relapse leukaemic cell samples in 4 cases showed inhibition of migration of autochthonous as well as allogeneic remission leucocytes. The same batch of CML antigens inhibited migration of normal leucocytes at the level of 22-2%. The difference between inhibition of migration shown by remission leucocytes and normal leucocytes in presence of CML antigens was statistically significant. Solubilized antigens, similarly prepared from normal leucocytes, showed inhibition of migration of remission leucocytes to the extent of 15% only. The difference between the reactivity of CML remission leucocytes to normal and CML antigens was also statistically significant. No enhancement of migration of remission leucocytes was seen with CML antigens."}
+{"text": "The macrophage electrophoretic mobility test described by Caspary and Field (1971) and modified by Pritchard et al. (1973) was investigated in various models of cell-mediated immune conditions in the guinea-pig and in cancer in man. No positive results were obtained in 92 guinea-pig experiments. Only 17 of 154 experiments on 74 patients gave definite positives in experiments with human cancer and a few positive results were obtained with normal healthy subjects."}
+{"text": "Forty-four (44) patients with Burkitt's lymphoma received identical combination chemotherapy on the basis of body surface area. Patients with renal dysfunction, more common in those with abdominal tumours, were at significantly greater risk of developing severe leucopenia (less than 1000 cells/dl) than those with normal renal function (P less than 0.0001). Similar results were seen in a series of 8 patients with normal marrows treated with only i.v. cyclophosphamide and intrathecal methotrexate. Giving a lower initial dose of cyclophosphamide seemed to reduce the risk of severe leucopenia in 5 additional patients with evidence of renal dysfunction. The mechanism is postulated as delayed excretion of the active metabolites of cyclophosphamide. Adjustment of the chemotherapeutic dose should be considered when treating patients with renal dysfunction."}
+{"text": "We compared antimicrobial resistance patterns of Salmonella enterica serovar Typhimurium (ST) of isolates from humans (n = 715) and cattle (n = 378) in the Pacific Northwest from 1982 through 1997. The major changes in antimicrobial resistance can be attributed to the widespread clonal dissemination of multidrug-resistant definitive phage type 104 ST."}
+{"text": "Twenty-seven patients with malignant neoplasia were injected intradermally with the methanol extraction residue (MER) fraction of tubercle bacilli. Two schedules of treatment were used: every other week and once a month; 1-10 courses of MER were administered to the patients. The skin reactivity to 3 recall antigens, as well as to the injected MER itself, was used to monitor the immune response. Improvement of skin reactivity occurred in 9 of 18 patients tested with recall antigens. Five of 6 patients treated every other week improved in their immune capacity whereas only 4 of 12 patients improved on the monthly schedule. Thus, repeated injections given every other week were more effective in increasing the cutaneous reactivity than monthly injections of MER. The side-effects of MER treatment were tolerable."}
+{"text": "High levels of loss of distal markers on 17p13.3 in breast cancer suggested the presence within the region of at least one tumour-suppressor gene. Here we describe the derivation of two biallelic polymorphisms from the 17p telomeric yeast artificial chromosome (YAC) TYAC98. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex PCR analysis demonstrated that the high level of allelic imbalance observed in breast tumours represented loss of constitutional heterozygosity (LOH) and that this LOH extended to the telomere. Lung carcinoma (but not Wilms' tumour)-derived DNA again revealed a high level of loss of subtelomeric 17p sequences. Telomeric microsatellite polymorphisms from other chromosome arms did not show such elevated loss in either tumour type. This suggested that the 17p loss observed did not reflect a general telomeric instability and provided further evidence for the presence of a breast cancer tumour-suppressor gene in the distal region of 17p13.3."}
+{"text": "They co-evolved into an intricate splicing code together with additional functional constraints, such as tissue-specific and alternative splicing patterns. We used orthologous exons extracted from the University of California Santa Cruz multiple genome alignments of human and 22 Tetrapoda organisms to predict candidate enhancers and silencers that have reproducible and statistically significant bias towards annotated exonic boundaries.Auxiliary splicing sequences play an important role in ensuring accurate and efficient splicing by promoting or repressing recognition of authentic splice sites. These Tetrapoda enhancers and silencers were clustered into 15 putative core motifs based on their Markov properties. Most of these elements have been identified previously, but 118 putative silencers and 260 enhancers (~15%) were novel. Examination of previously published experimental data for the presence of predicted elements showed that their mutations in 21/23 (91.3%) cases altered the splicing pattern as expected. Predicted intronic motifs flanking 3' and 5' splice sites had higher evolutionary conservation than other sequences within intronic flanks and the intronic enhancers were markedly differed between 3' and 5' intronic flanks.A total of 2,546 Difference in intronic enhancers supporting 5' and 3' splice sites suggests an independent splicing commitment for neighboring exons. Increased evolutionary conservation for ISEs/ISSs within intronic flanks and effect of modulation of predicted elements on splicing suggest functional significance of found elements in splicing regulation. Most of the elements identified were shown to have direct implications in human splicing and therefore could be useful for building computational splicing models in biomedical research. Eukaryotic genes contain intervening sequences or introns that need to be removed from precursor messenger RNA (pre-mRNA) in a complex process termed splicing. During pre-mRNA splicing, relatively short exonic sequences are recognized by spliceosome, a large RNA-protein complex. During splicing, introns are removed and exons are joined together to form mature RNA. In addition to splice site (SS) signals at the exonic 5' and 3' ends, accurate discrimination of exons and introns requires additional auxiliary elements -3. Thesein vivo or in vitro selection methods have been employed to identify these motifs in the genomic sequences. For example, the RESCUE-ESE (Relative Enhancer and Silencer Classification by Unanimous Enrichment), a computational approach used in conjunction with experimental validation, predicted specific hexanucleotide sequences as candidate ESEs based on significantly higher frequency of occurrence in exons than in introns and also significantly higher frequency in exons with weak SSs than in exons with strong SSs  we have found 88 5'SS-related and 330 3'SS-related ISEs/ISSs [see Additional File Tetrapoda superclass  3'SS and 177 (6.95%) 5'SS supporting motifs are novel and have not been previously reported in systematic screens detecting such elements. Among our predicted elements, 51.81% were octamers and 41.08% of sequences were heptamers as compared to only 6.76% hexamers and 0.35% pentamers, suggesting that motifs of larger size play important role in splicing regulation. We detected intersections with some of the cis-acting elements reported in the previous studies, but not nearly as dramatic as we saw between the intronic elements predicted for primates and Tetrapoda non-eutherian (an outgroup) clades. It demonstrates high reproducibility of our results obtained for various vertebrate lineages and supports the existence of highly conserved splicing regulatory code across vertebrates. This result also suggests the implications of elements found in regulating human splicing and may help explaining human hereditary disorders caused by mutations modulating such elements. We have established the higher evolutionary conservation for the predicted intronic cis-acting elements within mammalian intronic flanks which indicates their functional significance in exon definition. The elements found contain many of the known cis-acting factor binding sites with functionality supported by experiments with splicing reporter constructs. All these lines of evidence suggest active involvements of the predicted elements in control gradient directing spliceosome to the proper exons in the process of pre-mRNA splicing [Using the orthologous exons currently available for 23 cis-acting elements with the secondary pre-mRNA local structure in the vicinity of the SSs, except for slightly increased single strandedness detected for 5' and 3' ISSs deep inside introns. This observation is in contrast to the earlier reported [We did not observe statistically significant association for the predicted groups of reported , where kA remarkable intersection between the 5'SS ISSs and the 5'SS ESSs [see Additional File [Homo sapiens), Chimpanzee (Pan troglodytes), Rhesus (Macaca mulatta), Mouse (Mus musculus), Rat (Rattus norvegicus), Rabbit (Oryctolagus cuniculus), Dog (Canis familiaris), Cow (Bos taurus), Armadillo (Dasypus novemcinctus), Elephant (Loxodonta africana), Tenrec (Echinops telfairi), Opossum (Monodelphis domestica), Chicken , Frog . The \"threaded blockset alignments\" [ against reference human chromosomal assemblies  using the BLAT program [We parsed and extended blocks of orthologous with human reference exons from multiple sequence alignment of 17 vertebrate genomes obtained from UCSC genome browser . The folgnments\" , built u program . Having  program ,35 and d program  to make Otolemur garnetti), Tree Shrew (Tupaia belangeri), Guinea Pig (Cavia porcellus), Shrew (Sorex araneus), Hedgehog (Erinaceus europaeus), Cat (Felis catus), Horse , Platypus (Ornithorhynchus anatinus), Lizard (Anolis carolinensis). The blocks from a total of 28 vertebrates multiple genome alignments are normally shorter than blocks from 17 vertebrates multiple genome alignments, therefore chances are higher that the block extension may not produce the correct exonic boundaries. Only the exons associated with the species not obtained through the first round should be processed in the second round.This exon set was extended with exons derived from processing of 28 vertebrates multiple genome alignments obtained from UCSC genome browser  from theTetrapoda organisms. For these purposes we have examined 489,668 extended exons in primates clade (Human (Homo sapiens), Chimpanzee (Pan troglodytes), Rhesus (Macaca mulatta), Bush Baby (Otolemur garnetti)) and 476,218 extended exons from non-eutherian Tetrapoda organisms (Opossum (Monodelphis domestica), Chicken , Frog , Platypus (Ornithorhynchus anatinus), Lizard (Anolis carolinensis)) taken as the most distant outgroup  among Tetrapoda organisms relative to primates.To establish the firm ground for using sequences from distantly related organisms in predicting common SS proximal elements and to estimate implication of elements found in modeling human splicing we conducted independent search for the elements in two distantly related clades of primates and non-eutherian Homo sapiens), Chimpanzee (Pan troglodytes), Rhesus (Macaca mulatta), Bush Baby (Otolemur garnetti)) and rodents (Mouse (Mus musculus), Rat (Rattus norvegicus), Guinea Pig (Cavia porcellus)) clades.To estimate the increased conservation of the intronic elements found within the intronic flanks we have used the Prank  tool to Through the literature search we collected the test set of 185 human genes previously linked to autism spectrum disorder and genes implied in environmental response . A set odepth correspond to the density of an oligonucleotide of size depth present at a certain positions within genome. A significant deviation of an oligo density in the proximity of SSs as compare to background locations is strongly indicative of important functionality of elements related to splicing [We measured a statistically significant bias for all the possible oligonucleotides of size equal or less than 8 bp in the vicinity of true 5' and 3' SSs compared to distant \"background\" locations as shown in Figures splicing ,15,33.\u03b1 = 0.011 using \u03c72 test involved 87,380 statistical hypotheses testing for all possible oligos of size less or equal to 8 bp located at certain position relative to a SS. Following the Bonferroni correction for multiple hypothesis testing we reduced the significance level to \u03c72 tests for the SS vicinity counts \u2265 63 or deep intronic/exonic counts \u2265 63 are statistically significantComparing oligo counts at the significance level of under conditionsorSkip value 29 nt, as shown in Figure Skip = 0 nt in Figure Skip = 29 nt in Figure Comparative measurements between the regions shown in Figure Extended orthologous exons associated with the same multiple genome alignment block frequently contain identical conserved oligonucleotides at certain positions relative to SSs, especially within exons. These conserved elements violate our assumption of independence of the sequences used for analysis of statistical significance; therefore within a block we counted unique element at certain position relative to SSs only once, disregarding all other identical motifs conserved since speciation from a common ancestor. To prevent substantial element underscoring in a counting round, since many of the elements at a certain position relative to a SS were sorted out due to evolutionary conservation, we shifted an element position by one within a counting region for each consecutive sequence as shown in Figure where mod is a modulo operation, counting round could be 0,1 or 2 and the sequence index goes from 1 to 2,333,379. Elements shifted by one position within the region are normally different and therefore not sorted out for being similar, which allows combining more elements in the region associated with a block under the same evolutionary pressure.These predicted groups of elements were clustered with the Mixture of Hidden Markov Models (MHMM), an unsupervised clustering method capable of modeling dependencies between neighboring positions in active motif cores [see Additional File . To accelerate finding average PU value for an element we calculated them only for the contexts of 11, 15, 20, 25 and 30 nt according to [The PU values for the predicted octamers surrounded by \u00b1 30 nt context were calculated as described in  using RNrding to  were makAC designed and implemented the framework to search for splicing regulatory elements and tested the application. CH initiated the study, provided many valuable suggestions steering the project and was the head of the lab where the work was done. IV provided necessary expertise to formulate the study objectives, obtained experimental data to support newly found elements and extensively edited the manuscript. All authors read and approved the final manuscript.Report and analysis of splicing regulatory elements found. Contains list of all the elements found along with their statistical significance and overlap between their groups. Functional analysis for these elements in context of alternative splicing constructs is reported. We provided brief description for an unsupervised clustering method used to group the elements found and grouped the elements within possible functional motifs. We also report elements found for primates and outgroup. Subset of novel elements is reported.Click here for file"}
+{"text": "Paraffin wax embedded formalin-fixed benign breast disease tissue taken from 17 patients (15 with microcystic disease and 2 with fibroadenoma) was studied for the presence of tissue bound prolactin using a rabbit antiserum against human prolactin applied in conjunction with a highly sensitive modified version of the dinitrophenyl (DNP)-hapten sandwich staining (DHSS) procedure. Sections taken from 14 of the 15 cases showing apocrine cystic changes exhibited strong prolactin staining restricted to the cytoplasm of metaplastic apocrine cells lining the cysts. Normal lobules and ducts and blunt duct proliferations were all negative, as were also the two cases of fibroadenoma. In contrast 6 out of 8 cases of breast cancer examined showed heterogenously distributed cytoplasmic staining in the cancer cells. Maximal prolactin staining in the apocrine cells was observed at antiserum dilutions as high as 1:60,000. This compared favourably with a 1:120,000 dilution that gave maximal levels of staining in the prolactotrophs present in serial sections taken from formalin fixed paraffin wax embedded post mortem human anterior pituitaries. In both types of tissues the specific staining was abolished by pre-absorption of the antiserum with human prolactin (10 micrograms ml-1). No staining was observed when the anti-prolactin serum was either omitted or substituted with DNP-labelled normal rabbit serum. Apocrine metaplasia in cystic disease of the breast has recently been found to be associated with an increased breast cancer risk. The strong and selective presence of immunohistochemically demonstrable prolactin in the metaplastic cells may be of significance in view of the hormone's known growth stimulating effect on the breast epithelium."}
+{"text": "Environ Health Perspect 117:A150\u2013A156 (2009)], a statement reads, \u201cThe primary global impact of oil sands comes through the release of greenhouse gases created when about 800 million cubic feet of natural gas  is burned daily to create heat for extraction and upgrading, says Stringham.\u201d To clarify: This statement refers to the global impact of oil sands production. As noted in the preceding paragraph of the article, most of the greenhouse gas emissions related to oil sands overall come from burning the fuel derived from these reserves.On p. A155 of the April Focus article ["}
+{"text": "Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the immunological destruction of intralobular bile ducts and serum anti-mitochondrial antibodies (AMA). Based upon previous work of oral tolerance and autoimmunity, we hypothesized that feeding the mitochondrial autoantigens of PBC would alter the clinical course and the level of antimitochondrial antibodies. The bovine pyruvate dehydrogenase complex (PDC) was purified and 5 mg fed in gelatin capsules to 6 patients with early stage PBC for 6 months. Antimitochondrial antibodies and liver biochemistries were measured at every 3 months for 12 months. The clinical trial was completed for all patients except for 1 who showed deterioration of pre-existing skin rash during treatment, which disappeared within 2 weeks after treatment was discontinued. However, after 1 year, neither the titers of AMAs nor liver biochemistries were significantly changed by this treatment. This is the first trial to test the efficacy of oral tolerance induction in PBC. However, the data, which limited in scope, did not demonstrate efficacy and further highlights the difficulties in showing continuing evidence of tolerance induction in autoimmunity."}
+{"text": "The immunofluorescent reaction of peripheral blood cells from 10 multiple myeloma, 10 Hodgkin's and 11 lymphosarcoma cases with antiviral (Rauscher) murine leukaemia (AMR) and antihuman stem cell leukaemia plasma (AHS) antisera was studied. Cells from 25 of these patients were reactive at least once with AMR and AHS or AHS alone. Absorption studies suggested that this cytoplasmic immunofluorescent reaction involved cellular isoantigens. Serial studies on multiple myeloma, Hodgkin's and lymphosarcoma cases with significant fluorescence, showed that the fluorescent cell count variation was correlated with the presence of active disease."}
+{"text": "Insulin resistance has been extensively investigated during the past decade because of its proposed role in initiating a cluster of cardiovascular risk factors including hypertension. Insulin resistance is an inherited genetic trait that precedes hypertension in Dahl salt-sensitive (S) rats, and is not present in Dahl salt-resistant (R) rats. Owing to the co-existence of insulin resistance and salt sensitivity of blood pressure in Dahl S, but not R rats, Dahl S rats are used to elucidate the role of dietary salt as a potential link in exacerbating both phenotypes . In light of available data, examining the impact of dietary salt on insulin resistance in Dahl S rats in terms of salt concentration and duration of exposure helps answer the following question: What percentage of dietary salt and for what duration of exposure would we expect an enhanced insulin resistance in Dahl S rats? This commentary gathers all available research done on insulin resistance in Dahl S rats in an attempt to unravel dietary salt contribution to insulin resistance in Dahl S rats. Over the past decades, insulin resistance and compensatory hyperinsulinemia have been proposed as the common disorder underlying a constellation of risk factors  referred to as the metabolic syndrome or syndrome X . InsulinTo be able to address the above questions, Dahl S rats have been examined at various stages (weanlings and fully developed hypertensive rats) and with various dietary salt regimens . Weanling Dahl S rats when examined before developing hypertension and prior to sodium loading were found to be significantly insulin resistant as evidenced by their higher plasma insulin levels compared to weanling Dahl R rats . This imKnowing that Dahl S rats are genetically insulin resistant as evidenced by the presence of insulin resistance in weanling Dahl S rats as well as in fully hypertensive Dahl S rats, it's time to address our third and fourth questions which inquire about the role of salt in insulin resistance and whether a specific salt concentration and/or duration of exposure is required for salt to play a role in insulin resistance in Dahl S rats. Controversial reports in the literature have been documented with some studies proposing no effect of dietary salt in advancing insulin resistance and others proposing a significant role of salt in suppressing insulin signaling and precipitating insulin resistance in Dahl S rats. That's why, it is important to analyze all available data in terms of salt concentration and duration of exposure. Salt loading in Dahl S rats did not further increase their insulin resistance when fed 3% NaCl for 1 week , or 8% NNot only did 4 weeks of high salt diet of 8% NaCl exaggerated insulin resistance ,6and conSalt-induced oxidative stress and inflammation might be the mechanism by which high dietary salt concentration of 8% suppresses insulin signaling and precipitates insulin resistance in Dahl S rats. Inflammatory mediators enhanced by high dietary salt include the tumor necrosis factor-alpha  or JNK might possibly interfere with normal insulin signaling via a number of mechanisms including: i) disruption of insulin-induced insulin receptor substrate-1 (IRS-1) and phosphoinositide-3 kinase (PI3K) phosphorylation and cellular distribution, ii) reduction in glucose transporter (GLUT4) expression levels, or iii) reduction in GLUT4 translocation to the plasma membrane -11. SuppWhile one would expect suppressed insulin signaling in Dahl S rats, Ogihara et al., reported that Dahl S rats had an enhanced insulin signaling manifested by an enhanced tyrosine phosphorylation of the insulin receptor, insulin receptor substrates, activation of PI3K and phosphorylation of Akt compared to Dahl R rats. These effects could be simply attributed to the fact that the authors starved the rats for 12 hours prior to the experiment. It is well documented that 12-hour of fasting upregulated hepatic insulin receptors in Sprague Dawley rats (from which Dahl rats were derived)  Insulin resistance in Dahl S rats precedes hypertension, 2) Insulin resistance in Dahl S rats is significantly enhanced after 4 weeks of 8% NaCl, which represents the threshold for a salt-induced suppression in the insulin signaling pathway, 3) Salt-induced insulin resistance in Dahl S rats (after 4 weeks of 8% NaCl) is accompanied by an enhanced oxidative stress and inflammatory responses that is manifested by increased levels of TNF-alpha and JNK proteins, 4) Increased TNF-alpha and JNK levels might disrupt the insulin signaling pathway at the level of the insulin receptor substrates' association with either upstream or downstream molecules in the insulin pathway or via suppressing GLUT4 expression and/or translocation. Finally, it is worth mentioning that the promoter regions of the insulin receptor substrates \u20131, and \u20132 comprises putative sodium-responsive elements that might be acted upon by excess salt to suppress their corresponding activity, expression and/or function ,17. Muta"}
+{"text": "The assessed lack of validated reference genes emphasizes the importance of a systematic study for their identification. For selecting candidate reference genes we have developed a simple The expression stability of 32 genes was assessed by qRT-PCR using a set of cDNAs from 24 different plant samples, which included different tissues, developmental stages and temperature stresses. The selected sequences included 12 well-known HKGs representing different functional classes and 20 genes novel with reference to the normalization issue. The expression stability of the 32 candidate genes was tested by the computer programs geNorm and NormFinder using five different data-sets. Some discrepancies were detected in the ranking of the candidate reference genes, but there was substantial agreement between the groups of genes with the most and least stable expression. Three new identified reference genes appear more effective than the well-known and frequently used HKGs to normalize gene expression in wheat. Finally, the expression study of a gene encoding a PDI-like protein showed that its correct evaluation relies on the adoption of suitable normalization genes and can be negatively affected by the use of traditional HKGs with unstable expression, such as actin and \u03b1-tubulin.The present research represents the first wide screening aimed to the identification of reference genes and of the corresponding primer pairs specifically designed for gene expression studies in wheat, in particular for qRT-PCR analyses. Several of the new identified reference genes outperformed the traditional HKGs in terms of expression stability under all the tested conditions. The new reference genes will enable more accurate normalization and quantification of gene expression in wheat and will be helpful for designing primer pairs targeting orthologous genes in other plant species. Arabidopsis (using the large public collection of data from Affymetrix GeneChip experiments) -1) \u00d7 100 -1) \u00d7 100, where m is the slope of linear regression model fitted over log-transformed data of the input cDNA concentration versus Ct values according to the linear equation y = m*log(x) + b. Moreover, the Mx3000PTM software system computed the R2 value (Coefficient of determination), which represents an indicator of the quality of the fit of the standard curve to the plotted data points. The R2 values calculated for all the standard curves in each of the two biological replicates were higher than 0.994, indicating a strong linear relationship between the detected Ct values and the correspondent relative amount of template in all the amplification reactions  from pooled cDNA. By plotting the Ct values of five different data-sets: 1) all 24 samples including tissues, developmental stages and temperature treatments; 2) 18 samples relative to different tissues and developmental stages; 3) six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C), each for 24 and 48 h and their controls; 4) six samples relative to the single floral organs from fully emerged spikes; 5) six samples referring to vegetative tissues and developmental stages . These data sets were used to evaluate the expression stability of the genes belonging to the four families by 18 primer pairs, 14 of them targeting specific gene transcripts of the gene families (five each for actin and \u03b1-tubulin and two each for ADP-ribosylation factor and translation elongation factor) and four primer pairs which amplified multiple transcripts for each of the four gene families . Table t differences (\u0394Ct = Ctmax-Ctmin) obtained by the 18 primer pairs for each of the five data-sets considered, whereas the complete statistics obtained by ANOVA analysis are reported in Additional file t values gives a straightforward indication of the expression stability of a particular gene; most genes with the lowest CV values showed also the lowest values of Ct range (\u0394Ct) and MST (Mean Square of Treatments)  and 13 lowly expressed genes, with mean Ct values above this value , Ta2776 (RNase L inhibitor-like protein), Ta54448 and Ta54733 (Proteins of unknown function), and Ta44405 (\u03b2-tubulin), with mean Ct values between 26 and 24 cycles  and moderately expressed (10 genes with more than 300 EST). Of the 13 reference genes with low Ct values, only three including more than 300 ESTs  were considered moderately expressed in UniGene, whereas the expression level of the remaining 10 genes was low (<300/>100 ESTs) or very low (<100 ESTs). In our opinion, these data indicate a substantial agreement between the gene expression levels evaluated by qRT-PCR analyses and those estimated by the number of ESTs included in each corresponding UniGene cluster. Ta54963 (GABA-receptor associated protein), Ta54238 (Ubiquitin-conjugating enzyme), Ta35497 (Cyclophilin), Ta53967 (Vacuolar ATP synthase 16 kDa proteolipid subunit) exhibited the lowest gene expression variation (less than 3 cycles), while Ta44405 (\u03b2-tubulin), Ta38797 (Histone) and Ta1698 (NADP-isocitrate dehydrogenase) showed the most variable expression (more than 5 cycles).In order to avoid possible errors due to the interaction of co-regulated genes, further analyses were carried out on 32 genes involved in distinct biological processes and metabolic pathways; they comprised 28 genes selected on the basis of their uniform expression detected in UniGene and TIGR and a single gene for each of the four gene families. The expression levels could be grouped into two arbitrary categories: 19 highly expressed genes, whose mean CAs discussed in the previous paragraph, it was evident that none of the 32 selected candidate reference genes showed a constant expression under all the tested conditions  in wheat. Hence, as expected, it was not possible to find an all purpose reference gene, and it would be necessary to select the most suitable one for normalizing gene expression considering the peculiar and specific experimental conditions. The relationships between expression stability of the 32 candidate genes and different types of tissues and/or experimental conditions were tested by running the programs geNorm  and Normrd, Cell division control protein, AAA-superfamily of ATPases), Ta2291 , Ta53899 , Ta4045 , Ta2776 , Ta53967 , Ta54963  and Ta53919  , Ta2291 , Ta54238 , Ta54948 , Ta2776 , Ta30797 , Ta54227  and Ta4045  , Ta54227 , Ta54238 , Ta53891 , Ta54447 , Ta2291 , Ta53919  and Ta55512 , whereas Ta1698 (NADP-isocitrate dehydrogenase) and Ta44405 (\u03b2-tubulin), with M values of 0.63 and 0.59, were the least stable genes  tested in our study are plotted in figure se) Fig. . The ranse) Fig. . The ranse) Fig. , and theThe high expression stability of a gene indicates that the use of a single internal control is appropriate, but some studies require the normalization based on two or more stable internal control genes. The geNorm program, in addition to the gene stability measure M, computes a normalization factor (NF) and assesses the optimal number of reference genes for generating that factor. The pairwise variations Vn/Vn+1 between two sequential normalization factors (NFn and NFn+1) are used to determine the necessity of adding the next more stable control gene for reliable normalization. Pairwise variations were calculated using geNorm for each data set to determine the optimal number of internal control genes for normalization Fig. . In all nd, ADP-ribosylation factor), Ta2776 , Ta35284 , Ta53919 , Ta53967 , Ta54171 , Ta54963 , Ta54733  and Ta4045  ; the two least stable genes were Ta44405 (\u03b2-tubulin) and Ta38797 (Histone), with stability values of 0.150 and 0.198 respectively, the same identified as the worst genes by geNorm. The best combination of two genes suggested by NormFinder was that of Ta54227 and Ta2291, which improved the stability value to 0.030, indicating a more reliable normalization than that based on single genes. Similar results were obtained for 18 samples including tissues/organs at different developmental stages of wheat, with the lowest stability value (0.032) for Ta54227 (Table NormFinder (the second adopted program based on a model approach) ranks the best candidate references genes according to their minimal combined inter- and intra-group variation of expression. The results obtained by NormFinder analysis for the five data sets are shown in Table The stability ranking of the reference genes across the five analysed data sets obtained by geNorm and NormFinder was not identical for the genes with the most stable expression Table . In partThe expression levels of the target gene TaPDIL1-1 were used as an example to show the effect of using different normalization genes on estimating its relative expression. TaPDIL1-1 encodes the typical PDI (Protein Disulfide Isomerase) which accomplishes several metabolic functions, the most important consisting in disulfide bond formation and isomerization during the folding of secretory proteins ,40. PrevNormalization of the expression of TaPDIL-1-1 using the reference genes selected by the three methods based on geNorm and NormFinder programmes did not detect significant differences in the relative expression of the gene of interest in all the four analysed data sets Figs.  and 6. AArabidopsis to identify new reference genes, which has been based on the data furnished by the microarray datasets [in silico method exploiting UniGene and TIGR, two publicly available databases of wheat sequences enclosing non-redundant EST-indices. The method consists of two steps, each exploiting the peculiar features of these wheat-specific databases. Basically, an effective reference gene has to fulfil three main requirements: 1) moderate to high level of expression ; 2) expression in several tissues and developmental/physiological states; 3) low variation of gene expression across different tissues and developmental, physiological and environmental conditions [T. aestivum UniGene database (see Methods), which were accomplished by 177 out of the 42,256 sequence clusters therein contained. The second step consisted in the scanning of the TIGR wheat gene index database (TaGI version 11) for the identification of the TC (Tentative Consensus) or group of TCs corresponding to each of the 177 clusters previously selected in UniGene. The identification of TCs was important because these outputs are more effective for gene functional annotation and for designing gene specific qRT-PCR primers. The frequency  of each TC or group of TCs linked to the 177 selected UniGene clusters was determined and was used to pinpoint the most suitable candidate reference genes to be included in a preliminary screening.To the best of our knowledge, the present research represents the first effort aimed to the identification and systematic comparison of a large number of potential reference genes and of the corresponding primer pairs specifically designed for gene expression studies in wheat, in particular for qRT-PCR analyses. As mentioned in the \"Introduction\", so far most studies on gene expression in wheat have been carried out using single reference genes, without any preliminary validation of their expression stability  has been one of the most suitable reference genes in a set of tissue samples in rice, whereas the expression of UBQ10 was unstable [ACT2/7 was stably expressed, whereas ACT11 showed variable profiling [Among the 177 ol genes ,20,52. Tunstable . A similt values [Since the search for suitable reference genes is both time-consuming and cost intensive, several computer programs based on different statistical approaches have been developed to assist the selection of a reference gene among several HKGs. The software geNorm has been reported in 2002  and has t values . Accordit values , this apt values ,56, or tt values . The chot values ,57,58. St values  and Normt values  and compAs discussed by different authors ,57-59, sThe mathematical model of gene expression used by NormFinder enables to estimate both the overall variation of the candidate normalization genes and the variation between subgroups of the sample set. This approach has been reported to perform in a more robust manner than geNorm and has been shown to be less sensitive to the presence of co-regulated genes , therefot 24.79), whereas that of Ta2291 (mean Ct 21.97) and of Ta54227 (mean Ct 21.56) is high, they are suitable as reference genes in a large data set of wheat samples, but also for the normalization of target genes with contrasting expression levels.Expression stability analyses showed that the most stable reference gene identified by NormFinder and geNorm was not the same for the five data sets analysed Table . Even thth among the 32 candidate reference genes , \u03b1-tubulin (Ta25534), \u03b2-tubulin (Ta44405), Ubiquitin (Ta50503), GAPDH (Ta30768), Cyclophilin (Ta35497), Translation elongation factor (Ta53964), Translation initiation factor (Ta54280), Ribosomal protein (Ta27771) and Histone (Ta38797), in fact most of them classified as the least stable genes both by geNorm and NormFinder in the five data sets analysed , Ta2291 (ADP-ribosylation factor) and Ta2776 (RNase L inhibitor-like protein) resulted the best and most stable reference genes to normalize gene expression in different tissue and development stages of wheat; they outperformed all traditional HKGs such as \u03b1-tubulin (Ta25534), \u03b2-tubulin (Ta44405), Ubiquitin (Ta50503), Actin (Ta54825), GAPDH (Ta30768), Ribosomal protein (Ta27771) and Histone (Ta38797). Although in our experimental conditions a single reference gene was adequate to normalize the qRT-PCR data, the use of normalization factors generated from the expression data of two or three most stable genes should be considered in future studies to improve the accuracy and reliability of expression analysis. The set of qRT-PCR specific primers for the novel and more stable reference genes developed in this study will enable more accurate normalization and quantification of gene expression in wheat. Moreover, the design of suitable primer pairs for their orthologous genes could contribute to the development of reference genes with stable expression in other plant species.In the present research we compared 20 novel candidate reference genes and 12 commonly used HKGs suitable for gene expression normalization in wheat. Both new and traditional reference gene sequences were fetched by an qRT-PCR: quantitative Real-time RT-PCR; HKG: Housekeeping gene; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; RT: Reverse transcriptase; EST: expressed sequence tag; TIGR: The Institute for Genome Research; PDI: Protein disulphide isomerase; TPM: transcripts per million; TC: tentative consensus sequence; Mv: mean value; V: variance; SD: standard deviation; CV: coefficient of variation; SSH: Suppression Subtractive Hybridization; CS: Chinese Spring; TEF-1\u03b1: Translation Elongation Factor-1\u03b1; ADP-RF: ADP-ribosylation factor; GO: Gene Ontology; ANOVA: analysis of variance; MST: mean square of treatments; MSE: mean square errors; NF: normalization factor; NCBI: National Center for Biotechnology Information.ARP performed all the sample preparations and experimental procedures and participated in data analysis. MC supervised the study, performed data analysis and draft the manuscript. OAT performed data analysis, revised the manuscript critically and participated in tables and figures drawing. EP revised critically the manuscript and gave financial support to the study. All authors read and approved the final manuscript.List of articles reporting the application of reference genes for qRT-PCR normalization in wheat. The list was obtained by a PubMed search from January 1996 to March 2008 and includes 26 articles reporting 16 reference genes.Click here for fileRT-PCR primers used in this research. Table showing UniGene clusters and linked TC sequences of the reference genes used in qRT-PCR analysis, their primer sequences and characteristics of the corresponding amplicons.Click here for fileUniGene clusters and corresponding TC sequences of 177 selected candidate reference genes of wheat. The file reports the transcription profiles of the genes corresponding to the UniGene clusters in six wheat tissues  calculated as a value representing the number of transcripts per million (TPM). Mean value (Mv), Variance (V), Standard deviation (SD) and Coefficient of Variation (CV) were determined on the expression values (TPM) of the 177 Unigene clusters in the six wheat tissues. The highest and lowest expression values, the relative expression (percentage) in the six wheat tissues and the number of ESTs included in each UniGene cluster are also reported. The frequency  was determined for each TC or group of TCs linked to the 177 selected UniGene clusters.Click here for fileClassification of the 177 selected candidate reference genes of wheat on the basis of their putative functions. File showing the UniGene clusters and corresponding TC sequences of the 177 selected candidate reference genes of wheat and their putative functional annotation determined on the basis of their orthologous genes of rice and relative GO annotations.Click here for fileLevel of expression of the 177 selected candidate reference genes determined on the basis of the number of EST sequences included in each UniGene cluster. File showing UniGene clusters and corresponding TC sequences of the 177 selected candidate reference genes of wheat sorted in ascending order on the basis of the number of EST sequences included in each UniGene cluster.Click here for fileUniGene clusters and corresponding TC sequences of ten genes of the actin and \u03b1-tubulin families. Gene transcription profile of each UniGene cluster in six wheat tissues  is reported as a value representing the number of transcripts per million (TPM). Mean value (Mv), Variance (V), Standard deviation (SD) and Coefficient of Variation (CV) were calculated on the expression values (TPM) of the ten Unigene clusters in the six wheat tissues. The highest and lowest expression values, the relative expression (percentage) in the six wheat tissues and the number of ESTs included in each UniGene cluster are also reported. The frequency  was determined for each TC or group of TCs linked to the 177 selected UniGene clusters.Click here for filewcor14 and TaHSP101B.Expression analysis by RT-PCR of the genes  Agarose gels of RT-PCR products of wcor14 and TaHSP101B genes after 35 PCR cycles in six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C) for 24 and 48 h and their controls . The transcripts of the constitutively expressed gene encoding actin (UniGene cluster Ta54825) were amplified as control. M = part of the DNA molecular weight marker XIV (Roche), the most intense band is 500 bp in length.Click here for fileSpecificity of qRT-PCR amplification. Figures A1\u2013A3 report the dissociation curves of 42 selected reference genes showing single peaks, they were obtained from three technical replicates of 18 cDNA pools representing different tissues and developmental stages of wheat. Figures B1\u2013B3: Agarose gels (2%) showing amplification of a specific PCR product of the expected size for each candidate reference gene.Click here for filet values for 46 primer pairs and 24 tissue samples used in this research.PCR efficiency and C The file shows PCR efficiency and Ct values of two biological replicates performed on 24 tissue samples; three technical replicates were carried out for each of the 46 primer pairs. The 24 tissue sample comprised: 1) Roots from plants with single shoot and three leaves unfolded ; 2) Shoots1 = single shoots and leaves from plants at Feekes scale 1.3; 3) Shoots2 = shoots at the beginning of tillering ; 4) Shoots3 = shoots from plants with formed tillers ; 5) Shoots4 = shoots at the beginning of erect growth ; 6) flag leaves at booting stage ; 7) stems at booting stage ; 8\u201310) Spikes1\u20133 = spikes collected at intervals of 10\u201312 days ; 11\u201316) single floral organs  from fully emerged spikes ; 17\u201318) Seeds 1\u20132 = seeds collected 15 (medium milk stage) and 30 (hard dough stage) days after anthesis; 18\u201324) six samples  consisting of two temperature treatments (4\u00b0C and 33\u00b0C) for 24 and 48 h and their controls .Click here for filet values obtained in five different data-set. Expression stability of the genes belonging to four families  evaluated by statistical analysis of raw CANOVA analysis and statistics determined on raw Ct values obtained by 18 primer pairs which amplified either specific or multiple (m) gene transcripts of four gene families  in five different data-sets: 1) all 24 samples including tissues, developmental stages and temperature treatments; 2) 18 samples relative to different tissues and developmental stages; 3) six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C), each for 24 and 48 h and their controls; 4) six samples relative to the single floral organs from fully emerged spikes; 5) six samples referring to vegetative tissues and developmental stages .Click here for fileRanking of the expression stability of the reference genes as calculated by geNorm in four data sets. geNorm output charts of M values for the 32 selected reference genes in four data sets: (A) = 18 tissues and developmental stages; (B) = six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C) for 24 and 48 h and their controls; (C) = six floral organs from fully emerged spikes; (D) = six vegetative tissues and developmental stages .Click here for fileDetermination of the optimal number of control genes for accurate normalization calculated on the basis of pair-wise variation (V) analysis in four data sets. geNorm output charts of V values for the 32 selected reference genes in four data sets: (A) = 18 tissues and developmental stages; (B) = six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C) for 24 and 48 h and their controls; (C) = six floral organs from fully emerged spikes; (D) = six vegetative tissues and developmental stages .Click here for file"}
+{"text": "Two hundred and eleven patients with node-positive stage II and III breast cancer were treated with eight cycles of adjuvant chemotherapy comprising cyclophosphamide, doxorubicin and oral ftorafur (CAFt), with and without tamoxifen. All patients had undergone radical surgery, and 148 patients were treated with post-operative radiotherapy in two randomized studies. The impact of haematological toxicity of CAFt on distant disease-free (DDFS) and overall survival (OS) was recorded. Dose intensity of all given cycles (DI), dose intensity of the two initial cycles (DI2) and total dose (TD) were calculated separately for all chemotherapy drugs and were correlated with DDFS and OS. Patients with a lower leucocyte nadir during the chemotherapy had significantly better DDFS and OS (P = 0.01 and 0.04 respectively). Dose intensity of the two first cycles also correlated significantly with DDFS (P = 0.05) in univariate but not in multivariate analysis, while the leucocyte nadir retained its prognostic value. These results indicate that the leucocyte nadir during the adjuvant chemotherapy is a biological marker of chemotherapy efficacy; this presents the possibility of establishing an optimal dose intensity for each patient. The initial dose intensity of adjuvant chemotherapy also seems to be important in assuring the optimal effect of adjuvant chemotherapy."}
+{"text": "Loss of mismatch repair proteins  or overexpression of nucleotide excision repair proteins (ERCC1) was not detrimental for the cellular sensitivity to BBR 3464. Moreover, interesting differences in the kinetics of formation and removal of DNA lesions at the single-gene (N-"}
+{"text": "Trans-[PtCl2(isopropylamine)] is a novel trans-platinum compound that shows cytotoxic activity in several cisplatin resistant cell lines. The aim of this paper was to analyse, by means ofmolecular cell biology techniques and total reflection X-ray fluorescence (TXRF), the cytotoxic activity, theinduction of apoptosis, the cellular uptake and the DNA binding of trans-[PtCl2(isopropylamine)] in the cisplatin resistant cell line A2780cisR. The results show that this drug is more cytotoxic and induces a higher amount of apoptotic cells than cisplatin in A2780cisR cells. However,the intracellular accumulation and extent of binding to DNA of trans-[PtCl2(isopropylamine)] is lower than that of cis-DDP. Moreover, trans-[PtCl2(isopropylaminae)] is partially inactivated by intracellular levels of glulathione. The resultsuggest that circumvention of ciplatin resistance by trans-[PtCl2(isopropylamine)] in A2780cisR cells might be related with the ability of this drug to induce apoptosis."}
+{"text": "To investigate the underlying mechanisms of carcinogenesis, we have developed a technique to determine the frequency of genetic changes in prostatic carcinoma tissue. We have demonstrated that at a ratio of between 1:4 and 1:9 mutant-normal alleles, the signal from a mutant TP53 allele is not apparent after polymerase chain reaction (PCR) amplification and further direct sequencing or single-strand conformation polymorphism (SSCP) analysis. To bypass this problem, which is inherent in the heterogeneity of the prostate tissue and of the tumour, we selected areas of graded prostate tumours (Gleason score) from cryosectioned preparations and microdissected these cells (20-100 cells). After anionic resin removal of proteins, PCR amplification of TP53 gene exons 5/6 and SSCP analysis, an abnormal SSCP band shift was observed in suspected tumour cells, compared with microdissected stromal cells used as an internal control, while (1) a crude preparation of tissue DNA carrying the tumour did not show any abnormality and (2) immunostaining by a set of monoclonal antibodies against TP53 protein remained negative. Nucleotide sequence analysis of the different bands confirmed the presence of a mutation in the TP53 gene exon 6 position 13,336 in an abnormal band for one specimen, while no mutation was detected in the normal SSCP band. By targeting recognised tumour cells we can find DNA mutations which are undetectable using the standard technique of whole-tissue DNA extraction, particularly in a heterogeneous tumour such as carcinoma of the prostate."}
+{"text": "The resultsindicate that all these antibiotics effectively bind copper(ll) at physiological pH. Cyclic voltammetryinvestigations and kinetic studies of H2o2 disproportionation and hydroxyl radicals detection made it possibleto support the mechanism of oxidative reactivity of cupric complexes of aminoglycosides, which involvesCu(1) and Cu(lll) redox states and metal-bound, rather than free radical species. The mechanism of thisprocess appears to be complicated, and may have deleterious side-effects by leaking radical intermediates.The presence of these reactive oxygen species may be responsible for modulating the biological activity ofthese drugs.The majority of aminoglycosidic antibiotics anchor Cu(ll) ions by {NHphe in both the presence and absence of hydrogen peroxideshowed that the complexes with H2o2 are the most efficient oxidants, converting dG to its 8-oxo derivative,generating strand breaks in plasmid DNA and multiple cleavages in tRNAphe. Some of these reactions mayplay a role in aminoglycoside-induced ototoxicity and nephrotoxicity; moreover, they may suggest thatCu(ll)-aminoglycosides are potentially dangerous genotoxic agents.These complexes were also screened for their antibacterial activity and bioassays were engaged to findout the possibility of Cu(ll)-kanamycin A complexes to induce tumor necrosis factor (TNF), interferon (IFN)and interleukin-10 (IL-10) in human peripheral blood leukocytes. The aim of these studies was to comparethe biological action of antibiotic alone and complexed with copper(ll) ions in both neutral and oxidativeenvironment.The interactions of copper(ll) complexes of aminoglycosides with oxidation-susceptible biomolecules:2\u2019-deoxyguanosine, plasmid DNA and yeast tRNA"}
+{"text": "Concentrations of circulating immune complexes (CIC) were measured serially during chemotherapy of 22 patients with gestational trophoblastic tumours (GTT) and 11 patients with malignant teratoma (MT) by the polyethylene glycol precipitation and CIq solid-phase assays. Results were correlated with tumour response as measured by serum concentrations of human chorionic gonadotrophin (hCG) and alpha-foetoprotein (AFP). CIC concentrations correlated with disease status in the early stages of treatment in 4/22 patients with GTT and 5/11 with MT. CIC assays were less sensitive than hCG and AFP as a monitor of disease, and also less specific, in that 8 patients with GTT and 5 with MT developed raised CIC concentrations during chemotherapy in spite of sustained complete remission. Measurements of CIC concentrations by present methods are neither sufficiently sensitive nor specific to be of clinical value as a tumour marker in GTT and MT, and this casts doubt on their potential value in other malignancies. Attention should be directed to identification of the components of CIC, some of which may be more cancer-specific."}
+{"text": "The leukaemic lesions in intact and ovariectomized mice of strain ICRC, induced with 20-methylcholanthrene (20-MCA) in combination with or without hormones were investigated for the presence of mouse leukaemia virus (MuLV) by (i) bioassays and (ii) electron microscopy. The different experimental groups treated with 20-MCA were (i) intact females, (ii) ovariectomized females, (iii) ovariectomized females with pituitary graft, (iv) ovariectomized females with 10 mug oestradiol/day for 30 days and (v) ovariectomized females with 1 mug oestradiol together with 1 mg progesteron/day for 30 days. It was possible to transmit nearly all these experimentally induced leukaemias to syngeneic mice through acellular extracts, compared with very poor transmissibility of spontaneous leukaemias in the ICRC strain, indicating functional activation of viral agents on combined treatment with carcinogen and hormones. Potency of the acellular leukaemic extract from the mice of group (ii) without the ovarian hormones was much weaker than that from mice of the other experimental groups. The leukaemogenic activity of MuLV was enhanced on serial transmission in syngeneic hosts. Leukaemic lesions of ovariectomized mice treated with 20-MCA and oestradiol were also transmissible to the sucklings of allogeneic mice of strain C3H-MTV, C57-BL and Dba-MTV. The cell-free supernatant medium of the cultures of these leukaemic lesions induced leukaemias on back inoculation into syngeneic mice. Electron microscopic studies of lesions induced with carcinogen and oestradiol consistently showed abundant intracytoplasmic type A particles. Numerous intracytoplasmic type A particles as well as some type B particles were found in the leukaemic tissues of ovariectomized females treated with MCA and oestradiol combined with progesterone. Type C particles, characteristic of MuLV were seen in the leukaemic tissues of all other experimental groups. These findings indicate a significant influence of the physiological condition of the host, particularly the hormonal make up, on expression and activity of specific viral agents."}
+{"text": "A series of 155 cases of hepatic hydatid disease, occurring in 121 patients, were operated on at the Navaland Veterans Hospital of Athens. Ultrasonography and computerized axial tomography provided thepreoperative diagnosis in 89 and 93 percent of the cases respectively in recent years. Thirty one percentof the cases presented with complications, the commonest of these being infection of the cyst (10percent) and rupture of the cyst into the bile ducts (17 percent). Total cystectomy was performed inthree cases and removal of the endocyst with its content in the remaining 152. The remaining cavity waseither externally drained (57 cases), or filled with omentum (omentoplasty \u2014 95 cases). External fistulaand infection of the residual cavity occurred in 32 and 56 percent after simple drainage and in 4 and 2percent respectively after omentoplasty. Differences are statistically significant (p <  0.001).Hospitalization was also significantly longer after drainage than after omentoplasty (p < 0.01).Obstructive jaundice after intrabiliary rupture of the cyst was more successfully managed afteradditional choledochoduodenostomy than after simple drainage of the common bile duct.Intrapericoneal recurrence of hydatid disease occurred in two cases. The conclusion of the present studyis, that ultrasonography and computerized axial tomography provide an acceptable rate in the diagnosisand that omentoplasty offers a very low complication rate in the management of hydatid cystic disease ofthe liver."}
+{"text": "The aim of our research is to evaluate the advantage by the combined use of fiberopticbronchoscopy and laryngeal mask during the performance of percutaneous dilatationaltracheostomy in an intensive care unit.Patients: 16 adult patients who were candidates to middle-long term mechanicalventilation.Environment: Intensive Care Unit of a Community General Hospital.Results: We experienced 3 minor complications (2 minor bleedings and 1 neck emphysema).Difficulties were found in 3 patients with particular anatomical conformation.Conclusion: The combined use of fiberoptic tracheo-bronchoscopy with the laryngealmask permits a better endoscopic visualisation of the operatory field, providing a moresecure and precise procedure."}
+{"text": "The aims of this study were: (1) To examine the presence of alphafetoprotein (AFP) bearing tumour cells in PBSC harvests from advanced GCT patients obtained after multiple cycles of induction chemotherapy. (2) To determine whether induction chemotherapy contributed to in vivo purging of the tumour. We evaluated cryopreserved PBSC samples from 5 patients with advanced stage II/III AFP producing GCT. PBSC were separated after the first, second and third cycles of induction chemotherapy. Those samples were analysed using the nested reverse transcription polymerase chain reaction (RT-PCR) method to detect AFP mRNA. Although, in all patients, AFP mRNA was detected in PBSC samples after the first or second cycle of induction chemotherapy, but was not detected in 3 of 4 samples after the third cycle of chemotherapy. Although it is not clear whether tumour cells contaminating PBSC fraction contribute to disease relapse, PBSC harvested after at least 3 cycles of induction chemotherapy might be recommended to avoid such a possibility. \u00a9 2001 Cancer Research Campaign"}
+{"text": "There was an error in the last sentence of the legend to Figure 4.-/- (thin line histogram).The correct text should read: Representative histograms were shown to analyze relative bacterial number in macrophages (MAC) and neutrophils (Neu) between WT (gray-filled histogram) and Rip2"}
+{"text": "Primary pancreatic lymphoma (PPL) is an extremely rare neoplasm, which may be confused with pancreatic adenocarcinoma. So far only about 150 cases of PPL have been reported.We present our experience of 3 cases of PPL over a 4-year period.All the patients presented with vague abdominal pain of duration ranging from 1\u00bd months to 3 months. Two patients had diagnosis confirmed histologically by CT-guided core biopsy or Fine needle aspiration procedure. We were able to avoid unnecessary laparotomy in 2 patients using preoperative guided Fine needle aspiration Cytology, although the third patient did undergo a Whipple\u2032s procedure as the diagnosis of PPL was not considered during the initial workup.There is no significant difference noted with regard to patient\u2032s age or duration of symptoms between patients with either pancreatic adenocarcinoma or PPL. The differential diagnosis of PPL includes pancreatic adenocarcinoma and secondary involvement of pancreas from extra-nodal lymphoma. Combination of two things is suggestive of Pancreatic lymphoma: (1) Bulky localized tumor in pancreatic head (2) Absence of significant dilatation of main pancreatic duct strengthens a diagnosis of pancreatic lymphoma over adenocarcinoma. Majority of patients can be managed with chemotherapy with much better prognosis compared to patients with pancreatic adenocarcinoma. Larger series of patients are needed to evaluate whether chemotherapy, eventually followed by involved-field radiation therapy, is the treatment of choice for PPL. Gastrointestinal (GI) tract is the most common site of extra-nodal non-Hodgkin\u2032s lymphomas (NHLs), accounting for 15% to 20% of all NHL cases.14 SignifiTo date, approximately 150 cases of PPL have been reported in the English-language medical literature. There isWe present our experience of treating primary pancreatic lymphoma in patients at our hospital. Medical records of patients identified during a retrospective review of prospectively maintained database in the cancer institute of our hospital were retrieved after obtaining informed consent from the concerned patients. A pathologist reviewed slides and blocks to reconfirm the diagnosis. Literature was accessed on the Internet through PubMed search using the string 'primary pancreatic lymphoma.'Over a period of 4 years, we have diagnosed and treated 3 cases of primary pancreatic lymphoma . All theHematoxylin and eosin-stained sections from tumor in all the 3 patients showed monotonous population of small round cells in sheets separated by sparse fibrous septae infiltrating the pancreatic parenchyma . NeoplasTwo patients received chemotherapy  for 4 cycles followed by radiotherapy (45 Gy in 20 fractions for 1 patient and 30 Gy in 18 fractions for the other) using antero-posterior and postero-anterior pair beams. One patient who was diagnosed following Whipple\u2032s procedure received adjuvant chemotherapy with CHOP regimen (6 cycles) alone.All the patients are currently on follow-up  and are so far free of disease recurrence.Diagnostic criteria for PPL include presence of main mass in the pancreas with lymph nodal involvement confined to the peri-pancreatic region with no hepatic or splenic involvement; absence of superficial lymphadenopathy and mediastinal lymph node enlargement; and a normal leukocyte count in peripheral blood.9Literature suggests a strong male predominance .10There iMost common presenting symptom reported in literature is abdominal pain, found in about 83% of cases, followed by (in order of frequency) abdominal mass (58%), weight loss (50%), jaundice (37%), acute pancreatitis 12%), small-bowel obstruction (12%) and diarrhea (12%).131013]"}
+{"text": "Roquinimex (Roq) is an immunomodulator known to stimulate cellular immune responses. It is currently used for immunotherapy after bone marrow transplantation (BMT). One of the major features of this compound is an enhancement of natural killer (NK) cell activity and numbers. We studied the in vitro effect of Roq on human peripheral blood NK and adherent lymphokine-activated killer cell (ALAK) activities. In cultures supplemented with recombinant interleukin 2 (rIL-2) (1000 U ml-1) and Roq a significant increase in NK and LAK function was observed without a parallel increase in cell numbers. We also examined the generation of NK cells from human bone marrow (BM) immature progenitors, obtained by purging with 4-hydroperoxycyclophosphamide (4HC). NK cell numbers and activity were both increased when cultures with rIL-2 (10 U ml-1) were supplemented with Roq. These results confirm findings obtained in vivo and in vitro in the murine system and suggest that Roq is an active agent on these lymphoid populations. These properties and good tolerability make Roq an attractive tool for immunotherapy."}
+{"text": "We discuss the evaluation of the Engaging Older Adult Learners as Health Researchers (ENGOAL), a program designed to educate older adults from underserved and underresourced communities about geriatric health and research methods, enabling them to become Research Partners. Quantitative and qualitative data were collected for evaluation from 21 participants aged 53-79. We used All Aspects of Health Literacy Scale  and an adaptation of Stanford Patient Education Research Center Chronic Disease Self-Efficacy Scale to assess pre-post and follow-up changes, using repeated measures analyses. Results suggest notable increases in self-efficacy, but only small improvements in subjective health literacy. Themes identified through qualitative analysis of interviews with participants included: (1) Finding our Voices (2) Race and Health (3) Faith and Health (4) Communicating with Providers and (5) Sharing and Advocacy. Emerging community leadership of participants are further evidence of confidence gains in our participants."}
+{"text": "The evaluation on the characteristic dataset and figures presented here, are related to our latest research data entitled \u201cFabrication of chitosan based magnetic nanocomposite by click reaction strategy; evaluation of nanometric and Cytotoxic characteristics\u201d [1]. FTIR, Vibrating Sample Magnetometer (VSM) measurements, Xray diffraction (XRD) information and the resulted figures for structural confirmation of the prepared chitosan based nanocomposite are presented in this article. The morphological changes of the Fibroblast, Saos, MCF7 and Hela cell lines after treatment with the mention compound were displayed. The additional adsorption data for the synthesized nanobiocomposite were also demonstrated with graphs. The resulted FT-IR spectra and the corresponding data of the synthesized products were presented in The magnetic nanocomposite was prepared using chitosan. To prepare functionalized chitosan, the chitosan was azidated using chloroacetyl chloride and sodium azide. Then click reaction which has been incorporated in our recent studies ,3 and als) of 25.4 (emu/g) has super paramagnetic characteristics. Moreover; the corresponding data were presented in Magnetization experiments of the prepared magnetic nanocomposite (MNC) were obtained using VSM technique at room temperature. As can be seen in 3O4 nanoparticles  theory were performed. The isotherm plots were used to calculate the specific surface area and the average pore diameter of the chitosan/magnetic nanocomposite and the difference between adsorption and desorption steps.For evaluating the cell cytotoxicity of the prepared sample (MNC) according to the literature , some kn"}
+{"text": "Qualitative research on positive coping approaches actually used by caregivers can inform interventions that can be feasibly implemented. Absent from previous qualitative research is how caregivers respond to strain in the relationship, specifically. Eight focus groups were conducted with a purposeful sample of racially and ethnically diverse family caregivers in Los Angeles (n=75). An additional 8 in-depth follow-up interviews were conducted. Content analysis was used to understand the mechanisms employed by caregivers to cope with strain and tension in the caregiving relationship. Preliminary results revealed twenty-two individual themes, which were subsequently grouped into four main superordinate themes: 1) Self-care; 2) Adaptation of behaviors and feelings; 3) Seeking and utilizing assistance and respite; and 4) Education and support groups. This work can help inform the design of programs to support caregivers and prevent potentially harmful behaviors, through understanding the experiences of caregivers in their own words."}
+{"text": "Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC). It is so named because it lacks expression of estrogen/progesterone receptors and does not overexpress the human epidermal growth factor receptor 2 (HER2). While only 15\u201320% of all BC cases are classified as TNBCs, they account for over 50% of BC mortality. TNBCs include the BRCA1/2- defective BCs and largely overlap with the basal-like BC group. As of today, no targeted therapies are available for these BC subtypes and despite advances in cytotoxic therapies they still carry a grim prognosis, with relapses typically occurring as soon as 3 years after treatment [TNBCs trace their origin to the genomic instability (GI) associated with defects in DNA repair (notably homology-directed repair (HDR)) and thus, compared to other BCs show increased rates of pathologic complete response following chemotherapy . Yet, deDNM2 was associated with lower relapse-free survival and very short times (3\u20135 years) to relapse after chemotherapy in TNBC. Below we provide a mechanism that explains how increased DNM2 expression may shape resistance in later stages of the disease and why it is so uniquely important for the outcome in TNBC.We have recently shown that the efficiency of HDR depends on dynamin 2 (DNM2), a large GTPase best known for its role in intracellular molecular trafficking [RAD51 might similarly reverse the HDR defects induced by DNM2 deficiency. However, although we successfully rescued the DNM2 inhibition-induced HDR phenotypes in all other cells, this was not the case for cells derived from advanced TNBCs, which remained strikingly dependent on DNM2 function for their survival after treatment with chemotherapy. We concluded that in the absence of BRCA and other proteins that control recruitment of RAD51 to the sites of DNA damage and/or stalled replication forks, RAD51 trafficking to the nucleus and subsequent cell resistance to chemotherapy was largely dependent on DNM2. This reasoning is supported by observations of aberrant cytoplasmic-to-nuclear ratios of RAD51 in late-stage TNBCs, suggesting the importance of RAD51 trafficking between nucleus and cytoplasm for the aggressiveness of TNBC [High genomic instability (GI) is a characteristic feature of TNBCs. One mechanism often employed by TNBCs to counteract GI is overexpression of RAD51, a protein central to HDR . As a DN of TNBC .Recent single-cell sequencing of longitudinal TNBC samples  has showIn summary, increased DNM2 and associated intra-cell trafficking explain how DNA repair-deficient cells could acquire both resistance to chemotherapy and mobility, thus providing one possible solution to the triple-negative paradox of BC (Figure"}
+{"text": "Here, we investigate cross-seeding of full-length human Tau (FL Tau) with fibrils assembled from K18 and K18\u0394K280 fragments of Tau in the presence of poly-L-glutamate (poly-Glu) as an enhancer of Tau aggregation. To study cross-seeding between Tau polypeptides and the role of the conformational memory effect in induction of Tau amyloid polymorphism, kinetic assays, transmission electron microscopy, infrared spectroscopy and limited proteolysis have been employed. The fastest fibrillization was observed for FL Tau monomers seeded with preformed K18 amyloid yielding daughter fibrils with unique trypsin digestion patterns. Morphological features of daughter FL Tau fibrils induced by K18 and K18\u0394K280 seeds were reminiscent of the mother fibrils , respectively) but disappeared in the following generations which became similar to unpaired FL Tau amyloid fibrils formed de novo. The structural evolution observed in our study was accompanied by disappearance of the unique proteolysis profile originated from K18. Our findings may have implications for understanding molecular mechanisms of the emergence and stability of Tau amyloid strains.Amyloid aggregates of Tau protein have been implicated in etiology of many neurodegenerative disorders including Alzheimer's disease (AD). When amyloid growth is induced by seeding with preformed fibrils assembled from the same protein, structural characteristics of the seed are usually imprinted in daughter generations of fibrils. This so-called conformational memory effect may be compromised when the seeding involves proteins with non-identical sequences leading to the emergence of distinct structural variants of fibrils (amyloid \u2018 In A and B, lane 1 shows molecular weight marker. Note different pattern of bands in the range of 15 to 20 kDa in lane 3.(TIF)Click here for additional data file."}
+{"text": "The study examined attitudes towards Advance Care Planning (ACP) as a potential mediator in the association between acculturation and willingness to use nursing home in Korean American older adults (aged 60 and older). Data were driven from a cross-sectional study of 235 community-dwelling Korean American older adults (aged 60 and older) in 2013. Multivariate regression models of willingness to use nursing home were entered in the following order: (1) demographics, (2) health, (3) acculturation, and (4) attitudes towards advance care planning. The mediation effect of attitudes towards ACP in the relationship between acculturation and willingness to use nursing home was separately examined using the bootstrapping method. Higher acculturation was associated with positive attitudes towards ACP and more likelihood of using nursing home. The proposed mediation model was fully supported: positive attitudes towards ACP served as an intervening step between acculturation and willingness to use nursing home. The mediating role of attitudes towards ACP yields implications for developing culturally sensitive advance care planning education program targeting older individuals."}
+{"text": "A 39-year-old man presented with a productive cough, a history of chronic dyspnea and recurrent lower respiratory tract infections. Physical examination and laboratory tests were unremarkable. A chest X-ray (A) showed an enlarged tracheal diameter (white arrows), with multiple cysts in the lower lobes (red arrows). A computed tomography scan of the chest (B) showed the dilatation of both the trachea and the two main bronchi (white arrows) with multiple diverticulae (blue arrows). It also revealed bilateral cystic bronchiectasis involving both lower lung zones (red arrows). A possibility of Mounier-Kuhn syndrome (MKS) was considered. MKS is a rare condition characterized by recurrent lower respiratory tract infections and tracheobronchial dilation that is due to atrophy of the muscular and elastic tissues in the trachea and main bronchial wall. The patient underwent bronchoscopy which demonstrated tracheal dilation with diverticulae and enlargement of both main bronchi confirming the diagnosis of MKS."}
+{"text": "We discuss the evaluation of the Engaging Older Adult Learners as Health Researchers (ENGOAL), a program designed to educate older adults from underserved and underresourced communities about geriatric health and research methods, enabling them to become Research Partners. Quantitative and qualitative data were collected for evaluation from 21 participants aged 53-79. We used All Aspects of Health Literacy Scale  and an adaptation of Stanford Patient Education Research Center Chronic Disease Self-Efficacy Scale to assess pre-post and follow-up changes, using repeated measures analyses. Results suggest notable increases in self-efficacy, but only small improvements in subjective health literacy. Themes identified through qualitative analysis of interviews with participants included: (1) Finding our Voices (2) Race and Health (3) Faith and Health (4) Communicating with Providers and (5) Sharing and Advocacy. Emerging community leadership of participants are further evidence of confidence gains in our participants."}
+{"text": "The management of multiple chronic conditions (MCC) in older adults living in the community is complex. Little is known about the experiences of interdisciplinary primary care and home providers who care for this vulnerable group. The aim of this study was to explore the experiences of healthcare providers in managing the care of community-living older adults with MCC and to highlight their recommendations for improving care delivery for this group. A qualitative interpretive description design was used. A total of 42 healthcare providers from two provinces in Canada participated in semi-structured interviews. Participants represented diverse disciplines  and settings . Thematic analysis was used to analyze interview data. The experiences of healthcare providers managing care for older adults with MCC were organized into six major themes: (1) managing complexity associated with MCC, (2) implementing person-centred care, (3), involving and supporting family caregivers, (4) using a team approach for holistic care delivery, (5) encountering rewards and challenges in caring for older adults with MCC, and (6) recommending ways to address the challenges of the healthcare system. Healthcare providers highlighted the need for a more comprehensive integrated system of care to improve care management for older adults with MCC and their family caregivers. Specifically, they suggested increased care coordination, more comprehensive primary care visits with an interprofessional team, and increased home care support."}
+{"text": "Recent data from an individual patient data (IPD) meta-analysis of 17 randomized control trials including >100,000 women living in low- and middle-income countries found that multiple micronutrient supplementation (MMS) in pregnancy reduced the risk of low birth weight, preterm birth, and being born small for gestational age. Further, MMS reduced the risk of neonatal and infant mortality for females, and there was no evidence of increased risk among the 26 subgroups examined. The 2016 WHO antenatal care guidelines, which were released before the IPD meta-analysis, did not universally recommend MMS, noting: \u201cThere is some evidence of additional benefit \u2026 but there is also some evidence of risk.\u201d The guidelines suggest that MMS may increase the risk of neonatal mortality based on an exploratory subgroup analysis of 6 randomized trials. However, we identified several issues with this subgroup analysis. In this report we correct and update the subgroup analysis and show that there is no evidence that MMS increases the risk of neonatal mortality. There is growing scientific consensus that MMS containing iron and folic acid (IFA) is superior to IFA alone. The WHO guidelines currently state that \u201cpolicy-makers in populations with a high prevalence of nutritional deficiencies might consider the benefits of MMN [multiple micronutrient] supplements on maternal health to outweigh the disadvantages, and may choose to give MMN supplements that include iron and folic acid.\u201d This equivocal guidance has created confusion about the best course of action for public health programs in low- and middle-income countries. Given the new evidence, WHO should review their statements regarding the potential neonatal mortality risks and re-evaluate the overall potential benefits of implementing MMS as a public health program. Micronutrient deficiencies in pregnancy are common and are associated with adverse birth outcomes . PrenataThe 2016 WHO antenatal care guidelines do not universally recommend MMS, noting: \u201cThere is some evidence of additional benefit of MMN [multiple micronutrient] supplements containing 13\u201315 different micronutrients (including iron and folic acid) over iron and folic acid supplements alone, but there is also some evidence of risk\u201d (1) corrected the Bhutta et al. estimate, which is consistent with the updated 2017 Cochrane Review (2) included the omitted MINIMat study (3) added 2 recently published trials (lipid-based supplements arms excluded) (4) included 2 trials that used a 60 mg Fe/d control but were excluded due to using a 250 \u00b5g/d folic acid dose  addexcluded) , 7; and cid dose , 9. The cid dose  and was cid dose . The Fawcid dose  trial wacid dose  neonatalcid dose \u201316, and cid dose .and the effect of additional micronutrients. The lower dose of iron in the MMS (30 mg/d) as compared with the control arm (60 mg/d) may explain negative effect estimates seen in some trials. The 2017 Cochrane Review examined the effect of MMS on perinatal mortality stratified by iron dose in the MMS and control arms  with an IFA control arm containing high-dose iron (60 mg/d). These trial designs simultaneously address 2 questions about the effect of a lower dose of iron rol arms . Among trol arms . We argudecrease the risk of infant mortality for infants born to women without access to a skilled birth attendant (\u223c18% risk reduction)  . The IPDOur update of the WHO subgroup analysis showed no increased risk of neonatal mortality and the results are consistent with the findings of the updated 2017 Cochrane Review and our recent IPD meta-analysis which found that MMS did not increase the risk of neonatal mortality overall or in any of 26 subgroups of pregnant women and newborns . In fact"}
+{"text": "SLE and Serum Complement: Causative, Concomitant or Coincidental?2017, 11: 113-122The Open Rheumatology Journal, The revised last paragraph of conclusion in abstract is mentioned below:It is clinically important to find novel ways to assess disease activity in SLE. Increased serum levels of cell-bound complement activation products may more accurately reflect disease activity than conventional serum C3 and C4 monitoring.The original last paragraph of conclusion provided was:It is clinically important to find novel ways to assess disease activity in SLE. Reduced serum levels of cell-bound complement activation products may more accurately reflect disease activity than conventional serum C3 and C4 monitoring.The revised last paragraph of conclusion is mentioned below:With recent studies demonstrating that increased levels of serum cell-bound complement activation products may more accurately reflect disease activity than conventional complement C3 and C4 monitoring, we believe that this is an important area for future SLE research and look forward to further studies on research in the complement in SLE.The original last paragraph of conclusion provided was:With recent studies demonstrating that reduced levels of serum cell-bound complement activation products may more accurately reflect disease activity than conventional complement C3 and C4 monitoring, we believe that this is an important area for future SLE research and look forward to further studies on research in the complement in SLE."}
+{"text": "Parkinson\u2019s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear."}
+{"text": "Macromolecular complexes are essential to intracellular signal transduction by creating signaling niches and enabling a chain of reactions that transmit external signals into various cellular responses. Analysis of SMYD3 interactome indicates this protein lysine methyltransferase might be involved in calcium dependent signaling pathways through forming complexes with the phospholipase PLCB3, calcium/calmodulin dependent kinase CAMK2B, or calcineurin inhibitor RCAN3. SMYD3 is well-known as a histone H3K4 methyltransferase involved in epigenetic transcriptional regulation; however, any roles SMYD3 may play in signaling transduction remain unknown. KEGG pathway enrichment analysis reveals the SMYD3 interacting proteins are overrepresented in several signaling pathways such as estrogen signaling pathway, NOD-like receptor signaling pathway, and WNT signaling pathway. Sequence motif scanning reveals a significant enrichment of PXLXP motif in SMYD3 interacting proteins. The MYND domain of SMYD3 is known to bind to the PXLXP motif. The enrichment of the PXLXP motif suggests that the MYND domain is likely to be a key interaction module that mediates formation of some SMYD3 complexes. The presence of the PXLXP motifs in PLCB3 and CAMK2B indicates the potential role of the MYND domain in mediating complex formation in signaling. The structural basis of SMYD3 MYND domain-mediated interactions is unknown. The only available MYND-peptide complex structure suggests the MYND domain-mediated interaction is likely transient and dynamic. The transient nature will make this domain well-suited to mediate signaling transduction processes where it may allow rapid responses to cellular perturbations and changes in environment. The N-tThe structure of SMYD3 in complex with a MAP3K2 peptide provided the structural basis for SMYD3-substrate complex formation . The weak interaction suggests the MYND-mediated interactions are transient in nature. Transient interactions usually show a fast bound-unbound equilibrium and can readily switch between different binding partners (Perkins et al., MYND domain-based interactions show relatively low binding affinities with KThe structural basis of SMYD MYND domains-mediated interactions is unknown. Based on the structural superposition , the pepIn contrast to binding specificity, MYND domains also show promiscuous binding. Many MYND domains are capable of binding to multiple targets, and single peptide motifs can be recognized by different MYND domains. The MYND domain of BS69 is able to bind to MGA, E1A, and EBNA2 proteins (Ansieau and Leutz, Motif scanning using ScanProsite (de Castro et al., The significant enrichment of PXLXP motif in SMYD3 interacting proteins suggests that the MYND domain is likely to be a key interaction module that mediates the formation of some SMYD3 complexes. The presence of PXLXP motifs in PLCB3 and CAMK2B indicates the potential role of the MYND domain in mediating complex formation in signaling including the aforementioned estrogen signaling pathway, GnRH signaling pathway, NOD-like receptor signaling pathway, and WNT signaling pathway. In PLCB3 there are two PXLXP motifs, PPLRP at residues 265\u2013269 and PSLEP at residues 530\u2013534 . The for2+ concentrations; as intracellular Ca2+ concentrations rise, the holoenzyme is released from the cytoskeleton and enters the cytosol (Swulius and Waxham, CAMK2B has only one PXLXP motif, PCLSP at residues 476\u2013480. This motif is located at the variable segment of CAMK2B . The varPseudomonas aeruginosa-induced intracellular calcium signaling and regulates the activation of PKC and the nuclear transcription factor NF-\u03baB in human bronchial epithelial cells (Bezzerri et al., Analysis of SMYD3 interactome reveals SMYD3 might be involved in signal transduction pathways in addition to epigenetic gene regulation. Most enriched KEGG pathways are associated with the signaling processes in cancer. Among them, the WNT signaling has been shown to affect the maintenance of stemness and metastasis of cancer cells (Zhan et al., Caenorhabditis elegans orthologs, Bra-1 and Bra-2, have been shown to participate in BMP and TGF\u03b2 signaling pathways (Kurozumi et al., The MYND domain might be a key complex-forming module in SMYD3 complexes. The PXLXP motif to which the MYND domain may bind is significantly enriched in SMYD3 interacting proteins. However, there is no significant difference in the enrichment between the interactors involved in signaling transduction pathways and epigenetic transcriptional regulation suggesting that the MYND domain does not have any particular binding preferences in either of these processes. No MYND domain has been directly linked to signaling, but some MYND domain-containing proteins such as BRAM1 as well as its SMYD3 interacting proteins were retrieved from four protein-protein interaction databases including GPS-Prot (Fahey et al., Pathway enrichment analysis of SMYD3 interactors was performed using STRING web-based analyzer (Szklarczyk et al., The presence of PXLXP motif in SMYD3 interacting proteins was scanned using ScanProsite (de Castro et al., All datasets generated for this study are included in the article/supplementary material.ZY and YZ contributed conception and design of the study, performed the database and statistical analyses, and prepared the figures. ZY wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Candida spp., the rate of acute kidney injury (AKI) defined by a creatinine above 3.5\u2009mg/dl or the need of any form of renal replacement therapy (RRT) was around 20% in the bacteria group versus above 40% in the candida group, while having similar Acute Physiology and Chronic Health Evaluation (APACHE) II scores [d-glucan (BDG) could be a very good candidate associated to PCT. Indeed, BDG could be even a better candidate as its molecular weight ranges from several hundred thousand to 10 million daltons and does not pass through any membrane [Candida albicans that increases serum BDG without candidemia [In their recent systematic review, Cortegiani et al. found that serum procalcitonin (PCT) concentrations were higher in patients with bacteremia as compared to candidemia . QualityAndrea Cortegiani, Mariachiara Ippolito and Antonino GiarratanoCandida spp. receiving CRRT and blood purification techniques should be addressed in future studies. Another interesting aspect would be the impact of CRRT in the trend of PCT values in these patients, since almost all the included studies reported the values at the beginning of the diagnostic process [We would like to thank Dr. Honore et al. for discussing the potential role of acute kidney injury (AKI) and continuous renal replacement therapy (CRRT) as potential confounders on the different values of procalcitonin (PCT) in patients with bacteremia versus candidemia in the intensive care unit (ICU) in our systematic review . We eval process . However process \u20139. These"}
+{"text": "The efficiency of organotin(IV) complexes as photostabilizers was determined by monitoring the changes in the weight, growth of specific functional groups , viscosity, average molecular weight, chain scission and degree of deterioration of the polymeric films upon irradiation. The results obtained indicated that organotin(IV) complexes stabilized poly(vinyl chloride) and the dimethyltin(IV) complex was the most efficient additive. The surface morphologies of poly(vinyl chloride) films containing organotin(IV) complexes were examined using an atomic force microscope and scanning electron microscopy. These showed that the surface of polymeric films containing organotin(IV) complexes were smoother and less rough, compared to the surface of the blank films. Some mechanisms that explained the role of organotin(IV) complexes in poly(vinyl chloride) photostabilization process were proposed.Three organotin(IV) complexes containing ciprofloxacin as a ligand (Ph The market for poly(vinyl chloride) (PVC) has grown significantly over the years due low production cost and its large versatility ,2,3. HowA UV light of a wavelength longer than 190\u2013220 nm is not expected to be absorbed by PVC since it only contains single bonds  . CommercAs a continuation of our research in the field of polymers ,38,39,403SnL, Me2SnL2 and Bu2SnL2; 2SnL2 and Bu2SnL2) and triorganotin (Ph3SnL) were used. Also, the substituents on the Sn were varied as small (Me) and bulky (Bu and Ph) groups.Three organotin-ciprofloxacin complexes  complex is the least sterically hindered among the additives used and, therefore, it acts as a better primary photostabilizer compared to the others. Triphenyltin complex shows the least photostabilization effect presumably due to the presence of bulky phenyl groups.Photodegradation of PVC produces low molecular weight fragments as well as hydrochloride (HCl) that lead to a weight loss . The wei\u22121), C=O (1722 cm\u20131) and C=C (1602 cm\u22121) , can be used to evaluate the changes in PVC average molecular weight [\u03b7]=The PVC molecular weight was calculated from the intrinsic viscosities using Equation (6).Three organotin(IV) complexes containing ciprofloxacin as a ligand have been used as photostabilizers to inhibit the photodegradation of PVC films, upon irradiation with ultraviolet light for a long period. Various methods such as the growth of certain functional groups in the infrared spectra, percentage of weight loss, variation in molecular weight, chain scission and degree of deterioration were used to determine the efficiency of organotin(IV) complexes. In addition, the atomic force and scanning electron microscopy were used to assess the surface morphology of poly(vinyl chloride) films. The organotin(IV) complexes used act as efficient photostabilizers and reduce the photodegradation rate of poly(vinyl chloride). It is believed that organotin(IV) complexes act as hydrogen chloride scavengers, peroxide decomposers, free radical scavengers and UV absorbers. For future research using organotin complexes as PVC photostabilizers, the possible leakage of tin should be assessed in order to allow the long-term use of such additives."}
+{"text": "The discovery of the involvement of defined molecular pathway(s) in tumor development and therapeutic targeting of such pathway(s) has revolutionised cancer treatment. More than 50 targeted therapeutic agents have been approved by the Food and Drug Administration (FDA) in the last two decades . Unlike ALK G1202R mutation. It is also highly permeable through the blood brain barrier and hence effective in targeting central nervous system metastasis. Recently published results of the global phase II study has shown superior objective response rate (ORR) and intracranial ORR in comparison to the first and second generation ALK TKIs [V600E/K melanoma patients that relapse on monotherapy [Anaplastic Lymphoma Kinase (ALK) exemplifies the use of targeted therapeutic agents in combating cancer, as well as the challenges that arise in terms of resistance mechanisms against such agents in clinical settings . A numbeALK TKIs . As the ALK TKIs . OrganicALK TKIs , 9. One otherapy . However"}
+{"text": "In the third (HSP90(Cyt)) and fourth (HSP60(Mit)) panels of Both the HTML and PDF versions of the article have been corrected. This error appears only in print and in PDF versions downloaded on or before March 28, 2019."}
+{"text": "Although significant animal suffering caused by preventable diseases is frequently seen in developing countries, reports of this are scarce. This report describes avoidable animal suffering owing to a suspected canine distemper (CD) outbreak in unvaccinated dogs owned by low-income families in Mozambique that killed approximately 200 animals. Affected dogs exhibited clinical signs, and gross and microscopic lesions compatible with CD. Immunohistochemical staining confirmed the presence of canine distemper virus (CDV) in the kidney of one dog from the cohort. This brief communication again illustrates that large outbreaks of CDV in unvaccinated dogs occur and that large-scale avoidable suffering and threats to the health of dogs and wild canines continue. Mass vaccination supported by government and non-government organisations is recommended. Morbillivirus within the subfamily Paramyxovirinae.Canine distemper (CD) is a highly contagious, acute or subacute systemic viral disease that has a high mortality rate in dogs and wild canines. It is caused by canine distemper virus (CDV), which belongs to the genus et al. et al. et al. et al. et al. et al. et al. Vaccination remains the principal strategy for protection, and once clinical signs develop, treatment is limited to supportive care. Even in settings where a diagnosis is rapidly reached, a high standard of care is available and high levels of vaccination are achieved, CD outbreaks continue to occur amongst domestic dogs .The most obvious gross post-mortal lesions were cachexia (3/3), mucopurulent exudate in the trachea and bronchi (2/3), focal pneumonia (3/3), cyanotic heart (2/3), splenic atrophy with increased consistency (2/3), pale kidneys (3/3) and contracted bladders with multifocal haemorrhages in the mucosa (2/3).Histopathological examination of the lung, bronchi and bronchioli showed extensive areas of severe purulent inflammation (2/3). Splenic and lymph node tissues appeared moderately active to highly active (2/3). In the grey matter of the cerebellum, multifocal blood vessels showed notable leukostasis, predominantly with lymphocytes and a few macrophages, and there were also mononuclear infiltrates visible in the perivascular spaces in these areas. There was mild gliosis in the tissue. A few blood vessels in the meninges also showed perivascular cuffing with mononuclear leukocytes, predominately lymphocytes (2/3). A few multifocal aggregates of neutrophils were visible in the parenchyma of the liver, and a mild degree of leukostasis was evident in the sinusoids. The portal regions showed the presence of leukocytes (3/3). Focally extensive severe interstitial inflammation of a chronic lymphoplasmocytic appearance was seen in the prostate (3/3).The history of the disease, the clinical signs and gross and histopathological presentations raised the probability of the presence of a CDV infection. To support this putative diagnosis, immunohistochemistry was performed, which confirmed the disease through positive immunoreactivity to CDV antigens in one of these three cases.et al. et al. The incidence of CDV infections worldwide has decreased thanks to the introduction of the highly protective CDV-modified live virus (MLV) vaccines more than 60 years ago (Martella This report illustrates the highly contagious nature of the disease and the threat to animal welfare posed by non-vaccination. Valuable wildlife would also potentially be threatened by this disease in dogs."}
+{"text": "This methodological paper discusses the process of co-creating a documentary film with seven formerly homeless older adults, highlighting some of the tensions carrying out community-based participatory research (CBPR). This paper is part of a larger study that explored \u2018finding home\u2019 through a series of individual and group audio and video-recorded interviews  with seven adults (aged 50+) with diverse homeless histories. In addition to the main findings, participants shared their experience of filmmaking and CBPR. Findings revealed four main tensions: 1) openness of sharing stories versus privacy and anonymity; 2) balancing participation/engagement and over-burdening; 3) negotiating interpersonal conflict and community building; and 4) ethical issues surrounding copyright and ownership of the film. Ultimately, we advocate for more CBPR film projects, as they not only provide a rich contextualized window into people\u2019s everyday lives but serve to advance the voices of marginalized populations beyond traditional academic circles."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Acculturation and discrimination are associated with negative health outcomes including functional disability. The effect of these on functional disability in older African immigrants in the United States is not well understood. The purpose of this study is to describe and examine the experiences of acculturation, racial discrimination and functional disability in older African immigrants. METHODS/STUDY POPULATION: This study will use cross-sectional quantitative and qualitative mixed methods design. We plan to recruit 150 older (>55 years) participants through the African Immigrant Health Study and community-based organizations serving African immigrants. We will use the PROMIS physical function measure to assess functional disability, the Everyday Discrimination scale and the Psychological Acculturation scale will be used to measure discrimination and acculturation respectively. Higher scores indicate greater severity. RESULTS/ANTICIPATED RESULTS: We have recruited 12 participants so far. The mean age is 57 years and mean length of stay in the United States is 23 years. Mean disability score is 6.5 (range 1\u201338). Mean discrimination is 8.2 (range 4\u201315). The prevalent acculturation strategy of these participants (7) is marginalization (neither identified with the American nor African cultures). DISCUSSION/SIGNIFICANCE OF IMPACT: Preliminary results indicate pervasive discrimination and marginalization of study participants. Exploring these experiences can inform preventive strategies of coping and health behaviors that can decrease the negative effects of discrimination, acculturation and functional disability in African immigrants."}
+{"text": "Roughly one-third of dissolutions among married persons aged 50 and older occur through divorce rather than widowhood, reflecting the rising gray divorce rate and lengthening life expectancies. We use data from the 1980 Vital Statistics and the 2017 American Community Survey (ACS) to estimate the divorce and widowhood rates among married individuals (aged 50+) in 1980 and 2017 to track how much the widowhood rate has declined and the divorce rate has risen. In 1980, women\u2019s widowhood rates exceeded their divorce rates at all ages. For men, the rate of divorce outpaced the rate of widowhood through ages 50-54. By 2017, divorce rates were higher for women through ages 55-59 and for men through ages 60-64, coinciding with the growth in gray divorce. We also examine subgroup variation in the 2017 patterns and the sociodemographic correlates of having experienced divorce versus widowhood during the past year using the ACS data."}
+{"text": "This study aims to understand the roles that psychosocial factors play on the longitudinal associations between sensory (including hearing and vision) loss and cognitive decline. Specifically, we hypothesized that (1) loneliness mediates the associations between sensory loss and cognitive decline; and (2) social support moderates the associations between sensory loss and cognitive decline. We used longitudinal parallel process (LPP) modeling with data from the Health and Retirement Study (HRS) and the Aging, Demographics, and Memory study (ADAMS). Age variable centered at its mean age of 82. In the most parsimonious model, loneliness fully mediated the associations between vision loss and the average cognitive status at age 82 (p < .05). Social support moderated the associations between vision loss and the average cognitive status at age 82 . No moderation or mediation effect was found for the psychosocial factors on the associations between hearing loss and cognition."}
+{"text": "The last poliomyelitis cases reported in Papua New Guinea occurred in 1996. Papua New Guinea is one of 37 countries (or areas) of the World Health Organization Western Pacific Region that were certified free of indigenous wild poliovirus in 2000. On June 22, 2018, the National Department of Health confirmed an outbreak of poliomyelitis caused by circulating vaccine-derived poliovirus type 1 (cVDPV1) following isolation of genetically linked virus from a patient with paralysis and nonhousehold community contacts. The index patient was a boy aged 6 years from Lae, Morobe Province, with onset of paralysis on April 25 and history of having received 2 doses of Sabin oral poliovirus vaccine (OPV).cVDPVs can emerge in underimmunized populations when Sabin vaccine poliovirus is extensively transmitted person-to-person and reverts to neurovirulence  (Round 1 and Round 2)  with bivPapua New Guinea was at risk for delayed detection of poliovirus because of an insufficient surveillance system for acute flaccid paralysis (AFP) and delays in seeking health care, often because of geographic inaccessibility. After the initial cVDPV1 case was detected, active AFP case-finding at health facilities was intensified. The annual national nonpolio AFP rate, a key indicator of surveillance sensitivity (A December outbreak response assessment concluded that cVDPV1 transmission likely continues, given the dates of isolation of cVDPV1 from environmental surveillance and the most recent confirmed case. Additional SIAs are planned in Papua New Guinea in 2019. Because of the outbreak, on July 12, 2018, CDC issued a Level 2 Travel Health Notice recommending that all travelers to Papua New Guinea be fully vaccinated against polio. Before traveling to Papua New Guinea, adults who completed their routine polio vaccine series as children are advised to receive a single, lifetime adult booster of polio vaccine."}
+{"text": "Following publication of the original article , the autOriginally, the sentence was stated as:(ii) exhibited no evidence of prostate cancer as determined by blood test (PSA < 4 mg/dL)The correct sentence is:(ii) exhibited no evidence of prostate cancer as determined by blood test (PSA < 4 ng/ml)"}
+{"text": "Rhinusa and Gymnetron, two closely related groups of weevils that feed and develop inside plant tissues of hosts within the families Scrophulariaceae and Plantaginaceae. We found strong evidence for phylogenetic conservatism of host use at the plant family level, most likely due to substantial differences in the chemical composition of hosts, reducing the probability of shifts between host families. In contrast, the use of different plant organs represents a more labile ecological trait and ecological niche expansion that allows a finer partitioning of resources. Rhinusa and Gymnetron weevils initially specialized on plants within Scrophulariaceae and then shifted to the closely related Plantaginaceae; likewise, a gall inducing behavior evolved from non-galler weevils, possibly in response to resource competition, as galls facilitate larval development by providing enhanced nutrition and a favorable microhabitat. Results from trait-dependent diversification analyses suggest that both use of hosts within Plantaginaceae and parasitism on fruits and seed capsules are associated with enhanced diversification of Rhinusa and Gymnetron via low extinction rates. Our study provides quantitative evidence and insights on the ecological factors that can promote diversification in phytophagous insects that feed and develop inside plant tissues.Weevils (Coleoptera: Curculionoidea) represent one of the most diverse groups of organisms on Earth; interactions with their host plants have been recognized to play a central role in their remarkable diversity, yet the exact mechanisms and factors still remain poorly understood. Using phylogenetic comparative analyses, here we investigate the evolution of host use and its possible role in diversification processes of  Comprising approximately 5,800 genera and more than 60,000 described species , weevilsRhinusa and Gymnetron (Curculionidae: Curculioninae), endophagous parasitic weevils whose larvae feed and develop within tissues of plant species in the families Scrophulariaceae and Plantaginaceae. The genus Rhinusa comprises approximately 40 species with a Palearctic distribution  as host plants  assess phylogenetic conservatism in host use by plant family and in different modes of parasitic behavior; (2) estimate ancestral states of traits associated with host plant use; and (3) assess possible effects of these traits on speciation and extinction rates within the Rhinusa/Gymnetron species complex. These analyses should provide valuable insights into the evolution of different traits of host plant use and their role in diversification processes of phytophagous insects that feed and develop inside plant tissues.Here, we use a previously inferred phylogeny from mitochondrial and nuclear DNA sequence data  in conjuRhinusa representing approximately 80% of recognized species, with representatives from the three main taxonomic groups proposed by Gymnetron from the Palearctic and Afrotropical regions (approximately 40% of recognized species). Additionally, since some of the analyses performed in this study require ultrametric trees, we performed a Bayesian analysis for the same dataset of concatenated sequences using BEAST 2.1.3 ST 2.1.3 .We used Mesquite 3.1  to assesUsing the same host plant use categorization as for phylogenetic conservatism analyses, ancestral states were reconstructed across the random sample of 1,000 post burn-in trees from the analysis performed with MrBayes. We used the Bayesian approach reversible jump MCMC (rjMCMC), implemented in BayesTraits 2.0 ; the advFor comparison with the rjMCMC approach and to account for differential speciation, extinction and character transition rates in the reconstruction of ancestral states, we additionally performed ancestral state reconstructions using maximum likelihood under binary and multi-state speciation and extinction models (BiSSE/MuSSE)  in the RRhinusa/Gymnetron species complex. We independently used the model to assess the effect of host plant family use (Scrophulariaceae or Plantaginaceae) and the mode of parasitism as gall or non-gall inducer. The model estimates six parameters; speciation (\u03bb) and extinction (\u03bc) rates for states 0 and 1  and transition rates from state 0 to 1 and vice versa (q01 and q10). Similarly, a multi-state speciation and extinction (MuSSE) model was employed to assess the effect of different modes of parasitism on either roots, stems or fruit/seed capsules. The MuSSE model is an extension of the BiSSE model to discrete traits with more than two states or combinations of binary traits analyzed simultaneously . Eight parsimony steps were observed against 14 expected steps at the lower confidence limit under 10,000 character randomizations of the null model. When host plant use is categorized according to the plant parts being parasitized and as gall inducer vs. non gall inducer, the distribution of characters over the Bayesian consensus tree is marginally significant at the 0.05 confidence level, that is, in both cases the difference between the expected (null model) and observed number of parsimony steps is only one. A similar trend was observed for the results from the estimation of Pagel\u2019s lambda parameter, which indicate a strong phylogenetic signal for host use by plant family (\u03bb = 1) but less phylogenetic signal for both host use as either gall or non-gall inducer and parasitic mode on different plant structures , providing enhanced nutrition and a favorable microhabitat which facilitates larval development. The use of restricted sets of host plants is phylogenetically conserved, most likely because of substantial differences in the chemical composition of their hosts, thus reducing the probability of host shifts. In contrast, the utilization of different plant organs represents a more labile ecological trait that allows a finer partitioning of resources; this ecological niche expansion is associated with enhanced diversification rates in weevils exhibiting a parasitic behavior on fruits and seed capsules. Our results show that ecological factors such as host plant use and specialized endoparasitic habits can promote diversification via low extinction rates in phytophagous insects that require plant tissues for the completion of their reproductive cycle.10.7717/peerj.6625/supp-1Supplemental Information 1Extinction rates associated with (A) use of either Scrophulariaceae or Plantaginaceae as host plant families and (B) use of different plant organs: roots, stems or fruits and seed capsules.Click here for additional data file.10.7717/peerj.6625/supp-2Supplemental Information 2Extinction rates associated with use of Plantaginaceae taxa as hosts (A) and use of fruits and seed capsules (B) estimated with MCMC analyses (BiSSE and MuSSE models) from pruned simulated trees. The red line indicates the true parameter value used to simulate the tree.Click here for additional data file."}
+{"text": "We deeply appreciate the great contributions of many physicians in the registry of esophageal cancer cases. The Comprehensive Registry of Esophageal Cancer in Japan, 2012, was published here, despite some delay. The registry complies with the Act for the Protection of Personal Information. The encryption with a HASH function is used for anonymity in an unlinkable fashion.We briefly summarized the Comprehensive Registry of Esophageal Cancer in Japan, 2012. Japanese Classification of Esophageal Cancer 10th [We hope that this Comprehensive Registry of Esophageal Cancer in Japan for 2012 will help to improve all aspects of the diagnosis and treatment of esophageal cancer in Japan.I.Clinical factors of esophageal cancer patients treated in 2012Institution-registered cases in 2012Patient backgroundTableAge and genderTablePrimary treatmentTableTumor locationTableHistologic types of biopsy specimensTableDepth of tumor invasion, cT (UICC TNM 7th)TableLymph node metastasis, cN (UICC TNM 7th)TableDistant metastasis, cM (UICC TNM 7th)TableClinical stage (UICC TNM 7th)II.Results of endoscopically treated patients in 2012TableDetails of endoscopic treatment for curative intentTableComplications of EMR/ESDTablePathological depth of tumor invasion of EMR/ESD specimensFigureSurvival of patients treated with EMR/ESDFigureSurvival of patients treated with EMR/ESD according to the pathological depth of tumor invasion, pT (UICC TNM 7th)FigureSurvival of patients treated with EMR/ESD according to the lymphatic and venous invasionIII.Results in patients treated with chemotherapy and/or radiotherapy in 2012TableDose of irradiation TableDose of irradiation FigureSurvival of patients treated with chemotherapy and/or radiotherapyFigureSurvival of patients treated with definitive chemoradiotherapy according to clinical stage (UICC TNM 7th)FigureSurvival of patients underwent radiotherapy alone according to clinical stage (UICC TNM 7th)IV.Results in patients who underwent esophagectomy in 2012TableTreatment modalities of esophagectomyTableTumor locationTableApproaches to tumor resectionTableVideo-assisted surgeryTableFields of lymph node dissection according to the location of the tumorTableReconstruction routeTableOrgans used for reconstructionTableHistological classificationTableDepth of tumor invasion, pT (JES 10th)TablePathological grading of lymph node metastasis, pN (JES 10th)TablePathological findings of lymph node metastasis, pN (UICC 7th)TablePathological findings of distant organ metastasis, pM (JES 10th)TableResidual tumorTableCauses of deathFigureSurvival of patients who underwent esophagectomyFigureSurvival of patients who underwent esophagectomy according to clinical stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to clinical stage (UICC 7th)FigureSurvival of patients who underwent esophagectomy according to the depth of tumor invasion, pT (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis, pN (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis, pN (UICC 7th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to residual tumor (R)Institution-registered cases in 2012Tables\u00a0Tables\u00a0Tables\u00a0Tables\u00a022"}
+{"text": "Since the early reports of neurofibrillary Tau pathology in brains of some Huntington\u2019s disease (HD) patients, mounting evidence of multiple alterations of Tau in HD brain tissue has emerged in recent years. Such Tau alterations range from increased total levels, imbalance of isoforms generated by alternative splicing (increased 4R-/3R-Tau ratio) or by post-translational modifications such as hyperphosphorylation or truncation. Besides, the detection in HD brains of a new Tau histopathological hallmark known as Tau nuclear rods (TNRs) or Tau-positive nuclear indentations (TNIs) led to propose HD as a secondary Tauopathy. After their discovery in HD brains, TNIs have also been reported in hippocampal neurons of early Braak stage AD cases and in frontal and temporal cortical neurons of FTD-MAPT cases due to the intronic IVS10+16 mutation in the Tau gene (MAPT) which results in an increased 4R-/3R-Tau ratio similar to that observed in HD. TNIs are likely pathogenic for contributing to the disturbed nucleocytoplasmic transport observed in HD. A key question is whether correction of any of the mentioned Tau alterations might have positive therapeutic implications for HD. The beneficial effect of decreasing Tau expression in HD mouse models clearly implicates Tau in HD pathogenesis. Such beneficial effect might be exerted by diminishing the excess total levels of Tau or specifically by diminishing the excess 4R-Tau, as well as any of their downstream effects. In any case, since gene silencing drugs are under development to attenuate both Huntingtin (HTT) expression for HD and MAPT expression for FTD-MAPT, it is conceivable that the combined therapy in HD patients might be more effective than HTT silencing alone. HTT gene, while individuals with expansions of 40 or more repeats develop HD. Carriers of 36\u201339 CAG repeats have lower penetrance and later onset of the disease  is an autosomal dominant neurodegenerative disorder caused by a mutation in the gene that encodes for the protein Huntingtin (Htt). This mutation consists on an abnormal expansion of a CAG triplet (>35) in exon 1 of the gene that encodes for a stretch of polyglutamine (polyQ) in the N-terminal region of the protein  and in the nucleus where gene expression can get altered  that was first discovered in 1975 by Weingarten when it was co-purified along with tubulin  and/or neuropil threads  primary Tauopathies that are a major class of Frontotemporal Lobar Degeneration (FTLD) neuropathology and can present clinically with several forms of Frontotemporal Dementia (FTD)\u2014like Frontotemporal Dementia with parkinsonism linked to chromosome 17\u2014(FTDP-17), progressive supranuclear palsy syndrome (PSP) or corticobasal degeneration (CBD); and (b) secondary or non-primary Tauopathies like Alzheimer\u2019s disease (AD) in which neurofibrillary Tau neuropathology occurs in addition to the amyloid-\u03b2 (A\u03b2) plaques. The various Tauopathies affect different brain regions and cell types and they also show differences in the ratio of Tau isoforms present in the Tau filaments  was found in the cortex of HD patients and this is accompanied with the appearance of lower molecular weight (35 and 39 KD) bands  and FTLD with Tau+ inclusions (FTLD-Tau), alteration of alternative splicing of exon 10 produces an imbalance in 4R-Tau and 3R-Tau isoforms  proteins participate on constitutive splicing while also regulating alternative splicing. Some members of this family promote the inclusion of exon 10, while others suppress it. Several studies have shown that SRSF1 (ASF/SF2), SRSF2 (SC35), SRSR6 (SRp55), and SRSF9 (SRp30c) promote exon 10 inclusion, while SRSF3, SRSF4, SRSF7, and SRSF11 suppress its inclusion  could also be responsible for the 4R-Tau/3R-Tau imbalance as it has been shown to modulate exon 10 splicing and to interact with FUS, one major component of mHtt inclusions  and Tau deposits stained with antibodies that recognize 3R-Tau, 4R-Tau or pathologically phosphorylated Tau (AT-8 and pS199) has been detected in cortical and striatal sections of HD patients  or 103Q mHtt and Tau fused with non-fluorescence halves of a fluorescence reporter protein, Blum et al.  also known as Tau Nuclear Rods (TNRs) in the striatum and cortex of HD patients  Brain Bank , the Neurological Tissue Bank of the IDIBAPS Biobank , the Banco de Tejidos Fundaci\u00f3n Cien  and the Netherlands Brain Bank . Written informed consent for brain removal after death for diagnostic and research purposes was obtained from brain donors and/or next of kin. Procedures, information and consent forms have been approved by the Bioethics Subcommittee of Centro Superior de Investigaciones Cient\u00edficas .Both authors (MF-N and JL) revised the literature and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "On January 7, 2019, three patients arrived at the Community Regional Medical Center emergency department in Fresno, California, after snorting  white powder they thought was cocaine. One (patient A) was in cardiac arrest, and two (patients B and C) had opioid toxidrome  . After sAfter notification of the initial three cases, a multiagency response was implemented by FCDPH; Fresno County Sheriff-Coroner\u2019s Office; Fresno Police Department; Fresno County Department of Behavioral Health; Community Regional Medical Center; University of San Francisco-Fresno; and the Drug Enforcement Administration. Initial actions included 1) disseminating a news release targeting the media and other emergency departments; 2) holding a multiagency press conference; 3) conducting media interviews; 4) informing law enforcement, prehospital providers, and the public about naloxone distribution and use; 5) educating persons on the proper disposal of old or new but unused medications through the Fresno County Department of Behavioral Health/California Health Collaborative drop-off containersOn January 12, 2019, a similar drug overdose incident was reported in Chico, California, in which postmortem toxicology testing for one person confirmed fentanyl (Death rates involving cocaine increased by approximately one third during 2016\u20132017. In 2017, nearly three fourths of cocaine deaths also involved opioids, with the arrival of synthetic opioids driving much of this increase (In the days following the multiagency press conference, FCDPH disseminated a California Health Alert Network message to approximately 700 Fresno County providers about free online medication-assisted treatment waiver training and encouraged use of the Controlled Substance Utilization Review and Evaluation System prescription drug\u2013monitoring program for opioid users."}
+{"text": "Variation in reproductive lifespan and female fertility have implications for health, population size and ageing. Fertility declines well before general signs of menopause and is also adversely affected by common reproductive diseases, including polycystic ovarian syndrome (PCOS) and endometriosis. Understanding the factors that regulate the timing of puberty and menopause, and the relationships with fertility are important for individuals and for policy. Substantial genetic variation exists for common traits associated with reproductive lifespan and for common diseases influencing female fertility. Genetic studies have identified mutations in genes contributing to disorders of reproduction, and in the last ten years, genome-wide association studies (GWAS) have transformed our understanding of common genetic contributions to these complex traits and diseases. These studies have made great progress towards understanding the genetic factors contributing to variation in traits and diseases influencing female fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. Many variants implicate DNA damage/repair genes in variation in the age at menopause with implications for follicle health and ageing. In addition to the discovery of individual genes and pathways, the increasingly powerful studies on common genetic risk factors help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits. Reproductive life span from the onset of puberty, age-specific fertility rates, and twinning frequency all contribute to fertility.12 This genetic contribution to reproductive traits and diseases can result from rare mutations in specific genes and common variation at many sites in the genome each with small effects. In the last decade, genome-wide association studies (GWAS) have transformed our understanding of genetic contributions to these complex traits and diseases.13 The results of these studies have led to discovery of novel genes and pathways influencing specific traits and diseases, new discoveries in disease epidemiology, and the discovery or repurposing of candidate therapeutics.13 Results for GWAS studies for reproductive traits , breast cancer and cardio metabolic disease.28 At the other end of the distribution, delayed puberty is associated with short stature and lower bone mineral density.29Menarche occurs with maturation of the reproductive endocrine system and denotes the onset of menstrual cycles and sexual maturity for women. It usually occurs between 9 and 14 years of age. The average age at menarche has declined over the last century in high income countries including Europe and North America.30 These include mutations in genes for kisspeptin (KISS1), GnRH (GNRH1), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and their respective receptors. Some rare mutations for IHH have been implicated in less severe delayed puberty and may contribute to the population variability in AAM.11 In contrast, activating mutations in KISS1 and kisspeptin receptor (KISS1R), and paternally inherited mutations in two imprinted genes Makorin ring-finger 3 (MKRN3) and Delta-like 1 homologue (DLK1) can result in central precocious puberty (CPP).32MKRN3 is an intronless gene located on the long arm of chromosome 15 in a cluster of imprinted genes in the region associated with Prader\u2013Willi syndrome.31MKRN3 is expressed from the paternal allele  in the arcuate nucleus and inhibits the secretion of GnRH during the prepubertal period in childhood.33 Mutations associated with CPP31 include a four-base deletion in the proximal promoter of MKRN3 identified in a girl with non-familial idiopathic CPP who exhibited pubertal development around the age of seven.34 The deletion was associated with reduced promoter activity in vitro.34DLK1 is located on chromosome 14 and encodes a transmembrane protein with multiple epidermal growth factor repeats. Like MKRN3, DLK1 is expressed from the paternal allele and paternal inheritance of a complex genomic rearrangement including the translation start site of DLK1 was associated with isolated familial CPP.32 The association of CPP with loss-of-function alleles in two paternally expressed genes supports a role for imprinting affecting the timing of puberty.32The timing of puberty varies between individuals and is a highly polygenic trait with both rare and common variants contributing to the variation in age at menarche (AAM). Rare mutations in genes that disrupt the development and function of the gonadotrophin-releasing hormone (GnRH) pathway, pituitary hormones, and their receptors can result in idiopathic hypogonadotropic hypogonadism (IHH) and the absence of puberty.30 The Lin-28 Homologue 28 (LIN28B) at 6q21 was the first of the many loci identified from five independent GWAS for AAM.35 The most recent GWAS conducted in \u223c370,000 women of European ancestry identified 389 independent signals explaining \u223c7.4% of the population variance in age at menarche , and genes disrupted in rare disorders of puberty GNRH1 and KISS1.36 Analyses of the data sets for genetic effects on gene expression demonstrated positive enrichment for AAM-associated variants in five central nervous system tissues, notably the pituitary gland and hypothalamus36 supporting an important role of central mechanisms in reactivation of the hypothalamic pituitary axis and onset of puberty. Expression of 205 genes in these tissues were regulated by AAM-associated variants including higher expression of LIN28B in the pituitary gland associated with later AAM.36 Formal analysis of overlap in signals for AAM and genetic effects on gene expression in blood  identified evidence for causal or pleotropic effects for 60 regions36 with the variant(s) associated with AAM driving variation of a specific genes in each region.GWAS of AAM in healthy women in European and Non-European populations have identified key genetic factors regulating puberty timing as reviewed previously.37 GWAS in 67,029 women identified 10 significant association signals for age AAM, including signals in two novel regions not reported previously in European women and one novel Japanese-specific signal in a previously reported region near PTPRD. More variants had larger effects on early, compared with late menarche timing, consistent with evidence in European studies.37In Japanese women, the mean age at menarche was 13.9 years with a strong secular trend for decreasing age at menarche to a mean age of 12.3 years for women born after 1965.38 The age at menopause (ANM) has a strong genetic component with more than 50% of variation due to genetic factors.39 A genomic analysis for age at natural menopause was conducted in ~70,000 women  with a range of effect sizes from 0.07 to 0.88 years per allele. Exome array analysis identified genome-wide significant evidence for association with two correlated low-frequency missense variants in DNA helicase B (HELB). Although interpretation of the GWAS results have limitations because specific target genes in each region are yet to be determined, the results implicate a substantial role for DNA damage repair in reproductive ageing40 including repair of double strand breaks, mismatch repair and base-excision repair. Pathway analysis also suggested enrichment for a set of genes associated with POI, including MCM8, POLG and MSH5.40Menopause is defined as the permanent cessation of menstruation resulting from the loss of follicular activity. Menopause generally occurs between ages of 40\u201360 years with the average age of ~51 years in western countries.NLRP11, TMEM150B and BRSK1.41 A recent GWAS study for ANM in 43,861 Japanese women identified 16 independent genome-wide significant signals , cardiovascular disease, and effects on gynaecological, gastrointestinal, musculoskeletal, and respiratory conditions.14 The relationships are complex with non-linear relationships between AAM and T2D and cardiovascular disease.42 Early menarche increases risk for both T2D and cardiovascular disease while later menarche also increases risk for cardiovascular disease, but is neutral for T2D.11 BMI also plays a role for many of the same health outcomes. Following adjustment for body composition and socio-economic status, associations with early menarche remained significant for 14 health outcomes and associations with late menarche were significant for eight health outcomes.14 Early menarche was associated with higher risks for uterine fibroids, endometriosis and earlier natural menopause.Variation in AAM and ANM have wide-ranging effects on human health. In a study in the UK Biobank, age at menarche was associated with 26 adverse health outcomes.BRCA1, MSH6 and CHEK2 that also predispose to familial cancers.39 In addition, later age at menopause results in longer exposes to high levels of oestrogen for women. Poor DNA damage response that increases cancer risk might be expected to lead to earlier menopause, opposite to the evidence from epidemiological studies. Using the available genetic data from studies for breast cancer and age at menarche, predicted age at menopause from genetic variants showed increased risks of breast cancer with later age at menopause40 and the effects were greater in oestrogen receptor positive breast cancer. Genetic variants associated with DNA damage repair genes had smaller effects than other markers.40 Taken together, the results suggest that increased exposure to oestrogen with increased reproductive lifespan is the predominant effect on risk for breast cancer.Later age at menopause is associated with increased risks for breast, ovarian and endometrial cancer. Many of the genetic markers influencing menopause are related to DNA damage repair genes including 43 Successful reproduction denoted by age at first birth (AFB) and the associated behaviour of age at first sexual intercourse (AFS) are both moderately heritable and genetically correlated.44 Estimates from the UK Biobank for SNP-based heritability for AFS and AFB were 0.242 (s.e.\u2009=\u20090.010) and 0.290 (s.e.\u2009=\u20090.015) respectively. There was a strong genetic correlation between AFS and AFB (rg\u2009=\u20090.86) and moderate genetic correlations between menarche and both AFS (rg\u2009=\u20090.22) and AFB (rg\u2009=\u20090.24).44 GWAS identified 34 genome-wide significant signals associated with AFS in women with replication in deCODE data for the Icelandic population, and in the Women\u2019s Genome Health Study. The signals include association with intronic SNPs in the oestrogen receptor 1 (ESR1) gene that are also associated with AFB and with the number of children ever born. The ESR1 SNPs associated with AFB are unrelated to SNPs at this locus associated with puberty timing and breast cancer. On chromosome 3, the SNP rs2188151 associated with AFS is highly correlated with a missense variant in the semaphorin protein SEMA3F. The SNP also influences expression (is a cis-eQTL) for the RNA binding protein RMB6. The AFS decreasing allele is associated with later age at menarche, earlier AFB and greater numbers of children born.44Fertility traits in human populations are under genetic control.45 Follow-up analyses identified a number of genes in the genomic regions associated with AFB and number of children born that could be prioritised for functional studies. The critical SNPs on chromosome 1 associated with AFB and number of children ever born are correlated with likely functional nonsynonymous SNPs in two genes; the CREB-regulated transcription co-activator 2 (CRTC2) which acts downstream of FSH in ovarian granulosa cells, and CREB protein 3 like 4 (CREB3L4) which is highly expressed in reproductive tissues in both females and males.45 The lead SNP (rs2777888) for AFB on chromosome 3 is associated with altered DNA methylation or expression of several genes with a role in cell cycle progression and/or sperm function.45 Further functional experiments will be necessary to determine the specific genes and mechanisms of action of the large number of genetic variants influencing these important traits.A large study of genetic effects on reproductive behaviour in 62 cohorts of European ancestry  identified 10 independent genomic loci associated with AFB in women, men or both.46 POI is generally defined as the onset of menopause in women under the age of 40 years. Genetic mutations have been reported in a number of candidate genes, although many reported results have not been replicated.47 There is good evidence for deleterious effects of mutations in Bone Morphogenetic Protein 15 (BMP15), Progesterone receptor membrane component 1 (PGRMC1) and the pre-mutation in the Fragile-X mental retardation 1 (FMR1) locus on the X chromosome.47 Mutations in other genes, present in low frequencies in some populations, are likely to influence POI including GDF9, Folliculogenesis specific bHLH transcription factor (FIGLA), and Newborn ovary homeobox gene (NOBOX).47 The 5-prime untranslated region of the FMR1 gene contains a CGC repeat that varies in length and expansion of the repeat to >200 copies causes Fragile-X syndrome. Repeat expansion to the pre-mutation range is associated with premature menopause, but there is no influence of shorter repeat lengths in the normal range or the longer repeats that cause Fragile-X syndrome.48Ovarian reserve is one of the crucial elements of female fertility Fig.  and seve47 Although GWAS have identified multiple loci associated with POI in Chinese, Korean, and Dutch women,47 the small samples studied (<1000) have low statistical power and none identified signals exceeding 10\u22126. Pathway analysis of suggestive GWAS loci for ANM do show enrichment for known POI genes.39 There are ~80 gene disorders influencing extremes of reproductive function. The genes are involved in diverse biological processes, including control of the cell cycle, DNA damage response and repair, hormone signalling and gonadal development. Genetic variants in or near many of these genes have variable effects from very early menopause to alterations of just a few weeks.39 Future studies involving larger data sets and meta-analysis of combined GWAS will be necessary to identify risk loci associated with POF.A total of six GWAS have been conducted to identify the risk loci in POI in different populations as reviewed in detail elsewhere.49 DZ twins arise from the ovulation of two follicles after a complex process of follicle growth, selection and ovulation. The frequency of DZ twinning ranges from 6\u201315 per 1000 live births and varies with maternal age and ethnicity.50 DZ twinning is influenced by genetic factors and the DZ twinning rate for sisters of women with spontaneous DZ twins is ~2.5 times higher than the twinning rate in the general population.50 Direct evidence for genetic variants influencing rates of DZ twinning were first identified in animal studies. Domestic sheep generally have 1\u20132 offspring at each pregnancy. Linkage and positional cloning identified mutations in autosomal and X-linked genes that increased ovulation and twinning rates in heterozygous carriers.53 The mutations responsible were identified in the genes for Bone Morphogenetic Protein Receptor Type 1B (BMPR1B) and BMP15, respectively; a receptor and ligand in the ovarian signalling pathway for BMP15.53 Multiple mutations have now been reported in both BMP15 and the closely related signalling molecule growth differentiation factor 9 (GDF9).54 Physiological and genotype-phenotype studies of strains carrying the different mutations demonstrate the importance of BMP signalling, and the balance between BMP15 and GDF9 in follicle survival, maturation, and control of ovulation.54The spontaneous dizygotic (DZ) twinning rate is associated with fertility and comparisons with the frequency of monozygotic twins provide a useful index of fertility in a population.BMP15 and GDF9 have alternative phenotypes depending on whether they are heterozygous or homozygous (carried as one or two copies respectively). Increased ovulation rates occur in heterozygous carriers of the mutations as described above. In contrast, homozygous carriers with two copies of the loss-of-function mutations in BMP15 and GDF9 in sheep have streak ovaries and are completely infertile.54 These genes are candidates for infertility in women and studies in women with primary ovarian insufficiency (POI), also known as premature ovarian failure (POF), have identified mutations in both genes associated with POI.55 Confirmation through segregation studies is difficult in families with infertility disorders, but molecular and functional studies for several of these variants suggest loss-of-function effects consistent with the view that two functional copies of BMP15 are required for an adequate ovarian reserve in women.55 Low-frequency variants in GDF9 are associated with increased risk for DZ twinning in women heterozygous for these variants.56 Similar studies found no evidence that rare and low-frequency variants in BMP15 influence DZ twinning.57 Mutation screening of BMPR1B in mothers of DZ twins identified a coding variant (p.Gln294Glu) altering the same amino acid as a sheep BMPR1B functional variant.58 This mutation was not seen in other families and is of unknown significance.Some mutations in 56 In a search for common genetic variants influencing DZ twinning, a GWAS in 1980 mothers of spontaneous DZ twins and 12,953 controls identified significant association with DZ twinning for SNPs close to Follicle-Stimulating Hormone Beta Subunit (FSHB) and SMAD Family Member 3 (SMAD3).59 The risk alleles for the SNPs close to FSHB and SMAD3 increased the frequency of twin births in the Icelandic population by 18 and 9%, respectively. The lead SNP associated with DZ twinning on chromosome 15 maps to the first intron of SMAD3, strongly expressed in the human ovary, where it promotes granulosa cell proliferation and steroidogenesis.59 The region of chromosome 15q22.33 also includes SMAD Family Member 6 (SMAD6). A major gene increasing ovulation rate and twinning in cattle maps to the equivalent genomic region on bovine chromosome 10 (the location of both SMAD3 and SMAD6).60 Recent analysis of gene expression in granulosa cells from carriers and non-carriers of the cattle gene demonstrated a six-fold increase in expression of SMAD6 in gene carriers.61 SMAD6 is an inhibitor of BMP/SMAD signalling and over-expression of SMAD6 is consistent with loss-of-function mutations in BMP signalling increasing ovulation rate in sheep. Further research is required to determine whether variants associated with DZ twinning on chromosome 15 act through effects on SMAD3, SMAD6 or some other mechanism.Rare and low-frequency variants account for only a small proportion of variation in DZ twinning.63 PCOS is the most common cause of infertility64 and also increases the risk for type 2 diabetes, gestational diabetes, venous thromboembolism, cerebrovascular and cardiovascular disease and endometrial adenocarcinoma.65 The aetiology of PCOS remains unclear with diagnostic criteria proposed for PCOS66 including the National Institutes of Health (NIH), Rotterdam and Androgen Excess Society (AES) criteria. Familial aggregation and twin studies suggest genetic factors play a strong role in pathogenesis of PCOS with heritability estimates of 70%.66Polycystic ovary syndrome (PCOS) is a complex, hormonal and metabolic disorder affecting 5\u201320% of women of reproductive age globally and characterised by hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphology and gonadotropic abnormalities.67 Additional studies69 identify 16 independent signals in 15 genomic regions associated with PCOS including signals near important reproductive hormone genes FSHR, LHCGR and FSHB.70 The signals also include variants in or near three epidermal growth factor genes and genes associated with diabetes.70 As with similar studies in other reproductive diseases, the total heritability explained by GWAS identified PCOS risk SNPs is relatively low (<10%).65The first GWAS conducted in Chinese patients in 2011  has direct clinical applications for planning lifestyle modification as a prevention strategy and inclusion of metformin in treatment plans for PCOS.68 Discovery of additional genetic factors and further characterisation of the signals identified will provide greater insight into the pathogenesis of the complex phenotypes in PCOS.Mendelian randomisation is an analytical method using genetic variation to investigate the likely causal relationship between an exposure trait (or risk factor) and a health outcome. Genetic variants are inherited independently and fixed at birth and subject to less confounding than other measured risk factors. Increasing evidence of association between genetic variants and many common traits means Mendelian randomisation models can use genetic variants associated with a risk factor to infer relationships with a health outcome. The models assume the genetic variants used have strong evidence for association with the risk factor and do not influence the outcome through other unrelated biological pathways. In PCOS studies, Mendelian randomisation demonstrated causal roles for higher BMI, greater insulin resistance and reduced sex hormone binding globulin concentrations in serum.7 The disease affects 7\u201310% of women and is associated with pain and infertility. Early twin studies identified evidence for genetic effects on the liability for hysterectomy,71 one of the most commonly performed surgical procedures for women. Major indications for hysterectomies in reproductive age women are endometriosis (30%) and uterine leiomyomas (>50%).73 Subsequent studies in twins on genetic influences on the liability for endometriosis estimated the heritability at ~50%.75Endometriosis is a complex disease characterised by ectopic lesions of tissue resembling endometrium in the peritoneal cavity.78 The most recent meta-analysis  is the predominant receptor for oestrogen action in the endometrium.80 Genomic signals associated with endometriosis include regions flanking the gene for ESR1, signals upstream of follicle-stimulating hormone beta subunit (FSHB) known to increase FSH concentrations,79 and near the oestrogen-regulated and early response gene (GREB1) first identified in breast cancer cell lines and tumours.81 Other regions include candidate genes with roles in cell migration, adhesion and proliferation including Cell Division Cycle 42 (CDC42), Cyclin-Dependent Kinase Inhibitor 2B Antisense (CDKN2B-AS1) and Kinase insert domain receptor (KDR).84Genomic regions and genes associated with endometriosis risk are reviewed in detail elsewhere.sis Fig.  identifi85 On chromosome 1, studies on genetic regulation of gene expression in blood86 and endometrium86 show the critical SNPs in this region influence expression of both the long non-coding RNA LINC00339 and CDC42. There are chromatin interactions between risk SNPs and gene promoters for both LINC00339 and CDC42.86 Luciferase reporter assays support the effect of genetic differences on the interaction between the regulatory element and the promoter of CDC42.86 Formal analysis of the overlap of signals for endometriosis risk and genetic effects on gene expression provides strong evidence that key SNPs associated with endometriosis on chromosome 1 and chromosome 12 regulate LINC00339 and vezatin VEZT expression, respectively.87Mechanisms leading to formation of lesions are poorly understand, but one source for cells initiating these lesions is thought to be cells shed from the endometrium and deposited in the pelvic cavity through retrograde menstruation.TACR3 and age at menopause), rare, low-frequency and common variants all influence the same trait.11 In other examples , rare variants cause hypogonadotropic hypogonadism while common variants influence age at menopause.11 These differences, and evidence for the different effects on ovulation rate and streak ovaries for heterozygous and homozygous mutations in BMP15 and GDF9 in sheep54 show disruption of gene function or altered regulation of the same genes can have different effects on reproductive traits and diseases.Genetic studies discussed above demonstrate the complex variation contributing to the timing of puberty, menopause, ovarian function and twinning. Genetic contributions include the effects of multiple common variants with small effects on reproductive traits and disease, and rare variants with large effects contributing to failures in development, precocious puberty, delayed puberty, premature ovarian failure and increased twinning. In some cases  and genes associated with POI.40 Further research will help to understand the relationships between ovarian development, disorders of puberty, DZ twinning, POI, and age at natural menopause.Potential overlap for other traits includes genes influencing both DZ twinning and POI and endometriosis and ovarian cancer. There is a small, but significant increase in mothers of DZ twins reaching menopause before the age of 40 compared with mothers of MZ twins.92 The association signals are located in WNT4.92 Subsequent follow-up functional studies show correlated association signals for endometriosis in this region regulate LINC00339 and CDC42 not WNT4,83 and one or both target genes may also play a role in ovarian cancer risk. There is genetic association near the oestrogen receptor 1 (ESR1) locus with four independent signals for endometriosis and five independent signals for breast cancer93  overlaps completely with an association signal for ovarian cancer.94 The Polygenic risk score (PRS) combines association results from genome-wide genotyping into a single estimate of the genetic risk for a disease or trait for each individual. The PRS score is calculated from the number of risk alleles carried, weighted by the effect size estimated from the discovery sample.94 It is often standardised to a mean of zero with a standard deviation of 1 for ease of interpretation.94 The risk scores are not very informative for individual prediction, but explain sufficient variation to determine individuals at highest or lowest risk in populations, and to understand genetic contributions to related traits.13 Where samples are fully independent, calculating genetic contributions to related traits provides a powerful design reducing issues of shared environment and ascertainment in epidemiological studies. Overlap between endometriosis and ovarian cancer extends beyond the observed overlap at the chromosome 1p36 locus discussed above. Observations from epidemiological studies can be confounded due to diagnosis of endometriosis at laparoscopy close to a diagnosis of ovarian cancer. PRS analysis with genotype data from independent samples for endometriosis and ovarian cancer showed shared genetic risk between endometriosis and most histotypes of ovarian cancer95 suggesting some common molecular pathways for the two diseases including the overlap at chromosome 1p36. Prediction of individual risk is improving for some diseases with better estimates of the genetic risk factors. While not sufficiently predictive in isolation, risk scores may be used in combination with other clinical data for patient stratification. The application of risk prediction to inform breast cancer screening is being evaluated in the population based Women Informed to Screen Depending On Measures of risk (WISDOM) study.96In addition to discovery and overlap in effects for individual genes, GWAS data provides powerful approaches to understand shared genetic risk between traits and diseases. Genome-wide SNP genotype data from a discovery sample can be used to estimate the genetic variation due to common SNPs or SNP heritability, and to calculate a polygenic risk score for individuals in an independent sample.97 and number of children ever born.97 Results show a significant negative genetic correlation between number of children ever born and the age at first birth suggesting genes contributing to later first birth are associated with fewer children.97 These relationships are complex because environmental effects and demographic changes also play a role with women choosing to delay childbearing in many countries. Relationships between age at first birth and lifetime number of children are also associated with genetic effects on twinning. Mothers of twins tend to have an earlier age at first birth and raise more children to adulthood in favourable environments.99 Polygenic risk score analysis from the GWAS results for DZ twinning suggest genes contributing to DZ twinning may partly explain genetic effects on fertility. The polygenic risk score for DZ twinning was significantly associated with DZ twinning in an independent sample from Iceland.59 In this sample, the risk score for DZ twinning was associated with a higher likelihood of having children, earlier age at first birth, and greater number of children.59As noted earlier, there are significant additive genetic effects for age at first birth100 This epidemiological evidence is supported by the Mendelian randomisation analyses demonstrating the causal relationship between delayed natural menopause and increased breast cancer risk.40 Understanding these relationships is further complicated by effects of variation in body mass index (BMI). There is a strong inverse genetic correlation between AAM and BMI.36 Thirty-nine signals overlap between AAM and BMI, but most AAM signals make some contribution to adult BMI.36 Using information from different genetic studies allowed estimates of the direct effects of AAM on sex-steroid-sensitive cancers after adjusting for genetically predicted BMI. In these models, later AAM was associated with reduced risks for breast, ovarian and endometrial cancers.36 Analysis of cancer subtypes suggests effects were most strongly associated with oestrogen receptor positive breast cancer and serous ovarian cancer. The effects of earlier puberty timing on higher risks of the sex- steroid sensitive cancers might be related to longer duration of exposure to sex steroids and/or increased activity of the hypothalamic-pituitary axis associated with earlier puberty and reproductive traits including dizygotic twinning.Genetic studies can also inform complex relationships between reproductive traits and related health outcomes. A large-scale meta-analysis supported an association of early menarche and late menopause with increased risk of breast cancer and demonstrated that excess risk associated with advancing menarche by one year was higher than excess risk associated with lengthening menopause by one year.Recent studies have made great progress towards understanding the genetic factors contributing to variation in traits and diseases influencing female fertility. These genetic studies are providing important insights into the complex biology contributing to female fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. For example, many variants influencing menopause suggest genes and pathways with known roles in DNA damage/repair with implications for follicle health and ageing, although we do not yet have a full picture of the mechanisms responsible.The effect sizes for common variants are small and, as emphasised in this and other reviews, large studies are essential to identify a substantial fraction of common variants underlying variation for these traits and diseases. In addition, GWAS identify genomic regions, but not the specific genes and pathways regulating variation in traits and diseases. To date, we lack definitive evidence for the causal variants and target genes for most of these results. Despite these gaps, examination of potential candidate genes in the multiple regions identified through GWAS provide tantalising evidence for common pathways affecting reproductive lifespan and fertility.101 This in turn will provide much better understanding of the specific pathways regulating individual components of reproductive lifespan and fertility, and the complex interactions between pathways and health outcomes. The knowledge gained will suggest possible interventions and ways to better predict and minimise health impacts of these important life events.The challenge now is to provide functional evidence for the specific genes and pathways regulated by the genetic variation influencing fertility. Multiple lines of evidence from both functional and genomic studies will be required to identify these gene targets and the mechanisms responsible. This is becoming more feasible with advances in genomics, large-scale publically available data, and genome editing.Genetic risk scores from common variants are not able to predict disease risk for individuals. As the estimates improve from more powerful studies, they may be able to predict women at higher or lower risk for specific diseases and this may be useful in some diagnostic settings. Genetic variants associated with natural menopausal timing also influence the menopausal timing in women undergoing radiation or chemotherapy suggesting that in the future, genetic risk prediction models could be useful for counselling related to family planning, lifestyle choices or use of modern techniques for fertility preservation such as oocyte cryopreservation.Epidemiological evidence for comorbidity between traits can be difficult to interpret because of the issues of sample ascertainment. Genetic risk scores add a valuable method to gain insight into the complex relationships in the overlap between traits and diseases. These analyses will also improve as the risk scores can be derived from increasingly powerful studies to help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits."}
+{"text": "The USDA Forest Service and University of California researchers have developed a simple and inexpensive passive sampler for monitoring air concentrations of HNO3. Nitric acid is selectively absorbed on 47-mm Nylasorb nylon filters with no interference from particulate NO3-. Concentrations determined with the passive samplers closely corresponded with those measured with the co-located honeycomb annular denuder systems. The PVC protective caps of standardized dimensions protect nylon filters from rain and wind and allow for reliable measurements of ambient HNO3 concentrations. The described samplers have been successfully used in Sequoia National Park, the San Bernardino Mountains, and on Mammoth Mountain in California.Nitric acid (HNO"}
+{"text": "The authors note that the citation of Wright (1937) and Nei (1968) is incorrect in the \u201cModels of mutation-selection balance\u201d section in Results. Wright (1937) not only showed the equilibrium frequency of a deleterious allele for a population of infinite size (Eq 1) but also derived the full equilibrium frequency distribution of a deleterious allele under a finite effective population size. He also derived the mean (Eq 2) allele frequency of a fully recessive deleterious allele and gave approximations for large and small effective population sizes. Nei (1968) further derived the approximate variance (Eq 3) in allele frequency of a fully recessive mutation by using Wright\u2019s general formula. The authors confirm that this error does not affect the conclusions of the article."}
+{"text": "Scientific Reports 10.1038/s41598-019-54295-8, published online 29 November 2019Correction to: The original version of this Article contained a typographical error in the Abstract.\u201cAccording to the Dual Dodel of Social Hierarchy, one pathway for attaining social status is through dominance (coercion and intimidation).\u201dnow reads:\u201cAccording to the Dual Model of Social Hierarchy, one pathway for attaining social status is through dominance (coercion and intimidation).\u201dThis error has now been corrected in the PDF and HTML versions of the Article."}
+{"text": "With the current global downturn, the organizations need to develop new strategies and innovative approaches to ensure that every aspect of sustainability is achieved. For this purpose, the organizations need an indicator that measures the fitness if an organization. The purpose of this project is to analyze the \u2018Fitness\u2019 of an organization using the dataset related to leanness, agility and sustainability in ANFIS (Adaptive Neuro-Fuzzy Inference System) in order to determine whether the company is fit enough to sustain in global markets or not. The project does so by integrating both neural networks and fuzzy logic principles with lean, agility and sustainability principles. FIT manufacturing is the integration of Lean, Agile and sustainability manufacturing in one system as a whole which would help in attaining maximum output and sustain effectively in global markets. FIT Manufacturing adopts an integrated approach towards the use of Lean, Agility and Sustainability to achieve a level of fitness that is unique to each company. The database in the paper contains lean, agile and sustainable indices reviewed by experts. FIT does not prescribe that every aspect of Lean, Agile and Sustainability methodologies must be applied to every company, but a selective mix of components will provide the optimum conditions for a company to prosper. Specifications TableValue of the data\u2022Markets all over the globe are getting more and more competitive through the changes driven by emerging technologies which creates the need for an organization to be adaptive and compatible in order to dominate the market.\u2022FIT manufacturing is a perfect amalgamation of core principles of lean, agile and sustainable manufacturing.\u2022The data in this article helps to determine lean, agile and sustainability indices which provides an insight as to how to fit the organization is by providing a framework for the calculation of fitness index.\u2022Using this data, the efficiency and responsiveness of an organization towards the constantly changing markets can be analyzed.1This dataset consists of 5 fitness enablers, 69 fitness criteria and 205 fitness attributes. The data consists of all major dimensions or enablers of fitness such as management responsibility, manufacturing management, manufacturing technology, workforce and manufacturing strategy. The data on agile, lean and sustainability criteria, was collected from automobile components manufacturing company located in Tamil Nadu, India arranged in a matrix form , Table 52The methodologies that allowed the data presented are described in 2.1The data presented in the paper was collected from automobile components manufacturing company located in Tamil Nadu. India. The attributes pertaining to leanness, agility and sustainability criteria were obtained and rated on a scale from 1 to 10 by industry experts.2.2I.If (agility is not_agile) and (leanness is not_lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)II.If (agility is average) and (leanness is average) and (sustainability is average) then (fitness is avergge) (1)III.If (agility is agile) and (leanness is lean) and (sustainability is sustainable) then (fitness is fit) (1)IV.If (agility is agile) and (leanness is average) and (sustainability is sustainable) then (fitness is fit) (1)V.If (agility is agile) and (leanness is average) and (sustainability is average) then (fitness is avergge) (1)VI.If (agility is average) and (leanness is lean) and (sustainability is average) then (fitness is avergge) (1)VII.If (agility is average) and (leanness is lean) and (sustainability is sustainable) then (fitness is fit) (1)VIII.If (agility is average) and (leanness is average) and (sustainability is sustainable) then (fitness is fit) (1)IX.If (agility is average) and (leanness is average) and (sustainability is not_sustainable) then (fitness is avergge) (1)X.If (agility is average) and (leanness is not_lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)XI.If (agility is not_agile) and (leanness is average) and (sustainability is not_sustainable) then (fitness is not_fit) (1)XII.If (agility is not_agile) and (leanness is average) and (sustainability is average) then (fitness is avergge) (1)XIII.If (agility is average) and (leanness is average) and (sustainability is not_sustainable) then (fitness is avergge) (1)XIV.If (agility is not_agile) and (leanness is average) and (sustainability is sustainable) then (fitness is avergge) (1)XV.If (agility is agile) and (leanness is average) and (sustainability is not_sustainable) then (fitness is avergge) (1)XVI.If (agility is agile) and (leanness is not_lean) and (sustainability is sustainable) then (fitness is avergge) (1)XVII.If (agility is agile) and (leanness is not_lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)XVIII.If (agility is not_agile) and (leanness is not_lean) and (sustainability is sustainable) then (fitness is not_fit) (1)XIX.If (agility is not_agile) and (leanness is lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)XX.If (agility is not_agile) and (leanness is lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)2.3MATLAB 2016 was used for creation of Adaptive Neuro-Fuzzy Inference System. The ANFIS model was created using fuzzy logic designer with the corresponding matrices as input , Fig. 5.2.4See 3FIT manufacturing is the integration of Lean, Agile and sustainability manufacturing in one system which would help in attaining maximum output and prevent the damage caused to the environment. This paper deals with analyzing the \u2018fitness\u2019 of a company using ANFIS. The integration of the Fit principles can be employed to reduce the unnecessary cost and increase efficiency of production with less wastage in a market having mercurial demand patterns. The fitness index can be used as a benchmark to evaluate overall efficiency of an organisation."}
+{"text": "The Art to Life (ATL) program aims to improve the quality of life for persons living with dementia (PWD) through art therapy, intergenerational contact with college students, and life story preservation within an adult day service. This poster will present the results of an ongoing program evaluation to determine the effects of the intervention on PWDs\u2019 engagement in (1) communication with others and (2) art/creative activity. A two-member analysis team independently coded ethnographic field notes utilizing operational definitions of PWDs\u2019 observed behavior during momentary time sampling, and recording events of communication and art engagement using the modified ENGAGE measure . Results across sessions (N=97) reveal communication engagement  significantly exceeded art engagement , t (96)=20.85, p=0.001). These results suggest that engagement in reminiscence via intergenerational contact is a fundamental feature in comparison to art and creative activity within the ATL program. Exploratory qualitative content analysis of ethnographic field notes by a three-member coding team identified two key themes within the communication engagements. These emergent themes included validation of personhood and reminiscence of family ties. More studies are needed to determine if the scope and reach of intergenerational interventions may be increased through the nationwide translation of the ATL program."}
+{"text": "An outbreak of feline panleukopaenia virus (FPLV) infection was diagnosed by pathology, electron microscopy and polymerase chain reaction (PCR) in vaccinated captive-bred subadult cheetahs in South Africa. Subsequent to this disease outbreak, 12 cases of FPLV diagnosed on histology were confirmed by PCR in captive African black-footed cat, caracal, cheetah, lion, ocelot and serval. Phylogenetic analyses of the viral capsid protein gene on PCR-positive samples, vaccine and National Center for Biotechnology Information (NCBI) reference strains identified a previously unknown strain of FPLV, present since at least 2006, that differs from both the inactivated and the modified live vaccine strains. A previously described South African strain from domestic cats and cheetahs was identified in a serval. Surveys of FPLV strains in South African felids are needed to determine the geographical and host species distribution of this virus. Since non-domestic species may be reservoirs of parvoviruses, and since these viruses readily change host specificity, the risks of FPLV transmission between captive-bred and free-ranging carnivores and domestic cats and dogs warrant further research. Felis domesticus). FPLVs are classified under the family Parvoviridae and are related to mink enteritis virus (MEV) and canine parvovirus (CPV)  infection, the first viral disease identified in cats, is one of the most common viral diseases of domestic cats (Acinonyx jubatus)   , ocelot , puma (Puma concolor), Siberian tiger , and spotted cat (Leopardus tigrinus) , arctic fox (Vulpes lagopus) and raccoon (Procyon lotor), and is genetically very similar but distinct from CPV-like viruses from dogs (Canis familiaris) and raccoons , seven cheetahs, three lions, one ocelot and two servals . Clinical signs and pathological findings were not available from many of these cases. Before the 2012 cheetah outbreak molecular diagnostic confirmation of suspected FPLV cases was not readily available in South Africa. To investigate prior suspected or confirmed cases of FPLV molecular diagnostic testing was performed on archived tissue samples from felids in the NZG Biobank (Cases A\u2013G), including both suspected and histologically typical FPLV cases. Cases were from Gauteng and North West provinces and included one African black-footed cat (Felis nigripes), a domestic cat, three cheetahs and two lions. Samples from a puma, a leopard (Panthera pardus) and an ocelot in which clinical and histological evidence of FPLV was absent (Cases i\u2013iii) were included as negative control cases. DNA was also extracted from current Fellocell\u00ae and Fel-O-Vax\u00ae  vaccines. All the samples are archived at the NZG Biobank.Subsequent to the outbreak in cheetahs, animal carcasses, a rectal swab, formalin-fixed tissues or formalin-fixed paraffin-embedded tissues (FFPE) from various single or multiple cases in captive felids were submitted to the NZG for pathological examination and/or molecular diagnostic testing for FPLV infection by the owners, veterinarians and pathologists throughout South Africa (Cases 6\u201320). Submitted cases of suspected or confirmed FPLV based on clinical signs and typical macroscopic and histological findings, or diseases presenting with similar signs, included two caracals (TM Tissue MiniPrep kit (Zymo Research). DNA from FFPE samples were extracted using the MasterPure\u2122 Complete DNA & RNA Purification Kit (Epicentre) following the manufacturers specifications. Molecular analysis of the parvovirus genome from all the isolates was conducted by amplification of a ~1300 base pair (bp) region of the viral capsid protein (VP2) gene  treatment, cycle sequenced using the BigDye V3.1 (Applied Biosystems) chemistry and run on a 3130 genetic analyser (Applied Biosystems). The resulting sequences were analysed and aligned using the ClustalX  parvovirus reference strains. Results from NJ (10 000 bootstrap replicates) and BA (1 million generations) are presented in Clinical signs were described in detail only in the initial cheetah outbreak (Cases 1\u20135) and included pyrexia, haemorrhagic diathesis , hypersaOn necropsy examination, the cheetah cubs showed similar lesions including variable dehydration, mild acute diffuse tissue congestion, and moderate acute intestinal serosal congestion and haemorrhage . VariablEscherichia coli was obtained from the intestine from Case 1 and normal intestinal bacterial flora from Case 3. On negative contrast electron microscopy intestinal contents contained small numbers of parvovirus particles (Case 1).Histologically, extensive necrosis of the intestinal epithelium was accompanied by villous collapse, marked hyperplasia of scanty remaining epithelium, and a thick coat of fibrin, necrotic cellular debris and myriad bacteria on the mucosal surface . In addiThe pathological lesions were consistent with FPLV infection with secondary bacterial enteritis and septicaemia. Additional pathological findings included moderate diffuse acute interstitial pneumonia with moderate multifocal acute pulmonary oedema ; multifocal acute moderate necrohemorrhagic bacterial gastritis as well as lingual and gastric candidiasis, mild serosanguinous hydropericardium and hydrothorax and acute moderate segmental renal tubular necrosis (Case 2); oesophageal and gastric candidiasis and acute mild multifocal pancreatic necrosis (Case 3); and mild acute multifocal necrotising aspiration pneumonia (Case 5). All the cubs were in good body condition at the time of death and showed mild to moderate diffuse adrenocortical hyperplasia.\u00ae vaccine. Clade 2 is represented in the current dataset by one sample (Case 10), which clustered with previously described South African strains of FPLV isolated from a domestic cat (1999) and two cheetahs (2000) as well as an FPLV strain isolated from a wildcat and a mink in the USA (1995). This strain is 99.99% similar to the Fellocell\u00ae vaccine . All the samples from this study clustered separately from CPV (98% similarity) and clustered in two clades. Most of the positive cases (Clade 1) clustered closely (99.94% \u2013 100%) with reference samples  from carnivores in Japan and the United States of America (USA), and were similar to the Fell-O-Vax vaccine .Clinical features, pathology, electron microscopy and molecular diagnostic tests confirmed the presence of a previously unreported strain of FPLV in the cheetah cubs in the initial outbreak (Cases 1\u20134). This strain was also detected in archived samples from a lion that died in 2006 (Case A) and an African black-footed cat that died in 2007 (Case B), as well as in samples submitted from other captive felids that died throughout the country after November 2012, including cheetahs , a caracal (Cases 15), a lion (Case 14), an ocelot (Case 12) and a serval (Case 6).et al. The testing of archived samples confirms that the strain from Clade 1 was present in felids in at least North West province before the initial cheetah outbreak and Clade 1 virus subsequently caused disease in unvaccinated felids in Gauteng and North West. Clade 1 strain apparently co-exists with the previously described strain , F10 products  or swimming pool chlorine (2.67 g/L water). Biosecurity measures included staff movement from clean to infected enclosures for feeding and inspections; new and frequently changed cleaning cloths as well as overalls and boots for all staff; hand gels and body sprays of F10 products used when moving between enclosures.et al. Positive cases were detected from fresh and frozen tissue, a faecal swab and FFPE intestinal samples from 16 animals clinically and pathologically diagnosed as suffering from FPLV or suspected FPLV . Three cAlthough infections with viruses of the feline parvovirus subgroup have been reported before in several wild carnivore species, including African felids, this study reveals the first in-depth insight into strain diversity within captive felids in South Africa and the first documented cases of FPLV infection in the African black-footed cat and caracal. Further surveys are needed to determine the geographical and host species distribution as well as the genetic variability of FPLV in these species. Vaccine failure, inadequate vaccination and stress may be predisposing factors in the susceptibility to disease. Retention of the current vaccination programme as well as good hygiene practices at breeding and rearing facilities is recommended for the prevention and control of the disease."}
+{"text": "Containerized plant production represents an extremely intensive agricultural practice; 40,000 to 300,000 containers may occupy one acre of surface area to which a large amount of chemical fertilizer is applied. Currently, recommended fertilizer application rates for the production of containerized nursery ornamental plants are in excess of plant requirements, and up to 50% of the applied fertilizers may run off or be leached from containers. Among the nutrients leached or allowed to runoff, nitrogen (N) is the most abundant and is of major concern as the source of ground and surface water pollution. In this report, current N fertilizer application rates for different container-grown nursery ornamental plants, the amount of nitrate leaching or runoff from containers, and the potential for nitrate contamination of ground and surface water are discussed. In contrast, our best N management practices include: (1) applying fertilizers based on plant species need; (2) improving potting medium's nutrient holding capacity using obscure mineral additives; (3) using controlled-release fertilizers; and (4) implementing zero runoff irrigation or fertigation delivery systems that significantly reduce nitrate leaching or runoff in containerized plant production and encourage dramatic changes in N management."}
+{"text": "PRNP reported from several countries. The objective of this study was to investigate PRNP polymorphisms of native Ethiopian goat breeds and compare the results with other goat breeds.Polymorphisms of the prion protein gene may influence scrapie susceptibility in small ruminants through modified protein conformation. At least 47 amino acid substitutions and 19 silent polymorphisms have been described in goat PRNP in 229 goats belonging to three of the main Ethiopian native goat breeds showed a remarkably high frequency (>\u200934.6%) of p.(Asn146Ser) in these breeds, a variant involved in scrapie resistance in Cyprus. In addition, two novel amino-acid substitutions p.(Gly127Ala) and p.(Thr193Ile), with frequencies ranging from 1.5 to 7.3% were detected. Both amino acids are well conserved in prion proteins (PrP) of most species and these changes have never been reported before in goats worldwide. Residue 127 is within the N\u2013terminal domain of PrP and is probably involved in the recruitment of neural cell adhesion molecules (NCAM). Residue 193 is within the highly conserved string of 4 threonines that plays a role in determining the efficiency of prion protein conversion towards its pathological form.The analysis of the prion protein gene PRNP of Ethiopian goats. This finding increases the interest in exploring PRNP polymorphisms of native goat breeds in areas where cross breeding with foreign goats has rarely occurred.Two novel coding polymorphisms and a high frequency of a scrapie protective variant indicate a high level of genetic diversity in The online version of this article (10.1186/s12917-019-1870-4) contains supplementary material, which is available to authorized users. Camelus dromedarius) in Algeria enlarging the spectrum of animal species susceptible to prion disease [Scrapie is a fatal, neurodegenerative disease that affects small ruminants world-wide. It belongs to the group of prion diseases or transmissible spongiform encephalopathies (TSEs), such as bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids and Creutzfeldt\u2013Jakob disease (CJD) in humans. Recently, a new prion disease, Camel Prion Disease (CPD) of unknown origin was detected in dromedary camels ( disease .PRNP) sequences may influence scrapie susceptibility in sheep and goats through modified protein conformation [The conversion of normal prion protein (PrP) into pathogenic PrP conformers is central to prion diseases. Polymorphisms of the prion protein gene . The variant p.(Gly127Ala) showed a frequency of 4.1% in Western Highland goats and lower frequencies in Central Highland and Long-eared Somali goats respectively. The variant p.(Thr193Ile) showed higher frequencies in Western and Central Highland breeds and a lower frequency in the Long-eared Somali goat  are reported for Ethiopian goat breeds. The novel variant p. Gly127Ala) is located within the N terminal domain of PrP involved in the interaction with the neuronal cell adhesion molecule (NCAM) . A varia7Ala is lf Cyprus  but absef Cyprus . Both isf Cyprus .The presence of p.(Asn146Ser) in Halep (Damascus), Ethiopian and Tanzanian native goats suggests that the allele was naturally selected in the Middle East first, and spread through the central Sahara and Ethiopia later , 36 and PRNP of Ethiopian goats compared to other breeds. However, a low genetic variation among indigenous Ethiopian goats has been detected through genetic studies on microsatellites probably due to the ancient and widespread practice of nomadism [PRNP substitution frequencies among the breeds in this study. In any case extensive cross breeding with goats coming from other countries has never been performed in Ethiopia, except for some pilot studies with Saanen goats to increase milk production [The frequency of the protective variant p.Asn146Ser) in three of the main Ethiopian goat breeds and the presence of two novel amino acid substitutions in highly conserved regions of prion protein (PrP), show a major diversity in nomadism , 40. Thi6Ser in tPRNP characterization also in sheep populations of the same areas, especially because mixed holdings are very common. A surveillance plan for the disease in both goats and sheep populations would be also important to understand the true epidemiology of scrapie in the country. The occurrence of a new prion disease in dromedaries, CPD in Algeria, could be an impetus for a surveillance plan for prion diseases in Africa since dromedaries are often bred with sheep and goats simultaneously; sharing common pastures in many African countries such as in Ethiopia. A new prion disease in a farmed animal species requires a thorough risk assessment for implementing policies to control the disease in animals and minimize human exposure [PRNP polymorphisms of goats in economically marginal areas and increase the interest in exploring the genetic variation of the PRNP gene in native goat breeds and sheep as well, in countries where cross-breeding with imported animals has never been performed.The two novel amino acid substitutions and the high frequency of the scrapie protective variant p.Asn146Ser) might indicate a lower risk of scrapie in Ethiopian goats. It could be very important to perform 46Ser migPRNP gene: Western and Central Highlands and Long-eared Somali. Somatic aspects of the different goats have been already described [n\u2009=\u200952) were sampled in the Seka, Tiroafata and Omonada districts of Jimma; Western Highland (n\u2009=\u2009110) from the Ambo and Bako districts; and Long eared Somali (n\u2009=\u200967) from the Gursum and Jijiga districts of Eastern Hararghe. The samples consisted of 75% males and 25% females with no genetic relation.Three of the main Ethiopian native goat breeds were analysed for the escribed , 16, 41.PRNP (NM_001314247.1 for the cDNA position and NP_001301176.1 for the protein variants) was performed and direct PCR fragment sequencing was carried out as previously described [Polymerase chain reaction (PCR) amplification of the open reading frame of the caprine Raw data of Ethiopian goats genotyping are reported in Additional file 1Amino acid variants are described following recommendation of Den Dunnen et al. Allelic frequencies were calculated using the Hardy-Weinberg equation. Statistical differences between the breeds were calculated with a chi-square test.Additional file 1:Prion protein gene polymorphism in native Ethiopian goats. Excel file that include all information related to each single goat in the three Ethiopian regions. For each goat, information regarding sex, age in months and the related prion polymorphisms are reported. (XLS 60 kb)Additional file 2:Table of the genotypes combinations of Prion protein gene in native Ethiopian goats.. (PDF 423 kb)"}
+{"text": "Community engagement is increasingly recognized as a critical element of medical research, recommended by ethicists, required by research funders and advocated in ethics guidelines. The benefits of community engagement are often stressed in instrumental terms, particularly with regard to promoting recruitment and retention in studies. Less emphasis has been placed on the value of community engagement with regard to ethical good practice, with goals often implied rather than clearly articulated. This article outlines explicitly how community engagement can contribute to ethical global health research by complementing existing established requirements such as informed consent and independent ethics review. The overarching and interlinked areas are (1) respecting individuals, communities and stakeholders; (2) building trust and social relationships; (3) determining appropriate benefits; minimizing risks, burdens and exploitation; (4) supporting the consent process; (5) understanding vulnerabilities and researcher obligations; (6) gaining permissions, approvals and building legitimacy and (7) achieving recruitment and retention targets. Engagement therefore denotes a wide variety of activities, such as patient and public involvement events (e.g. science cafes events), consultation regarding study activities through community advisory boards . Informing and explaining a study to communities requires providing information about the researcher, the research institutions, the study concept and rationale in appropriate formats  involved  health care can help to build institutional trust  providing potential participants with adequate information about the proposed study; (2) potential participants understanding what is proposed and (3) participants being able to make a voluntary decision to participate , Although community engagement can help identify specific vulnerabilities, there can be inadvertent consequences of community engagement  that are difficult to reconcile with the limits of the protocol Lavery, . CommuniWhen seeking formal permissions, approvals and building legitimacy, focused and in-depth engagement is needed. One option is a deliberative approach that entails reaching a consensus while acknowledging differing views  respecting individuals, communities and stakeholders; (2) building trust and social relationships; (3) determining appropriate benefits; minimizing risks, burdens and exploitation; (4) supporting the consent process; (5) understanding vulnerabilities and researcher obligations; (6) gaining permissions, approvals and building legitimacy and (7) achieving recruitment and retention targets."}
+{"text": "In January 2016, highly pathogenic avian influenza (HPAI) A(H7N8) virus and low pathogenicity avian influenza (LPAI) A(H7N8) virus were detected in commercial turkey flocks in Dubois County, Indiana. The Indiana State Department of Health (ISDH) and the Dubois County Health Department (DCHD) coordinated the public health response to this outbreak, which was the first detection of HPAI A(H7N8) in any species ( On January 15, 2016, ISDH was notified by the Indiana State Board of Animal Health that HPAI A(H7N8) virus had been confirmed in a commercial turkey flock in Dubois County, Indiana. In accordance with USDA guidelines (ISDH and DCHD recommended that responders be monitored during the response and for 10 days after their last possible exposures for influenza-like illness (ILI), defined as either 1) self-reported fever with cough or sore throat, or 2) conjunctivitis with or without additional symptoms. All responders received instructions to seek medical attention and contact public health authorities if they developed ILI during the 10-day period. USDA monitored federal employees, contractors, and subcontractors who participated in the response. ISDH and DCHD monitored state and local responders, using adapted, unpublished USDA/CDC public health monitoring procedures for HPAI A(H5) that were first circulated in September 2015 and later updated in November 2015. Responders were classified into three risk categories: 1) no risk, 2) low but not zero risk, and 3) some risk. Responders with low but not zero risk were those exposed to infected or potentially infected birds or their environments while using appropriate personal protective equipment (PPE)  were monitored for some risk exposures, 67 (40%) were monitored for low but not zero risk exposures, four (2%) were monitored with no risk status recorded, seven (4%) had no exposure, five (3%) declined to be monitored, and nine (5%) were lost to follow-up. Among the 145 persons who were monitored, 14 (10%) reported current or recent ILI symptoms, 12 (86%) of whom were tested during January 16\u201322, 2016, with a median of 1 day from onset to medical evaluation. Nine patients had nasopharyngeal/oropharyngeal specimens collected, one had a conjunctival specimen collected, and two had both types of specimens collected. Specimens were tested for influenza A virus by real-time reverse transcription\u2013polymerase chain reaction at the ISDH Laboratories; all 12 patients tested negative for influenza A virus.On January 15, 2016, Indiana activated its Emergency Operations Center with staffing consistent with the Federal Emergency Management Agency Emergency Support Functions (ESFs) appropriate to the response .ISDH\u2019s major actions during the public health response included developing a demobilization packet for responders, issuing a Health Alert Network advisory to Dubois County and surrounding counties with recommendations for health care providers, establishing syndromic surveillance queries in the Indiana Public Health Emergency Surveillance System to detect community-acquired cases, and developing recommendations for the use of antivirals.Public health monitoring procedures for H7N8 responders were successfully implemented during this outbreak; no cases of zoonotic avian influenza infection were detected. The risk for zoonotic transmission in this outbreak was thought to be low at the time. No human infections with influenza A(H7N8) viruses had ever been reported,The unpublished USDA/CDC public health monitoring procedures that were adapted for use in this outbreak were developed for responders to an HPAI A(H5) outbreak. HPAI and LPAI are differentiated based on genetic features and the extent to which these viruses produce morbidity and mortality in poultry . The updated plan will allow for passive monitoring of persons wearing PPE and responding to certain influenza A H5 and H7 viruses that have caused outbreaks in the United States but have no history of causing human infections . The updated plan will also cover all avian influenza viruses of public health concern, including both HPAI and LPAI viruses.Several challenges to human health monitoring were identified during this outbreak. First, receipt of contact information for responders by the local health department was delayed in the initial stages because of the urgency and complexity of the animal health response. Complete information for exposed responders was not received by DCHD until 5 days into the response (on January 20), although preliminary information was provided earlier. Second, tears in Tyvek suits were reportedly common because of the nature of animal handling activities; this could have resulted in misclassification of disease exposure risk. Finally, mobilization of a large number of responders within a short period raised concerns that PPE and monitoring recommendations were not being implemented consistently.Enhanced communication and information sharing among local, state, and federal agencies would improve identification of exposed persons and coordination of specimen collection, testing, and medical care for ill responders. This could be accomplished by 1) effectively communicating public health needs and recommendations to all stakeholders in the response; 2) identifying processes for early identification of exposed persons ; 3) designating a local/state/federal public health department liaison to be embedded in the unified command post to facilitate coordinated implementation of human health monitoring, including obtaining names and contact information for responders; and 4) conducting daily debriefings with safety officers in the incident command system to identify injuries or breaches in PPE that could elevate responder risk. In future outbreaks, ISDH will also recommend that responders to outbreaks of AI viruses of public health concern entering the exclusion zone (hot zone) and contamination reduction zone (warm zone) in infected premises (Prolonged or close contact with birds infected with avian influenza (AI) virus increases the risk for zoonotic infection in humans. Monitoring exposed persons for 10 days might facilitate early detection and reporting of zoonotic AI.Monitoring procedures for highly pathogenic AI (HPAI) responders were successfully implemented during a 2016 outbreak of HPAI A(H7N8) in commercial turkey flocks in Indiana. No human cases of AI were identified.Collaboration among local, state, and federal partners is essential during AI outbreak responses. Monitoring should be considered for all responders who had contact with infected birds or their environments, regardless of whether personal protective equipment was worn."}
+{"text": "In November 2011, a government hospital physician in Shibganj sub-district of Bangladesh reported a cluster of patients with fever and joint pain or rash. A multi-disciplinary team investigated to characterize the outbreak; confirm the cause; and recommend control and prevention measures.Shibganj's residents with new onset of fever and joint pain or rash between 1 September and 15 December 2011 were defined as chikungunya fever (CHIKF) suspect cases. To estimate the attack rate, we identified 16 outpatient clinics in 16 selected wards across 16 unions in Shibganj and searched for suspect cases in the 80 households nearest to each outpatient clinic. One suspect case from the first 30 households in each ward was invited to visit the nearest outpatient clinic for clinical assessment and to provide a blood sample for laboratory testing and analyses.We identified 1,769 CHIKF suspect cases from among 5,902 residents surveyed (30%). Their median age was 28 (IQR:15\u221242) years. The average attack rate in the sub-district was 30% (95% CI: 27%\u221233%). The lowest attack rate was found in children <5 years (15%). Anti-CHIKV IgM antibodies were detected by ELISA in 78% (264) of the 338 case samples tested. In addition to fever, predominant symptoms of serologically-confirmed cases included joint pain (97%), weakness (54%), myalgia (47%), rash (42%), itching (37%) and malaise (31%). Among the sero-positive patients, 79% (209/264) sought healthcare from outpatient clinics. CHIKV was isolated from two cases and phylogenetic analyses of full genome sequences placed these viruses within the Indian Ocean Lineage (IOL). Molecular analysis identified mutations in E2 and E1 glycoproteins and contained the E1 A226V point mutation.The consistently high attack rate by age groups suggested recent introduction of chikungunya in this community. Mosquito control efforts should be enhanced to reduce the risk of continued transmission and to improve global health security. Togaviridae family, have been reported from several countries in Africa, Asia and the Western Pacific since 1952.[Aedes aegypti and Aedes albopictus mosquitoes are the two primary vectors transmitting CHIKV to humans.[Epidemics of chikungunya fever (CHIKF) caused by chikungunya virus (CHIKV), a mosquito-transmitted alpha virus of the nce 1952. Large ounce 1952.\u201312 Aedeso humans. Classicao humans.\u201316 Howevo humans., 17\u201319 Fo humans.\u201330During December 2008, CHIKV infection was confirmed for the first time in Bangladesh. The outbOn 5 November 2011, the primary healthcare physician managing the government hospital in Shibganj sub-district of Chapainababganj district in northwestern Bangladesh reported a cluster of 19 patients with fever, severe joint pain and/or rash to the Institute of Epidemiology, Disease Control and Research (IEDCR) of the Ministry of Health and Family Welfare. In response, a collaborative, multi-disciplinary investigation team from IEDCR and icddr,b conducted an investigation to (i) characterize the outbreak in terms of person, place and time; (ii) confirm the cause; and (iii) identify prevention and control approaches for future outbreaks.The team visited the hospital in the affected sub-district and conducted unstructured interviews with local healthcare providers, including physicians and field workers, to collect preliminary information about the clinical features, laboratory findings, and geographical distribution of affected patients. Based on these interviews, the experience of a similar outbreak in 2008, and giveGiven the lack of information regarding the prevalence of chikungunya fever from Bangladesh during the investigation period in 2011 and because the preliminary survey findings suggested a widespread distribution of suspect cases, the investigation team conducted a house-to-house syndromic survey in all of the 16 unions of Shibganj to calculate the attack rate. Using the attack rate of 34% as observed during the preliminary survey and assuming a type 1 error of 0.05, a precision of 5%, an average of 5 persons per household, a design effect of 3.0 to take into account the cluster sampling design and a non-response rate of 20% at the household level, we calculated a required sample size of at least 1,280 households from the 16 unions of Shibganj for the syndromic survey. In each To obtain clinical histories and collect biological specimens, data collectors invited one suspect case from each of the first 30 households visited in each ward to come to the nearest primary healthcare clinic to complete a clinical assessment and to provide a blood sample for testing. If a household had more than one eligible respondent, the data collectors requested the eldest household member present during the survey to select one resident for participation. Physicians on the team later interviewed and physically examined suspect cases who came to the local clinics.To test for IgM antibodies to CHIKV, trained phlebotomists collected 5 ml venous blood from each suspect case who had presented to the clinic and consented to participate. Phlebotomists stored all blood samples immediately after collection at 4\u22128\u00b0C. The samples were centrifuged on the same day and the sera were stored in the local hospital refrigerator and later transported in cool boxes to the Virology Laboratory of IEDCR. At IEDCR, each serum sample was divided into three aliquots before storing at -70\u00b0C until testing. At the beginning of the investigation, we only had 300 rapid test kits available, so we tested 300 randomly selected samples out of the 367 sera. We tested 338 randomly selected aliquots out of the 367 samples for anti-CHIKV immunoglobulin M (IgM) antibodies using an enzyme-linked immunosorbent assay (ELISA) test kit that was also available with our group during the investigation  in the Virology Laboratory of IEDCR following the manufacturer\u2019s guidelines.Acute sera that had been collected from suspect cases within two days of illness onset and tested negative for IgM antibodies to CHIKV were later tested for viral RNA using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The seraPhylogenetic analysis was performed as previously described. ChikunguAedes aegypti bred mainly in the water collected in artificial containers in the environment of human settlements in Asia,[Aedes albopictus bred predominantly in natural containers including coconut shells, leaf axils and tree holes, team entomologists looked for mosquito larvae in both man-made and natural water containers.[The entomological investigation was conducted during December 15\u221231, 2011 and focused on identifying vector species. Given that  in Asia, while Aentainers. To collentainers.We divided the total number of suspect cases by the total number of household residents surveyed in each cluster ward within each union composed of the 80 households nearest to an outpatient clinic in the ward to calculate the attack rates by cluster. We estimated the attack rate within the sub-district by calculating the mean of attack rates for the 16 clusters combined. We also calculated the attack rates by 5-year age groups and gender. We used the number of suspect cases instead of confirmed cases to estimate the attack rate because we only collected and tested the serum samples from a sub-set of suspect cases who later came to clinics for clinical assessment and sample provision. For the sub-set of patients who came to the clinics for clinical evaluation, we described their clinical features. Since many respondents were still symptomatic during the clinical survey, we estimated the median follow-up time from symptom onset till recovery for each of the four symptoms including joint pain, joint swelling, debilitating weakness and severe myalgia. Previous authors have suggested that length of follow-up time should be extracted from the time frame where the Kaplan Meier estimate was most stable. We consiThe Institutional Review Board (IRB) of IEDCR and the Ethical Review Committee (ERC) of icddr,b considers outbreak investigations that primarily aim to control outbreaks as public health practice and approval by research ethics committee is not required. This is in line with national and international ethical guidelines including the 1991 International Guidelines for Ethical Review of Epidemiological Studies by the Council for International Organizations of Medical Sciences.\u201349 SeverWe obtained informed oral consent for voluntary participation from adults and verbal assent from children. Past experience of research in similar settings suggested that obtaining written informed consent was difficult, time consuming and resource-intensive when dealing with illiterate participants who were often very cautious, as they did not know what they were signing or whether the signed document could be used against them. As a result, verbal informed consent procedure was allowed during this emergency outbreak situation, where the majority of the affected population were illiterate and ill, as obtaining written informed consent was considered unnecessary and not in the patient and community\u2019s best interest. The investigation team member who was informing a participant signed a form stating that the appropriate information was provided and verbal consent received before beginning any information and/or sample collection or any kind of investigation.The team identified 30 suspect cases from the hospital initially. These cases resided in six different unions within Shibganj. Their median age was 35  years and 45% were males. Fever (100%), polyarthralgia (90%), malaise (83%), severe weakness (66%), rash (48%), itching (38%), and headache (35%) were the predominant symptoms. Forty percent (12/30) of these patients had evidence of IgM CHIKV antibodies in their sera when tested using the rapid assay.We surveyed a total of 5,902 individuals from 1,283 households in the 16 unions of Shibganj. Of these, 1,769 (30%) met the suspect case definition. The median age of suspect cases was 28 (IQR:15\u221242) years. The average attack rate in the sub-district was 30% (95% CI: 27%\u221233%). Attack rates varied from 10%\u221244% across the 16 selected clusters within the 16 unions of Shibganj . The meaAmong the 1,769 suspect cases, 480 (27%) were invited to participate in the clinical survey and to provide blood samples. Seventy-nine percent (377/480) of the invited suspect cases gave consent for the clinical survey and physical examination, and 367 (77%) provided a blood sample. Among the serum samples tested with the rapid test, 73% were positive for chikungunya whereas IgM anti-CHIKV antibodies were detected in 78% (264/338) of the samples that were tested by ELISA. We found that the suspect cases tested within one week of illness onset (43%) were less likely to have IgM antibodies against Chikungunya compared to the suspect cases tested more than 60 days post illness onset (98%) .Among the 377 cases interviewed during the clinical survey, the median age was 40 years (IQR:30\u221250 years); 64% (241/377) were females; and 92% (347/377) were Muslims. The main clinical symptoms included fever (100%), joint pain (88%), debilitating weakness preventing routine activities (55%), rash (51%), severe myalgia (44%), itching (33%) and joint swelling (16%) . Thirty-In addition to fever, the predominant symptoms of serologically-confirmed cases (n = 264) among those who had provided sera after coming to the clinic included joint pain (97%), weakness (54%), myalgia (47%), rash (42%), itching (37%) and malaise (31%). The rashes were found on the trunk (36%), lower limbs (36%), palms and soles (33%), upper limbs in (14%), and face (8%). Of those who developed joint pain, 93% (238/256) reported pain in multiple joints and joints of the lower limbs were involved in 90% (230/256) of the cases. Among the cases reporting joint pain, severe pain that prevented sleep was reported by 61% (156/256), moderate pain that caused pain on movement was reported by 23% (59/256) and minor pain that did not interfere with daily activities but caused discomfort was reported by 17% (43/256). Severe weakness was reported by 40% (105/264), debilitating myalgia by 36% (94/264) and severe joint swelling by 14% (37/264). On examination, team physicians found restricted joint mobility in 23% (59/256) of the serologically confirmed cases. The rashes were maculopapular in 62% (69/112), macular in 33% (37/112) and popular in 5% (6/112) of the suspect cases with rashes. The median durations of symptom persistence of joint pain was 31 days, while joint swelling persisted for 7 days, debilitating weakness and severe myalgia, each persisted for about 12 days in the majority of this sub-set of confirmed cases . FurtherTwo out of the four patients from this outbreak in Shibganj and the single patient from the concurrent outbreak in Dohar sub-district of Dhaka whose acute sera were collected within two days of illness onset had detectable Chikungunya virus RNA with RT-qPCR. However, none of them had IgM antibodies in their sera. The three viral isolates, obtained from the two outbreaks including this outbreak in Shibganj (n = 2) and in Dohar (n = 1), clustered with strains from the 2006 Indian Ocean lineage and were most closely related to the Indian/Asian geographic isolates rather than the African isolates within that lineage . The sizAedes aegypti or Aedes albopictus mosquitoes during the investigation. The team found mosquito larva from only 1/160 households surveyed and the larvae that hatched from this household in IEDCR\u2019s Entomology laboratory yielded Culex quinquefaciatus species.The team did not find any larvae of Aedes aegypti or Aedes albopictus mosquitoes during the investigation.We identified CHIKF suspect cases among 30% of the residents surveyed across the 16 unions in Shibganj during the syndromic survey. The median age of suspect cases was 28 years. The lowest attack rate was found in children <5 years (15%). Anti-chikungunya virus (CHIKV) IgM antibodies were detected by an enzyme-linked immunosorbent assay (ELISA) in 78% of the case samples tested. In addition to fever, the predominant symptoms of serologically-confirmed cases, included joint pain (97%), weakness (54%), myalgia (47%), rash (42%), itching (37%) and malaise (31%). The median durations of symptom persistence of severe joint pain was 31 days, while severe joint swelling persisted for 7 days, debilitating weakness and severe myalgia, each persisted for about 12 days in the majority of this sub-set of confirmed cases. Among the sero-positive patients, 79% sought healthcare from outpatient clinics. CHIKV was isolated from two cases and phylogenetic analyses of full genome sequences placed these viruses within the Indian Ocean Lineage (IOL). Molecular analysis identified mutations in E2 and E1 glycoproteins and contained the E1 A226V point mutation. We did not find any larvae of The clinical syndrome of fever, multiple joint pain, with or without debilitating weakness or severe myalgia was consistent with previous CHIKF outbreaks., 5, 33 TThough several outbreaks have reported an increased propensity to cause clinical illness among females, our syndAedes albopictus larvae breeding in the numerous wet earthen and clay pots that were used for pottery.[Aedes mosquito from the affected area, a finding quite inconsistent with past outbreaks. The delayed reporting of the outbreak with the consequent delay in conducting the investigation during the dry winter months of November and December possibly prevented us from detecting the vector. Given the role of environmental variables on Aedes albopictus and on the pathogen transmissibility, we believe that transmission likely stopped due to changes in weather that constrained Aedes mosquito populations during this outbreak.[Aedes larvae by December, and other outbreaks in Bangladesh have also stopped abruptly around the months of November and December.[Aedes albopictus species.[Aedes albopictus were most likely responsible for transmission,[The first recognized outbreak in Chapainababganj district in 2008 predominantly affected Hindu potters and had limited geographic spread. The outbreak was reportedly precipitated by the high concentration of  pottery. During t pottery., 14, 56  pottery., 33 despoutbreak., 58 We wDecember., 33, 34  species. Another A major limitation of our investigation was that the suspect cases that presented for clinical assessment and blood collection were unlikely representative of the entire affected population. We expect that cases with severe and/or persistent symptoms were more likely to come to the clinic compared to milder cases or patients who had recovered, so our clinical descriptions of serologically confirmed cases were likely biased towards severe presentations. However, since almost half of the cases had already recovered from clinical illness during the clinical survey, we also captured some less serious disease. Given that an evaluation of the sensitivity and specificity of clinical criteria for CHIKV infection identified the syndrome combining fever and polyarthralgias to allow for the correct classification of 87% of those who had serologically confirmed CHIKV infections, our caseAedes populations.Though no recent community seroprevalence study of CHIKV has been published from Bangladesh, a post outbreak sero-survey conducted in selected outbreak affected communities under publication by the author group as well as a 1995 cross-sectional survey carried out in the neighbouring city of Calcutta, India indicated that the level of previous exposure to Chikungunya infection in the country remained low. FurthermAedes mosquitoes in the future may help provide important insight into emergence of epidemic strains in Bangladesh. Effective mosquito control using a comprehensive and integrated pest management approach targeted at every life stage of a mosquito could reduce the risk of CHIKV dissemination.[Population-based seroprevalence and risk factor surveys could help describe the true extent of previous circulation of this virus and identify factors that might put some communities at higher risk than others for outbreaks. Molecular clock analyses and monitoring the spread of genotype viruses and the proportion of the mination., 13 To eS1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S1 Dataset(SAV)Click here for additional data file.S2 Dataset(SAV)Click here for additional data file.S3 Dataset(SAV)Click here for additional data file."}
+{"text": "Exploring the natural occurring genetic variation of the wild barley genepool has become a major target of barley crop breeding programmes aiming to increase crop productivity and sustainability in global climate change scenarios. However this diversity remains unexploited and effective approaches are required to investigate the benefits that unadapted genomes could bring to crop improved resilience. In the present study, a set of Recombinant Chromosome Substitution Lines (RCSLs) derived from an elite barley cultivar \u2018Harrington\u2019 as the recurrent parent, and a wild barley accession from the Fertile Crescent \u2018Caesarea 26\u201324\u2019, as the donor parent  have been utilised in field and controlled conditions to examine the contribution of wild barley genome as a source of novel allelic variation for the cultivated barley genepool.Twenty-eight RCSLs which were selected to represent the entire genome of the wild barley accession, were genotyped using the 9\u2009K iSelect SNP markers  and phenotyped for a range of morphological, developmental and agronomic traits in 2 years using a rain-out shelter with four replicates and three water treatments. Data were analysed for marker traits associations using a mixed model approach.We identified lines that differ significantly from the elite parent for both qualitative and quantitative traits across growing seasons and water regimes. The detailed genotypic characterisation of the lines for over 1800 polymorphic SNP markers and the design of a mixed model analysis identified chromosomal regions associated with yield related traits where the wild barley allele had a positive response increasing grain weight and size. In addition, variation for qualitative characters, such as the presence of cuticle waxes on the developing spikes, was associated with the wild barley introgressions. Despite the coarse location of the QTLs, interesting candidate genes for the major marker-trait associations were identified using the recently released barley genome assembly.This study has highlighted the role of exotic germplasm to contribute novel allelic variation by using an optimised experimental approach focused on an exotic genetic library. The results obtained constitute a step forward to the development of more tolerant and resilient varieties.The online version of this article (10.1186/s12870-018-1527-7) contains supplementary material, which is available to authorized users. Breeding programmes have successfully increased yield and quality traits of major cereals including barley , 2. HoweHordeum are preserved in gene banks worldwide, second only to rice  and wheat  (FAO 2010) and provide an enormous potential resource for allele mining. There have been many descriptive and comparative studies examining diversity in wild and landrace barleys, but few examples utilising the allelic diversity have been reported ) and the recurrent parent ([Hv]) alleles obtained for the significant peak region were used to calculate the relative contribution (RP) of the exotic parent alleles on the trait performance as follows:The Best Linear Unbiased Estimates (BLUEs) for each trait for the donor ([2) were used to identify possible putative candidate genes underlying the predicted phenotypic variation. In this case the number of genes in the targeted regions was first estimated by looking at the physical position of the iSelect SNP markers in the newly released barley genome assembly [The position of major determinant genes related to plant phenology and morphology was estimated from previous studies and public gene databases to support the results obtained from this analysis. Additionally, some genomic regions accounting for a significantly large proportion of a trait\u2019s variance  of the k-th principal component axis, \u03b3ik and \u03b4jk are the genotype and the environment scores (eigenvectors) for the k-th principal component axis, \u03c1ij is the interaction residual and \u03b5ijk is the random error.Values for yield (DY) and grain weight (TGW) for each of the RCSLs were used to investigate the effect of the exotic genome in the performance and stability of the crop across the environmental conditions imposed in the field. Genotype by environment (GE) interaction was studied by means of an additive main effects and multiplicative interaction model (AMMI) for which six environments were defined as the combination of growing season and water treatment. Using this method, the overall variation observed for yield traits such as dry yield and thousand grain weight was partitioned into genotype main effects, environment main effects and GE interaction . The modAs a result, the interaction principal components generated (IPCA1 and IPCA2) are used to graphically summarise (biplots) the GE variation observed. The AMMI2 biplot uses the genotypes and environments scores for the first two IPCA components (IPCA1 on the X-axes and IPCA2 on the Y-axes) giving information about the GE patterns observed. Genotypes with IPCA scores close to zero are more stable or widely adapted to the tested environments whereas specific adaptation of the genotypes is determined by the length of the orthogonal projection of the genotype points onto the environmental vectors. In addition, the AMMI1 biplot tests the genotypes yield potential and stability simultaneously by plotting in the same diagram the average yields (X-axes) and the first dimension measure of GE interaction (IPCA1) for both genotypes and environments (Y-axes). AMMI model was computed using Genstat 17 .Additional file 1:Table S1. RCSLs genotypes determined for 1848 SNP markers from the 9\u2009K SNP chip for barley [r barley .  2013 and (B) 2014. Accumulated rainfall (mm) values per week (x axes), air maximum and minimum average temperature values per week (\u00b1 SE). Data obtained from James Hutton Institute weather station . Field trials were established in the week 16 both years. (DOCX 28\u2009kb)Additional file 3:Figure S2. Volumetric water content (ml\u2009cm\u2212\u20093) in the soil profile at (A) 100\u2009mm, (B) 200\u2009mm, (C) 300\u2009mm and (D) 400\u2009mm depth in the full irrigated (blue), partial irrigated (green), and drought (red) water treatment in 2013 (left) and 2014 (right) field trials. Vertical dashed lines indicate beginning and end of heading time referred to days after sowing (DAS) for year. Error bars indicate standard error of the mean. (DOCX 258\u2009kb)Additional file 4:Table S2. Climate data before sowing, during seedling establishment, before heading and during heading in the 2013 and 2014 growing seasons. Air and soil mean temperature values (\u00b1 SE) and accumulated rainfall (mm) values obtained from the James Hutton Institute weather station . (DOCX 15\u2009kb)Additional file 5:Table S3. Genotypic mean values (\u00b1 SE) for the morphological, developmental and agronomic traits registered in 2013 and 2014 field trials. Genotypes are arranged in ascending order from top to bottom of the table for collar height (COL), peduncle length (PdL), ear length (EAR), seed area (SdA), seed length (SdL), seed width (SdW), heading date (HEA), number of tillers (TILL), dry yield (DY), thousand grain weight (TGW), biomass yield (BY) and harvest index (HI). Best linear unbiased estimators (BLUEs) for genotypes labelled with different letters differ significantly . Harrington mean values highlighted in bold. (XLSX 20\u2009kb)Additional file 6:Table S4. Significant quantitative trait locus (QTLs) detected on the RCSLs exotic genetic library associated with thirteen morphological, developmental and agronomic traits. One trait per tab. (XLSX 167\u2009kb)"}
+{"text": "Scientific Reports 10.1038/s41598-019-48007-5, published online 16 August 2019Correction to: The Acknowledgements section in this Article is incomplete.\u201cThe authors thank Rothamsted Research (BBS/E/C/000J0100) for hosting animal work; Hannah Fleming, Bruce Griffith and Simon White for excellent support and animal care during sample collection periods (Rothamsted Research); the late Robert Orr for initial contributions towards study conceptualisation and extensive knowledge of the North Wyke Farm Platform operations (Rothamsted Research); Debbie Langton for sequencing support (University of Bristol). The authors acknowledge the support from the NIHR Health Protection Research Unit in Evaluation of Interventions at University of Bristol.\u201dshould read:\u201cThis work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) under an Industrial Case Studentship (BB/J012483/1). The authors thank Rothamsted Research (BBS/E/C/000J0100) for hosting animal work; Hannah Fleming, Bruce Griffith and Simon White for excellent support and animal care during sample collection periods (Rothamsted Research); the late Robert Orr for initial contributions towards study conceptualisation and extensive knowledge of the North Wyke Farm Platform operations (Rothamsted Research); Debbie Langton for sequencing support (University of Bristol). The authors acknowledge the support from the NIHR Health Protection Research Unit in Evaluation of Interventions at University of Bristol.\u201dIn addition, this Article contains ambiguous wording in the Results section, under subheading \u2018Duration of carriage and hazard of clearance\u2019. To clarify the findings, the following text should be disregarded:\u201cthese trends were non-linear with categories 2 and 4 associated with a longer duration (lower hazard) compared to category 3, and category 4 (highest density) associated with the longest subsequent carriage duration (Table 3).\u201d"}
+{"text": "Korean grandparents raising their grandchildren play significant roles as social and family resources in Korea. They experience caregiving stress that negatively influences their mental health while struggling with limited social support from peers, and minimal respite care and community resources. Despite a need for resources and information concerning this growing population, there is limited knowledge on Korean custodial grandparents, especially the distinctive cultural factors influencing their multigenerational caregiving experiences. This qualitative study explored Korean custodial grandparents\u2019 experiences of raising grandchildren and cultural meanings of multigenerational caregiving. Using a phenomenological approach, semi-structured interviews with 23 custodial grandparents were conducted from December 2018- January 2019 in two urban and three rural places in Korea. Among the grandparents, five were grandfathers. The mean age of the grandparents was 72 years old (range: 61-82), and the mean age of their grandchildren was 13 years old (range: 1-21). On average, the grandparents had raised 1.5 grandchildren (range: 1-3) for 11 years (range: 1.5-20). Four key themes emerged from the general structure of the lived experiences of Korean grandparents: a) intensive child care support from the grandchildren\u2019s uncle and aunt; (b) stigma of a child\u2019s divorce and custodial grandparenting; (c) different social expectations toward maternal grandparents; and (d) increased needs on financial educational support for grandchildren. The finding reinforces the significant function of collectivistic and family-based Asian culture in understanding experiences of Korean custodial grandparents. It also highlights society\u2019s view of only men carrying forward family lineage and its implications on grandparents\u2019 perceptions about multigenerational caregiving."}
+{"text": "Hypertrophic cardiomyopathy (HCM) is a common genetic diseases with prevalence of 1 in 200-500 in general population, and it can result in sudden cardiac death (SCD) . FurtherIn our recent study, we sought to address this knowledge gap by evaluating cardiac Magnetic resonance (CMR) in 1423 HCM patients with preserved EF for presence and extent of scar in the LV by late gadolinium enhancement (LGE) . Our stuIn the current AHA/ACC guidelines, CMR carries a weak recommendation (class IIB) (Level of evidence C) for use to assess presence of LGE in case of patients with inconclusive SCD risk stratification by conventional factors . Several"}
+{"text": "Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10 Primary immunodeficiency diseases (PID) are caused by genetic defects and lead to serious problems including chronic granulomas  of inflammatory cells), sometimes lasting for decades and sometimes leading to severe ulcers. Initial reports (2014\u20132016), including our report of a blinded study using ultrasensitive virus detection in biopsies, proved the association between granuloma of the skin in PID patients and rubella virus. The viruses in these reports and the current report were derived from a widely used vaccine strain of the rubella virus. Work reported here shows that these vaccine-derived viruses are biologically different from the vaccine virus and that their genomes have changed. Genomic changes could be analyzed largely because the exact sequence of starting vaccine virus genome was known. These genomic differences are likely generated via mechanisms similar to those occurring during normal circulation of wild type rubella. We present data that newly recognized mechanisms for generation of sequence diversity in viruses (because of cellular deaminases) likely occurs in the generation of these vaccine-derived rubella viruses. Thousands of PID patients in the United States are likely shedding these vaccine-derived rubella viruses. Our work presented here characterizing viruses in diagnostic specimens highlights at least two areas where insufficient work has been done: 1) research on the properties of rubella virus (limited understanding of the antibody binding sites on the virus); 2) controlled research studies to assess the public health impact of viruses in populations with high immunity. Rubivirus genus, which has been recently moved from the Togaviridae to a new family, Matonaviridae  [76 [7674] . Brieflyrrection .An 904-nt fragment of the E1 gene (nt 8672\u20139577 in the RV genome) was amplified from RNA isolated from a clinical sample or viral stock using the RV genotyping primers  and PlatComplete sequences of iVDRV genomes have been deposited in the NCBI database under accession numbers MK787188\u2014MK787191 and MK780807- MK780812.http://accelrys.com/products/collaborative-science/biovia-discovery-studio/visualization.html; Accelrys Inc., CA).The structures of the rubella E1 protein  were used as templates for computer modeling. The mutations were modeled as described earlier using the software package ECMMS  for molecular mechanics modeling , 84. TheECau, Enrichment  for uCa mutation signature is:We first created the list of 993 (out of 1074) mutations, in which ambiguous nucleotides were excluded from the analysis . These mMutCau\u2212counts of mutations in cytosines falling into uCa motif of the positive strand in a virus isolateConCau\u2212counts of uCa trinucleotide motifs in all 41 nucleotide sequences of the positive strand centered around the mutated positive strand cytosine basesMutC\u2212counts of mutations in cytosines of the positive strand in a virus isolateConC\u2212counts of C nucleotides in all 41 nucleotide sequences of the positive strand centered around the mutated positive strand cytosine bases.http://hci-bio-app.hci.utah.edu:8081/Bass/InosinePredict) and [Unlike the exquisitely specific to single stranded RNA and DNA APOBEC cytidine deaminases, ADARs act on adenines imbedded into double stranded RNA folds, so prediction of ADAR deamination sites should account for combination of knowledge about experimentally defined short nucleotide motifs and a potential to form double stranded structure. The prediction scores for ADAR activity on adenines were generated using the web-based tool InosinePredict (ict) and . A one-sS1 FigDouble immunofluorescent staining of granulomas with M2 macrophage-specific antibodies, CD206 (green), and either RV capsid antibody (Abcam) (red) or measles (MeV) nucleoprotein antibody 83KKII (Millipore)  was performed as described in Methods. Nuclei were counterstained with DAPI. Note strong staining for RV antigen and the lack of staining for measles antigen.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S1 DataSequences are shown in DNA format (T instead of U) to maintain compatibility with other outputs of mutation signature R-script.(XLSX)Click here for additional data file.S2 DataThe alignment was prepared with Mega7.(MASX)Click here for additional data file.S3 DataThe alignment was prepared with Mega7.(MASX)Click here for additional data file.S4 DataGenetic distances was computed using the Maximum Composite Likelihood method with Mega7.(XLSX)Click here for additional data file.S5 DataData for each gene are located in a separate sheet.(XLSX)Click here for additional data file.S6 Data(XLSX)Click here for additional data file."}
+{"text": "During the workshop, results from a systematic evidence review prepared by an Agency for Healthcare Research and Quality Evidence-based Practice Center to inform the workshop were presented, focusing on long term osteoporosis drug treatment. This talk will describe the goals of the systematic review, which addressed four questions: (1) What are the effects of long-term (>3 years) osteoporosis drug treatment versus control on risks of incident fractures and harms; (2) Do effects of long-term osteoporosis drug treatment vary as a function of patient, bone, or osteoporosis drug characteristics; (3) Among individuals receiving osteoporosis drug treatment to prevent fracture, what are the benefits and harms of continuing versus discontinuing treatment ; and (4) Do outcomes of drug discontinuation or drug holidays vary as a function of patient, bone, or osteoporosis drug characteristics?"}
+{"text": "Women continue to have higher prevalence rates of functional impairment and depressive symptoms than men. In addition, women from certain ethnic groups experience disproportionately higher rates of ADL limitation, and are less likely to be screened for depression. The current study examines the association between race/ethnicity and depressive symptoms on functional limitations in Black, White and Hispanic women. We examined prevalence and adjusted odds of ADL limitations by race in n=9,846 women aged 50+ with low (CESD <4) and high (CESD =>4) depressive symptoms from the 2014 wave of the Health and Retirement Study. Overall, Black and Hispanic women had significantly higher rates of depression (p <.001) and ADL limitations (p<.001) than White women. Among those with high depressive symptoms, Black OR 1.98  and Hispanic OR 2.82  women have significantly higher rates of ADL limitations as compared to White women."}
+{"text": "The application of image processing techniques for the analysis of CT scan images corresponding to lung cancer cells is gaining momentumin recent years. Therefore, it is of interest to discuss the use of a Computer-Aided Diagnosis (CAD) system using Computed Tomography(CT) images to help in the early diagnosis of lung cancer . We discuss and explorethe design and significance of a CAD-CT image processed model in cancer diagnosis. Small cell lung cancer and non-small cell lung cancer are commontypes of lung cancer . The genThe performance of Multilayer and Neural Network classifiertrained by 11 training algorithms with Independent ComponentAnalysis feature extraction is known . It is sA set of real patient CT scan images are obtained from the LungImage Database Consortium (LIDC) archive is used in this analysis.LIDC database contains lung cancer screening CT images fordevelopment, training, and evaluation of computer-assisteddiagnostic methods for lung cancer detection and diagnosis. TheNational Cancer Institute initiated it. It consists of 1018 cases ofdataset contributed by seven academic centers and eight medicalimaging companies  has deveThe CAD System has the following features: (1) It improves thediagnosis accuracy; (2) Assist in cancer detection at its earlier stageand (3) Reduces the time of the radiologist in evaluation.It is of interest to develop a CT scan image processed model for theearly detection of lung cancer where (1) preprocessing usingintensity measure helps to locate small particles in an image such asnode, speculation and angular margin; (2) high detection andclassification accuracy is established; and (3) removes noises thatcreate false detection.The first step is pre-processing of the image to locate particles usingintensity measure. The processed image is segmented using astandard segmentation technique. Thus, cancer nodules are markedin the image. In addition to features like area, perimeter andeccentricity, other features like centroid, diameter and pixel meanintensity have been extracted during feature extraction. Theclassification module follows this where distinction between benignand malignant tumors based on CT scan images is established.Extracted features are used as training features and thecorresponding trained model is generated for the classificationfollowed by model evaluation for detection and classification withimproved accuracy, specificity and sensitivity.The salient features of the method includes (1) image preprocessingby using filtering techniques and it smoothes the image andremoves speckle noise; (2) It segments the cancer nodule from theCT scan image. The segmentation method separates and identifiesthe touching objects in the image. This feature helps in propersegmentation of cancer nodules when it is touching to other falsenodules. (3) Features extraction where features like area, perimeter,centroid, diameter, eccentricity and mean intensity are extractedfrom the image. These features are used as training features todevelop the classifier; and (4) The classification module classifiesthe detected nodule as malignant or benign by using the trainedclassification method.Strengths of the method includes: (1) The improved accuracy ofcancer nodule detection; (2) classifies the detected lung cancer asmalignant or benign; and (3) Removes the noises that create falsedetection of cancer.We describe and discuss the application of a Computer-AidedDiagnosis (CAD) system using Computed-Tomography (CT)images to help in the early diagnosis of lung cancer . We report a framework forthe development of a model for early cancer detection using CADCTimage analysis."}
+{"text": "As we observe the 100th anniversary of the 1918 influenza pandemic, we are reminded ofthe importance of preparedness for and adequate response to influenza, and the criticalrole of influenza surveillance through laboratory detection. Influenza virus detectionhas helped drive the development of diagnostic and virology laboratories in the WorldHealth Organization (WHO) Western Pacific Region over the last 10\u201315 years, atthe same time strengthening their capacity to detect and respond to infectious threatsbeyond influenza. Such cross-cutting approaches are advocated under the Asia PacificStrategy for Emerging Diseases and Public Health Emergencies (APSED III),  laboratory network. . GISRS monitoring of circulatinginfluenza viruses in humans enables timely detection and reporting of significantchanges in seasonal influenza viruses such as the emergence of the influenza A(H1N1)pandemic virus in 2009 and the rapid global spread of oseltamivir-resistant seasonalH1N1 viruses in 2007\u20132008.  techniques developed in the past 25 years enabled therapid and specific detection of viral nucleic acid sequences, becoming the gold standardfor diagnosis and surveillance. Since 2004, PCR has been instrumental in the earlydetection of various zoonotic influenza viruses in humans, including A(H5N1), A(H5N6),A(H7N9), A(H9N2) and others in the Western Pacific Region. (NICs are mandated to maintain high technical capacity for influenza testing (As the majority of NICs in the Region actually test a broad range of infectious diseasesor are housed in institutions that do, the benefits of technical and human resourcestrengthening through GISRS have been crosscutting. Annual NIC meetings bring togetherexperts to discuss progress, obstacles and best practices, helping to strengthencountries\u2019 laboratory technical capacity through better coordination, a keystrategic action in APSED III. Molecular testing available in the GISRS laboratorynetwork has also formed the basis of regional preparedness for detection of emergingpathogens, including Middle East respiratory syndrome coronavirus (Since the 1918 pandemic and the later introduction of GISRS, regional NICs have beenmaintaining traditional methods, incorporating new technologies and building humanresource capacity to help strengthen preparedness and response to influenza. Thecross-cutting advantages generated and the benefits of sharing and collaboration throughGISRS contribute to better preparedness for future outbreaks of influenza and otherinfectious diseases."}
+{"text": "Selective targeting of heteromers as a tool to modulate mu opioid receptor activity is therefore attracting growing interest and raises hopes for innovative therapeutic strategies.Mu opioid receptors modulate a large number of physiological functions. They are in particular involved in the control of pain perception and reward properties. They are also the primary molecular target of opioid drugs and mediate their beneficial analgesic effects, euphoric properties as well as negative side effects such as tolerance and physical dependence. Importantly, mu opioid receptors can physically associate with another receptor to form a novel entity called heteromer that exhibits specific ligand binding, signaling, and trafficking properties. As reviewed here,  The mu opioid (mu) receptor is a G protein-coupled receptor (GPCR) that neuromodulates several physiological functions, in particular nociception , and/or disruption of physical contact by an interfering peptide. The use of interfering peptide and/or mice deficient for one receptor also significantly contributed to demonstrate the specificity of the functional changes associated with heteromer formation and to establish a causal link with behavioral outputs. In native tissue, the mu receptor heteromerizes with the delta opioid (delta) or kappa opioid (kappa) receptors or with the non-opioid receptors ORL1, cannabinoid CB1, galanin Gal1, adrenergic \u03b12a, somatostatin sst2, dopamine D1, chemokine CCR5, and vasopressin V1b. Association between the mu receptor splice variant MOR1D and the gastrin-releasing peptide receptor (GRPR) has also been reported as well as mu physical proximity with the ion channel NMDA  is dynamically regulated and increased in hypertensive rats  binding and ERK1/2 signaling in SK-N-SH neuroblastoma cells  allosterically decreased dihydromorphine binding at the mu receptor in rat striatal membranes -C neuroblastoma cells co-expressing mu and ORL1 receptors, pretreatment with nociceptin decreased DAMGO potency and efficacy to inhibit adenylate cyclase  system of the leucine rich motif responsible for the receptor V1B-\u03b2-arrestin interaction increased morphine-induced analgesia and reduced adenylate cyclase supersensitization and morphine-induced tolerance and physical dependence  p38 activation in the mouse DRGs  pathway and contributes to morphine tolerance  hydrolysis inhibitor JZL184 increased the concentration of the endogenous ligand and enhanced social play behavior in adolescent rodents (Manduca et al., 1 receptors. Indeed, opiate hyperlocomotion and locomotor sensitization were abolished in dopamine D1 receptor in knock-out mice or following local injection of the D1 antagonist SCH23390 in the Nacc (Tao et al., Mu receptors are also involved in other aspects of opiate addiction such as locomotor sensitization and could achieve their modulatory control through heteromerization with dopamine DPharmacological and knock-out based studies linked an anxiogenic and depressant phenotype to mu receptor activation and, on the opposite, associated an anxiolytic and antidepressant phenotype with delta receptor activation (Lutz et al., Systemic administration or local micro-infusion in the Nacc of the delta agonist UFP512 promoted anxiolytic- and anti-depressant-like activity (Vergura et al., 2a heteromers in the NTS were correlated with increased blood pressure in hypertensive rats (Sun et al., 2a heteromerization induced by the mu agonist DAMGO was paralleled by increased blood pressure. Treatment with the mu antagonist CTAP antagonized DAMGO changes in normotensive rats and reduced mu-\u03b12a heteromerization and blood pressure in hypertensive rats (Sun et al., 2a adrenergic receptors thereby potentiating hypertension.Mu receptors are known to control autonomous functions. Higher levels of mu-\u03b1Interactions between mu and somatostatin receptors have been postulated to influence tumor cell growth (Hatzoglou et al., The bivalent ligand MDAN-21 composed of the mu agonist oxymorphone and the delta antagonist naltrindole tethered by a 21 amino acid long linker was developed to selectively target mu-delta heteromers (Daniels et al., More recently, the bivalent ligand MCC22 linking the mu agonist oxymorphone to the CCR5 antagonist TAK220 has been proposed to inhibit inflammatory and neuropathic pain by targeting mu-CCR5 heteromers (Akg\u00fcn et al., A major limitation to the therapeutic use of bivalent ligands is their poor capacity to cross the blood brain barrier (Le Naour et al., in vivo and their functional interactions addressed in a handful of tissue or brain areas. Moreover, heteromer expression is dynamically regulated depending on physiopathological conditions. No doubt that both novel functions and receptor pairs will be uncovered in the future, which further emphasizes their potential as innovative therapeutic targets.Our current appreciation of the role of mu heteromer is still in its infancy and their contribution to mu receptor-dependent behavior likely underestimated. So far, physical proximity has only been validated for a limited number of receptor pairs All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Augmented reality (AR), superimposing digital assets onto the real-world \u2014offers a paradigm shift in delivering immersive interventions for aging adults. Reminiscence and life review are robust intervention techniques that have decades of empirical support to boost mood and meaning in older adults. In this presentation, we demonstrate the applied research and technology development process to create an AR reminiscence and life review engine for aging adults and their caretakers. We conducted 25 needs assessment interviews with community-dwelling older adults, and assisted living facility directors, nurses, and residents. Initial analyses revealed the need for: (1) finding scalable and cost-effective solutions to alleviate time burden for caregivers; (2) increasing variety of activities that do not need much instruction; (3) producing activities that grab and maintain attention; and, (4) generating more personalized activities that do not divert too much time from caretakers. We integrated the findings to develop a working prototype AR engine called \u201cProject Phonado.\u201d From preliminary user testing, Project Phonado aids in boosting mental health and meaning in aging adults\u2014at least temporarily (immediate and one day follow-up). We will show clips of some pilot user testing of the engine and discuss the next evaluation and development steps."}
+{"text": "Sphenocentrum jollyanum (SJ) seed has many health benefits due to its very potent anti-inflammatory and antioxidant properties. Despite its widespread use, it has not been validated for use in the treatment of benign prostatic hyperplasia (BPH). This study was conducted to examine histomorphological effects of SJ seed on BPH that usually causes bladder outlet obstruction.There were a total of six groups of animals each comprising 5 adult male rats. Apart from group 1 , in the remaining five groups, BPH was induced. Group 2 (negative control) was sacrificed immediately after BPH induction; groups 3 and 4 received the extract at 300 and 600 mg/kg respectively by gavages for thirty days; group 5 received finasteride (0.1 mg/kg) for thirty days and group 6 received the extract (600 mg/kg) simultaneously with the steroid administration for thirty days. The animals\u2019 were weighed before the experiment and subsequently every three days until the end of the study.The extract caused marked decrease in prostate weight of rats with BPH with histo-morphology of the tissue showing degenerated stromal and epithelial cells with few epithelial involutions of glandular tissue. Prostate specific antigen (PSA) level as well as testosterone level significantly (p<0.05) decreased in the treated groups compared to negative control. BPH animals treated with extract/finasteride exhibited remarkable increases in anti-oxidant enzymes level with concurrent decreases in peroxidative activity.SJ effectively ameliorated prostatic hyperplasia in BPH animals causing marked degenerative changes in prostate stromal and epithelial cells and also exhibited marked anti-oxidant effect. Benign prostatic hyperplasia (BPH) is a noncancerous cell growth in the prostate gland. This clinical condition elicited by uncontrolled growth of glandular epithelial and stromal cells, induces lower urinary tract symptoms (LUTS) which include weak urinary stream, incomplete bladder emptying, nocturia, dysuria and bladder outlet obstruction , an active metabolite formed by enzymatic conversion of testosterone by steroid 5\u03b1-reductase enzyme  Pierre (Menispermaceae) is a perennial plant that grows naturally along the West Coast sub-region of Africa that includes Nigeria. It is deep rooted with few branches bearing fruits that contain a single large oval shaped seed , Ibadan where a voucher specimen was deposited (FHI/108203).Preparation of the petroleum ether extract of Sphenocentrum jollyanum seedoC) in three cycles using a Soxhlet extractor. The crude oil extract of SJ seed was concentrated in vacuo at 30 oC to obtain 146 g residue which was an equivalent of 9.3 % w/w. The residue was stored in an air-tight bottle kept in a refrigerator at 4 oC till used.A smooth powder was made of the dried seeds using an electric grinder. The seed powder, (1.57 kg) was extracted by petroleum ether  guidelines on the use and care of animals, in experimental studies  obtained from the Animal House of the University of Ibadan, Oyo State, Nigeria, were kept under standard environmental conditions of 12 hr /12 hr light/dark cycles. They were housed in polypropylene cages , and maintained on mouse chow (Livestock Feeds Nigeria Ltd) and provided with water TestosteroneThis is a steroid hormone from the androgen group and is found in mammals, reptiles and other vertebrates  for three weeks , in the remaining five groups, BPH was induced. Group 2 (negative control) was sacrificed immediately after BPH induction while groups 3 and 4 received the extract at 300 and 600 mg/kg body weight (bwt) doses, respectively by gavage for thirty days; group 5 received finasteride (0.1 mg/kg) for thirty days and group 6 received the extract (600 mg/kg) with simultaneous steroids injection (BPH induction) for thirty days. The animals were weighed prior to the commencement of the experiment and subsequently every three days till the end of the experiment. Assay for testosterone and prostate specific antigen (PSA) Enzyme immunoassay technique was used for the quantitative determination of testosterone concentration and PSA evaluation  was assayed utilizing the technique of Kakkar  activity was assayed colorimetrically at 620 nm and expressed as \u03bcmoles of HEstimation of glutathioneThe glutathione (GSH) level was determined by the method of Ellman  and hydroperoxides (HP) were measured by the method of Niehaus and Samuelsson . The tissue was thereafter treated with acetone and then cleared in xylene for 30 min to enhance the tissue transparency followed by impregnation and embedding in paraffin wax. The embedded tissue was sectioned at 5 \u03bcm, mounted on a slide and stained with hematoxylin and eosin (H&E) stains  has been reported to block testosterone/prazosin- induced increase in rat prostate weight  testosterone in the blood stream is noted for its key role in BPH progression. Studies showed that high levels of free testosterone promote the stimulation of 5\u03b1-reductase found mainly within the stromal cells which converts testosterone to a potent androgen, DHT that is responsible for the pathogenesis of prostate gland (Wong et al., 2000Several studies have shown that BPH is associated with increased oxidative stress which increases with increasing age (Aydin et al., 2006SJ seed extract which is recognized for its potent anti-inflammatory and antioxidant properties, effectively ameliorated prostatic hyperplasia by causing marked degenerative changes in prostatic tissue stromal and epithelial cells of the extract-treated animals. The extract also exhibited significant anti-oxidant effect with considerable prophylactic activity. However, further investigation is needed for its validation."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: To establish a conceptual framework todevelop a CTS-IDP with data analytics, and an e-Learning Faculty DevelopmentGuide on best practices and use of the IDP over the CTS academic life-course.METHODS/STUDY POPULATION: To accomplish our goal, we propose thefollowing methods: (1) an online survey, using a convenience sample of the 24KL2 CTSA IDP Collaborative members (conducted in 2017), to assess perceivedneeds for a universal CTS-IDP, current IDP practices, barriers to IDP use, andto discern and align each CTSA Hub\u2019s interests, expertise andcommitment to specific areas of the study; (2) A scoping narrative literaturereview, utilizing the Arksey and O\u2019Malley framework covering the timeperiod corresponding to the initiation of funding (1999) of the original K30Clinical Research Curriculum Awards through to the present CTSA funding period,incorporating Medical Subject Heading (MeSH) keywords , initially delineated by USC referencelibrarian and to be expanded by reference librarian services from the IcahnSchool of Medicine at Mount Sinai and University of Rochester, and performed onNIH searchable databases including NCBI PubMed, Central and Medline &Worldwide Science; Web of Science, ProQuest, ProQuest Abi/Inform,Google Scholar, Cochrane, Ovid MEDLINE databases, as well as Google forpublished papers in English and Spanish. For this portion of the work, we willdescribe and characterize (1) research career development or progressionconstructs, domains, and milestones; (2) establish the presence or absence ofdefined and/or pre-specified timed milestone objectives and inclusionof SWOT analytics and/or Gantt chart approaches; (3) delineate IDPs structure, toolkitsand their key features ; (4) and identify specific gaps to best address the need forpersonalized career development education. Based on this review, we willsynthesize CTS milestones, develop a time frame for meeting RCD expectations,and establish RCD benchmarks for achieving these milestones, all in consensuswith the IDP Collaborative Workgroup. RESULTS/ANTICIPATED RESULTS:Seventy-seven percent of the IDP CTSA\u2019s responded to the onlinesurvey, led by University of Rochester, and the results can be summarized asfollows: (1) 100% agreed that the IDP process is important and shouldbe considerably improved to optimize effectiveness; (2) a range of diverse IDPformats are utilized, making comparisons across programs difficult; (3)50% of CTSA hubs report only fair to good compliance with the IDPprocess; (4) a major barrier to the IDP process is lack of instruction regardinghow best to utilize; (5) poor alignment of currently available IDPs designed forbasic science PhDs with CTS investigators; (6) an absence of a CTS specific IDPto best foster RCD for this specific career trajectory. When asked: What are thebarriers to writing a detailed and thoughtful IDP, responses in order ofagreement from greatest to least were: No verification of acquired competencies,beyond self-report (56%), Static platform (38%), Notconstructed for clinical and translational researcher (31%), Noanalytical or documentation on use (31%), No instruction given toscholars on how to use it effectively and efficiently (31%), The IDPwe are using is more constructed for PhD students and postdoctoral fellows(25%), No instruction given to the scholars on why it is important asadult learners (19%), and Not constructed for early careerphysicians/scientist (13%). Additional progress has beenmade on our Scoping review: An initial ABI/Inform and PubMed USCresearch librarian conducted search using Author names yielded 72 articles, ofwhich only 2 were relevant to the topic at hand. A ProQuest\u2122 searchyielded 19 potentially relevant articles, 11 of which were of relevance to thetopic of IDPs; and a Google Scholar search yielded 18 and 25 on careerdevelopment and self-management, respectively. This has enabled us to put forthan initial model of factors that impact the purpose and design of IDPs thatincludes? DISCUSSION/SIGNIFICANCE OF IMPACT: Discussion: Our initialdata suggests that many CTSA institutions see the need to further enhance thementoring process with a more informed and personalized IDP template andprocess. Furthermore, our initial scoping review suggests a framework upon whichto build specific components of a more ideal and useful IDP to best guidementored research career development of CTS trainees. Significance: Developingand evaluating collaborative evidence-based CTS IDP and corresponding e-LearningGuide could potentially prevent or reduce important delays in RCD, a commonroadblock for the translation of clinical interventions. Ultimately, the CTS-IDPserves not only to support and frame a scholar\u2019s RCD\u201chabits of mind\u201d during training and early careerdevelopment but to also to achieve a sustainable long-term career at a CTSresearcher equipped to meet the ever challenging and dynamic researchlandscape."}
+{"text": "Dear Editor,Enterobacterales, and it matched cases who had extended-spectrum cephalosporin (EC)\u2013resistant enteric uropathogens (EUs) 1:1 with controls with EC-susceptible EUs to predict a scoring system tool for EC resistance [We read with great pleasure the recently published study by Weinstein et al. . This caEnterobacterales [Escherichia coli isolates and 81.3% (608 of 748) of EC-resistant Klebsiella pneumoniae [E. coli after treatment with oral nitrofurantoin was 3.2% (1/31) at 4 weeks after finishing therapy [This clinical scoring system is highly useful for empiric antibiotic treatment for urinary tract infections (UTIs), especially the complicated ones, which often require treatment based on in vitro antibiotic susceptibility testing. The Infectious Diseases Society of America (IDSA) and the European Society for Microbiology and Infectious Diseases (ESCMID) guidelines for UTI emphasize the importance of empiric treatment of uncomplicated UTI without a urine culture and susceptibility testing. Those guidelines recommend either a single dose of oral fosfomycin, 5 days of oral nitrofurantoin, 3\u20137 days of pivmecillinam (which is only available in Europe and is not licensed for use in North America), 3\u20137 days of oral \u03b2-lactam , or 3 days of oral trimethoprim-sulfamethoxazole  [ 608 of 78 of EC-r Additionally, urine cultures are regularly ordered in healthy outpatient women with urinary symptoms even though they are often of limited value given the delay in obtaining results, the cost and inconvenience to the patient, and the high predictive value of symptoms alone in diagnosing acute cystitis . In someThe clinical tool developed by Weinstein et al. to predict EC resistance included recent trimethoprim-sulfamethoxazole exposure as unexpectedly the only antibiotic found to be significantly associated with EC resistance after multivariate analysis . Althoug In conclusion, the clinical prediction tool for EC resistance developed by Weinstein et al. could be most useful in the setting of empiric treatment choice for complicated UTI, but may be used less often in the case of uncomplicated UTI, where adherence to the IDSA and ESCMID UTI treatment guidelines would be the gold standard for empiric antimicrobial treatment . One cou"}
+{"text": "OBJECTIVES/SPECIFIC AIMS: The aims of this project are to: (1) examine placebo effects on subjective and objective outcome measures, (2) determine if an increase in the placebo is associated with changes in benefit, (3) evaluate if the trauma related insomnia placebo group in our study has different side effect reports compared with insomnia placebo participants in previous suvorexant trials, and (4) (Exploratory) examine associations between the placebo group\u2019s characteristics  and placebo effects. METHODS/STUDY POPULATION: The parent study is a randomized double-blind placebo-controlled clinical trial  of suvorexant for treatment of adults (age 18\u201355) with insomnia that started or worsened after trauma exposure. Suvorexant is a first in class orexin antagonist and is approved by the FDA for the indication of insomnia. In this 6-week trial, all participants initially take 10 mg of suvorexant/placebo, and the dose will be increased to 20 mg if participants continue to experience clinically significant insomnia symptoms 1 week after starting the medication. Sleep outcomes will be measured by polysomnography, daily sleep diary, and the Insomnia Severity Index. RESULTS/ANTICIPATED RESULTS: We hypothesize that (1) within the placebo group data both subjectively and objectively measured outcomes will similarly show improvement in insomnia symptoms, (2) the increase of the placebo medication dose will result in an increased benefit, (3) the trauma-related insomnia placebo group will have the same type and similar rate of side effects reported in previous suvorexant trials. DISCUSSION/SIGNIFICANCE OF IMPACT: Most previous studies examining placebo effects focused on pain and depression. Information obtained from this project will complement our current understanding of placebo effects by characterizing placebo effects on trauma-related insomnia. This study will inform the development of novel strategies to maximize utility of placebos in future clinical trials."}
+{"text": "Context: Tuberculosis (TB) has remained a devastating global public health problem. In the continuing search for effective treatment, polyherbal remedies used as alternative medicines in the Eastern Cape Province of South Africa were surveyed.Objective: The survey collected information and documents the list of ingredients such as the name of the plants used including the non-herbal inclusions, type and dosage of polyherbal formulations used for the treatment of TB.Materials and methods: The survey was conducted over a period of 6 months using semi-structured questionnaires amidst informal conversations with the traditional healers in five communities in the study area. The chosen study area is the third infected Province with TB in South Africa.Results: A total of nine polyherbal preparations were collected. Information on the parts of the plant used, mode of preparation and the dosage used were documented. In total, the herbs belong to 20 families of which Apiaceae, Liliaceae, Strychnaceae, Rutaceae and Hypoxidaceae are the most prominent. However, members of Apiaceae were commonly mentioned for the preparation of the remedies. The two most frequently used plants were Allium sativum L. (Liliaceae) and Strychnos decussata (Pappe) Gilg. (Strychnaceae). Rhizome was the commonest parts used, followed by the roots and barks.Conclusions: This paper provides significant ethno-medicinal information on polyherbal medicines used for the treatment of TB in the study area. The therapeutic claims made on medicinal plants used for the preparations are well supported by the literature, with many of the species having antimicrobial properties. Mycobacterium tuberculosis has remained one of the most prevalent causes of mortality in developing nations, especially in the Asian and African continents. The disease remains a big problem in these countries probably due to inadequate means for the management and treatment of the disease. According to World Health Organization (2002), about 95% of the approximately eight million cases of TB occur each year in Africa having the highest incidence. However, South Africa is the third highest incidence country after India and China with about 80% of the population infected with the disease. This rate has increased by 400% over the past 15 years most especially among the people living with human immuno-deficiency virus (HIV)  caused by M. tuberculosis to commonly prescribed antimicrobials has made people fall back on herbal medicines for various therapeutic purposes . Ethnobotanical surveys have extensively studied South African populations of adults and children with several illnesses Bodkin .A total of nine polyherbal medicines used for the treatment of TB were recorded and collected from the study area ; these aThe polyherbal remedies in the study area were prepared from 24 plants. The six most commonly mentioned plant families used in the preparation of the polyherbal formulations in terms of number and percentage are Apiaceae [5(25%)], followed by Liliaceae [4(20%)], Strychnaceae [4(20%)], Rutaceae [4(20%)], Solanaceae [2(10%)] and Primulaceae [2(10%)] . MembersAllium sativum L. (Liliaceae) [4(17%)], Strychnos decussata (Pappe) Gilg. (Strychnaceae) [4(17%)], Daucus carota L. (Apiaceae) [3(13%)] and Hypoxis argentea (Fiscand) (Hypoxidaceae) [3(13%)]. Other plants such as Agathosma betulina (Berg) (Rutaceae) [2(8%)], Capsicum annuum L. (Solanaceae) [2(8%)] and Rapanea melanophloeos L. (Primulaceae) [2(8%)] are used for a few polyherbal preparations in the Province as represented in The most frequently used plant parts in this study was rhizomes [10(27%)], followed by bark [8(22%)], and roots [8(22%)]. Others are leaves [6(16%)], corms (3(8%)] and vegetable [2(5%)] as shown in S. decussate, which should be chewed immediately after KWTb remedy has been administered ] and decoction [2(22%)] with the exception of nistered . This isnistered . The intMycobacterium tuberculosis. Probably, these therapies have gained popularity in both developed and developing countries because of their natural origin and fewer side effects for the treatment of various chronic and acute ailments (Ahmad et\u00a0al. The diverse uses of each plant can be explicated by the fact that, a single plant can serve many medicinal purposes or perform different functions (Lawal et\u00a0al. This paper provides significant ethno-medicinal information on polyherbal medicines used for the treatment of TB in Amathole District Municipality of Eastern Cape Province. Africa is endowed with a biodiversity of medicinal plants, many of which are currently used in the traditional management of TB. The study shows that people in the study area still depend on polyherbal medicines for the treatment and management of TB. The documented remedies reflect rich ethno-medicinal knowledge in the province. However, further test are required to validate the ethno-medicinal usage of these polyherbal remedies as anti-TB agents."}
+{"text": "Data for this study originated the Oklahoma 100 Year Life Project. A total N = 7 volunteer actors  were recruited to participant as actors to play the role of centenarians in a living history play based on oral historical narratives. Actors participated in preliminary (prior to play performance) and post (after play performance) focus group sessions. Focus group questions addressed four key ideas: (1) Perceptions of aging and human longevity; (2) Loss and decline in aging; (3) Narrative storytelling and; (4) Personal life goal(s). Qualitative content analysis was performed to assess general thematic evidence stemming from actor perspectives. Four predominant themes emerged suggestive of adaptation in actor perceptions about human aging and longevity. These themes included: (1.) Purpose seeking (e.g. \"It was interesting to see how much you can get out of life.\"); (2.) Age-embodiment ; (3.) Creative curiosity ; and (4.) Self-actualization . Results have implications relative to how oral historical narratives can be used to enhance the personification of aging on stage, as well as demystify personal myths about longevity. Applications for use within educational and community settings for theatrical performances will be shared."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: The overall goal of this project is to enhance the use of GCRA in Latina breast cancer survivors at high risk of hereditary breast and ovarian cancer to reduce disparities in GCRA uptake. The aims of the study are to (1) develop a cultural adaptation of an evidence-based TGC intervention that consists of phone genetic counseling and a booklet, (2) evaluate the impact of TGC Versus Usual Care, and (3) explore the communication patterns in TGC and genetic counseling sessions with an interpreter. METHODS/STUDY POPULATION: We are conducting a 2-phase, mixed methods study. In Phase I we will develop a cultural adaption of an evidence-based intervention (TGC) for high-risk Latina breast cancer survivors using the Learner Verification and Revision Framework (n=15). In Phase II we will use a cluster randomized design with four community sites randomized to Spanish TGC (n=2 sites) or usual care (n=2 sites) . The primary outcome is genetic counseling uptake. Among women who receive genetic counseling either through TGC (n~30) or with an interpreter (n~15), we will assess counseling quality by reviewing 20 randomly selected audiotaped sessions . We will evaluate women\u2019s HBOC knowledge and satisfaction with counseling. Communication processes and outcomes will be assessed using gold standard RIAS quantitative coding system and qualitative discourse analysis. RESULTS/ANTICIPATED RESULTS: We elicited input from transdisciplinary team members to develop an initial adaptation of a TGC print booklet and intervention protocol for use with high-risk Latina breast cancer survivors with limited English proficiency. The booklet contains low-literacy information about HBOC, risk factors, pros and cons of testing, and management strategies. Based on these materials and prior work, we anticipate TGC will consist of one 1 hour or less TGC session by phone. Participants interested in pursuing testing will receive a saliva kit and will participate in a second TGC session (30 min) to discuss test results and management options. DISCUSSION/SIGNIFICANCE OF IMPACT: Given access barriers and the shortage of Spanish-speaking genetic counselors, adapting and translating TGC intervention is a promising strategy that could reduce disparities by broadening the reach and accessibility to genetic counseling while enhancing the quality of the service for Latinas with limited English proficiency."}
+{"text": "Background: Death certificate inaccuracy increases at older ages. The Long Life Family Study (LLFS) utilizes a physician adjudication committee to review the death certificate, medical records and a family narrative about cause of death. We report here the adjudication process and the prevalent underlying causes of death for a subsample of those who have died so far. Methods: We first describe the adjudication process. There were ~1,250 deaths in LLFS. We report underlying causes of death for a subset of proband generation subjects enrolled and evaluated by two LLFS study centers. Results: As of May 2019, we have adjudicated 190 deaths  . Mean age 95 years (range 81-105 years). Top 5 causes of death for men: cancer (13%), coronary heart disease , dementia (13%), \"other\" (11%) and \"unknown\" (9%) and for women: dementia (21%), valvular heart disease (14%), coronary heart disease (12%), unknown (12%) and other (9%). Rate of death due to dementia was greater in women compared to men . Conclusions: In this pilot study, a significantly greater proportion of women died due to dementia compared to men. At least some portion of this difference may be due to the observation that women are known to survive chronic aging-related diseases more than men and thus have a greater opportunity to die from dementia at advanced ages. An additional cause to consider includes clinicians\u2019 gender bias in ascribing diagnoses in the medical records that were relied upon as part of the adjudication process."}
+{"text": "The House Calls and Behavioral Health Integration project was an inter-agency collaboration to address depression in the older adult population by increasing knowledge and awareness of the condition and providing better access to care. Rowan Medicine, New Jersey Institute for Successful Aging (NJISA) and Jewish Family and Children Services (JFCS) partnered to deliver a comprehensive education, screening and referral program for residents of 3 senior housing facilities serving an estimated 300 elderly and disadvantaged residents. The goal of this year long project was to provide depression education for both housing residents and staff; offer on-going access to free depression screens (using PHQ-9) for residents; and refer residents to an appropriate resource  depending on depression screen outcome. Depression education was provided to 15 housing staff and 78 older adult residents. A total of 34 depression screens were completed ; further evaluation of symptoms was indicated for 59% (n=20) of those screened. Seventeen of the 20 residents accepted a recommendation for a referral to supportive counseling; 3 declined. The average PHQ-9 score was 8.45 . Referrals to case management and house calls (n=4) were also made. Feedback from both housing residents and staff was positive and the project team learned valuable lessons about serving older adults in congregate living settings which has informed other programming. The project was successful in providing education, screening and referrals to residents who might not otherwise have access to specialized geriatric behavioral health interventions."}
+{"text": "We examine trait and state subjective aging as antecedents of control beliefs in older adults with a daily diary design. Adults (n=116) ranging in age from 60 to 90 (M=64.71) completed a nine-day daily diary study online. Participants reported trait aging attitudes  on Day 1 and daily Awareness of Age-Related Change (AARC) of loss and gain experiences and control beliefs (Locus of Control and Perceived Competence) on Days 2-9. Controlling for demographics and known antecedents of control beliefs , daily increases in AARC gain were associated with increases in both Locus of Control and Perceived Competence, and a cross-level interaction revealed that Locus of Control decreased for those with more positive ATOA on days when they reported more AARC losses. Discussion will focus on interpreting the interaction between trait and state subjective aging."}
+{"text": "The relationships between physical frailty and perceived neighborhood social cohesion (PNSC) and functional disability among community-dwelling older adults are poorly understood. This study aims to (1) examine the associations of frailty and PNSC with disability; and (2) evaluate low PNSC as a risk factor in the association between frailty and disability. A sample of 1645 older adults using multi-stage sampling method in Shanghai were randomly selected in this cross-sectional study. Frailty operationalized as Cardiovascular Health Study criteria  and PNSC measured as Neighborhood Cohesion Scale  were independently associated with basic and instrumental activities of daily living disability. A significant interaction of frailty and PNSC on disability =4.31, P=.014) was found, using a two-way analysis of covariance (ANCOVA). Compared to robust individuals with high PNSC, pre-frailty with high PNSC was not significantly associated with disability while pre-frailty with low PNSC was associated with approximate 4-fold increased prevalence of disability . Frailty with high PNSC was associated with higher likelihood of disability  and frail individuals with low PNSC stood out with 10-fold increased prevalence of disability . All analyses were controlled for demographical and clinical covariates. Our results suggest high level of social cohesion serves as a buffer against the impact of physical frailty on functional disability. These findings notably imply to the development of interventions for older frail adults from the neighborhood perspective."}
+{"text": "Plants grow continuously, forming new meristem-derived organs and tissues throughout their post-embryonic life. As sessile organisms, plants need to constantly integrate and reflect environmental fluctuations in their growth and development, which can translate into high level of developmental plasticity in response to environmental changes  evidences of molecular mechanisms that mediate the crosstalk between phytohormone signaling, chromatin structure and gene expression (2) how this crosstalk may link to plant developmental plasticity and robustness and finally (3) why meristems may represent central places for this crosstalk allowing plasticity and environmental memory.Phytohormone and epigenetic regulation can interact on multiple levels : (1) phyFLOWERING LOCUS C (FLC), preventing precocious floral transition  1 and 2 with histone-methyltransferase activity playing a major role in transcriptional regulation during development  genes is positively regulated by BRM establishing local auxin maxima and stimulating the expression of the RAM-specifying PLETHORA genes PLT1 and PLT2  is associated with changes in jasmonic (JA), salicylic acid (SA) and ethylene responses  control of cell identity genes in meristems, (2) chromatin-mediated stabilization of gene expression beyond the hormonal initial signal, (3) chromatin-governed integration of separate hormone signaling pathways.WUSCHEL (WUS) is regulated by cytokinin signaling, DNA methylation, H3K27me, or chromatin remodeling  their central role in postembryonic morphogenesis, plasticity and memory, (2) their particularities for phytohomone signaling and chromatin remodeling, (3) first evidences reported for this crosstalk in SAM.The meristems represent major sites of stem cell niches in plants Scheres, . Apical Phytohormone and epigenetic pathways play overlapping/complementary roles in meristem functions and developmental plasticity or robustness, laying the basis for a biologically significant crosstalk. Importantly, meristems have been shown to be the place of epigenetic control for stem cell pluripotency, differentiation, and reprogramming  in the SAM of Arabidopsis clv3 mutants (Lafos et al., Major evidence for phytohormone-chromatin crosstalk was obtained using Arabidopsis mutants, or applying phytohormones or chemical inhibitors of chromatin modifiers in various developmental processes (Yamamuro et al., In conclusion, phytohormone action and chromatin modifiers seem to be tightly interacting but the extent to which they act jointly or independently remains unclear (Ojolo et al., Current knowledge leads to the opinion that this crosstalk in meristems can integrate environmental cues for developmental outcome. Erasure of this signaling may allow continuous adjustment to new environmental conditions. Its maintenance through persistent chromatin states can however stimulate mitotic memory that could prime later organ formation. How the balance between erasure and memory is achieved remains enigmatic .While the mechanistic events could be more easily deciphered in well-established model annuals such as Arabidopsis, it is important to establish perennial models where the impact of mitotic epigenetic memory is of importance in the context of climate change. In addition to SAM and RAM, cambium, whose activity is crucial for environmentally controlled wood formation, may be an appropriate and highly relevant model (Wang et al., SM suggested and designed the opinion article. MDS and SM designed the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The scarce knowledge of multimorbidity development hampers the effectiveness of clinical interventions. We aimed to identify multimorbidity clusters, trace their evolution in a cohort of older adults, and detect the clinical trajectories of single individuals as they move among clusters over 12 years. Population-based study including 2931 persons 60+ with \u22652 diseases participating in the SNAC-K study. A fuzzy c-means cluster algorithm was used to group participants by disease patterns at baseline and follow-ups. Migration from one cluster to another was tracked over time, and the association between the clusters and mortality was tested. At baseline 52% of participants were classified into five clinically meaningful disease clusters: psychiatric and respiratory (5%), heart (9%), respiratory and musculoskeletal (16%), cognitive and sensory impairment (10%), and eye diseases and cancer (11%). The remaining 48% of participants (unspecified group) were grouped in any cluster at baseline but greatly contributed to the other clusters at follow-ups. Multimorbidity clusters that included cardiovascular and neuropsychiatric diseases presented a significantly higher mortality risk (odds ratios ranging 1.58\u20136.00) than the group not part of any clusters. Clusters characterized by cardiovascular and neuropsychiatric diseases included 25% of the study population at baseline and 28% of participants at six years, and they accounted for 51% of deaths at six years and 57% of deaths at twelve years. Multimorbidity clusters and clinical trajectories of older adults with multimorbidity show great dynamism over time. The multimorbidity clusters and trajectories identified in this study may help identifying groups with similar needs and prognosis."}
+{"text": "To address their needs for proactive self-care and end of life planning, we implemented a community based educational program that promotes future care planning (FCP) for community residing older adults. Extension specialists from Iowa State University implemented two brief FCP program sessions with older adults. Topics included both short-term and long-term future care planning activities and strategies. Baseline and post program surveys were completed by 216 community dwelling older adults (M=78.21). The program was successful in getting older Iowans in the rural area start end of life care preparation as well as helping them to make changes in their health care decisions. The majority of participants (89.6 %) reported high satisfaction with the programs. We also found a high rate of change (62%) in opinion regarding future care. The implication of future care planning for is discussed with recommendations for future research."}
+{"text": "The quality check and determination of permitted and non-permitted additive colors in food products is very important for customer\u05f3s right protection and health. This survey was undertaken to demonstrate the frequently use of additive colors and products targeted to color adulteration in Iranian foods and beverages. From the 1120 of the samples, 18.86% contained artificial colors, 11.89% contained natural colors and 69.25% of samples had no additive colors. Tartrazine (E102) was the only non-permitted artificial dye used in samples. Among products with additive colors, only 4.38% of samples failed to meet with national Iranian standard and 61.23% of non-compliance samples were from non-industrial sectors and mostly were saffron and food containing saffron such as saffron rock candy and saffron chicken. These places and products quality are main the concern to solve the color adulteration in Iranian food market. Specifications TableValue of the data\u2022The dataset shows the amount of additive colors in local food and beverage products.\u2022The dataset signifies the amount of permitted and non-permitted colors under Iranian laws.\u2022The dataset of this article identifies products with non-authorized colors, which can be useful for other investigators working in area of quality assurance of foods.1The dataset provided here , Table 32The Iranian national standard organization only permits seven artificial dyes of Quinoline Yellow (E104), Sunset Yellow FCF (E110), Azorubine (E122), as well as Ponceau 4R (E124), Allura Red AC (E129), Indigotine (E132) and Brilliant Blue FCF (E133) in different type of products. The prevalence use of permitted and non-permitted artificial dyes has been reported from different states of Iran, previously. The required data were collected from the results documented in Kimia Test FAM Laboratory during the five years of 2011\u20132015. The additive color of 1120 samples, which represent 30% of samples analyzed in Tehran city for additive colors, was determined using thin layer chromatography methods (TLC) according to 2634 Iranian national standard and were compared to 740 Iranian national standard for permitted food additive colors. The data were entered into an Excel spreadsheet and were analyzed by descriptive statistics"}
+{"text": "The HER4 receptor tyrosine kinase is known to have promiscuous activity in malignant cells, last but not least in breast cancer. Evidently, the prognostic and predictive impact of HER4 expression depends on the expression of different receptor isotypes, the way of receptor activation (ligand dependent vs. independent), and on the complex interaction of the HER4 intracellular domain (4ICD) with intracellular regulative molecules which results in either oncogenic or rather tumor suppressive HER4 activity. Recent data suggest that HER4 unfavorably affects the endocrine treatment of postmenopausal breast cancer patients with tamoxifen and therefore might represent an additional therapeutic target in luminal breast cancer. The Human Epidermal Growth Factor Related (HER) receptor family comprises at least four cognate receptor tyrosine kinases  which - as a functional unit - drive breast cancer disease and have prognostic and predictive impact . Remarkably, HER4 plays an extraordinary role in the context of HER receptor coexpression and interaction . Upon itIn contrast to its differentiation enhancing activity Her4 has also been shown to promote the proliferation of breast cancer cells , 16. It Notably, HER4 does not only affect tumor cell growth and survival but also appears to significantly impact antigen specific tumor treatments by definite intracellular molecule interaction . In thisThe finding that HER4 impairs the tamoxifen treatment efficiency has clinical implications and facilitates extended treatment strategies that involve multiple tumor cell targeting. This can in case of ER/HER4 double positive BC potentially be accomplished by a dual targeting of both receptor types using for instance tamoxifen and an HER4 specific antibody with anti-tumorigenic activity , 32. Alt"}
+{"text": "Ventenata dubia, an invading non-native annual grass, in geographic and ordination  space over time.The data and analyses presented here were collected at the Zumwalt Prairie Preserve (ZPP), northeastern Oregon. Vegetation composition was measured within 124 (1-ha) plots using the line point intercept method . These data include vascular plant species abundance matrices at two different time periods, seven years apart (2008/2009 & 2015/2016); boxplots of species abundance (cover and frequency) change over time; Non-parametric Multiplicative Regression (NPMR) estimated abundance of  The preon space , Fig.\u00a05.2The ZPP was categorized into prairie and canyon lands and the canyon lands were excluded from this data . The remVentenata dubia foliar cover and frequency within quadrats in both NMS ordination and geographic space (R2 (\u03c7R2) values were used to evaluate model fits and differ from the conventional R2 because it is based on the exclusion of each data point from the estimate of the response at that point Ventenata"}
+{"text": "The evaluation framework is developed for CO2 capture, geological utilization and storage (CCUS) project developments, including CO2 emission inventory, site suitability evaluation, and source\u2013sink matching with techno-economic models. The data shows the matched source (CO2 source)-sink (onshore aquifer site) pairs with sites distribution and levelized cost under various scenarios. Data also shows the geographic distribution of source-sink pairs, cost curve, annual cumulative CO2 storage capacity and enhanced water production under various scenarios. Potential large-scale deployments of CO2-EWR projects with low cost in the modern coal chemical industry in China are shown and identified in the dataset. This data article is related to the research article \u201cCost curve of large-scale deployment of CO2-enhanced water recovery technology in modern coal chemical industries in China\u201d .This data article presents the first systematic assessment on the potential of onshore CO The data show the details of matched source-sink pairs with potential costs. The data compiled in excel spreadsheets provides the inventory of several coal chemical processes, CO2 emission from industrial and dilute processes of each CO2 source, geographic distribution of potential integrated CCUS projects (source-sink pairs) with levelized costs and CO2 storage capacity, cumulative storage capacity and water production for the whole set of modeled CO2 sources and onshore aquifer sites in China under various scenarios of actual operating capacity in 2015, designed full capacity in 2015, and total capacity in 2016. The data can be used to identify various potential low-cost large-scale deployment of CO2-EWR projects using pure CO2 from the coal chemical industry in China. Data sheet and figures are compiled using Excel software  with levelized costs, cumulative storage capacity and water production for the whole set of modeled CO2 sources and onshore aquifer sites.The systematical evaluation framework is based on the"}
+{"text": "Inhibition of TORC1 has extended lifespan in multiple preclinical species. Thus drugs inhibiting TORC1 may have therapeutic benefit for aging-related conditions in humans. An aging-related condition that improves with TORC1 inhibition in old mice is immunosenescence (the aging-related decline in immune function). Immunosenescence leads to increased rates of infections including respiratory tract infections (RTIs) in the elderly. In two Phase 2 clinical trials in over 900 elderly subjects, the TORC1 inhibitor RTB101 was observed to improve immune function and decrease the incidence of RTIs. Decreasing the incidence of RTIs is important because RTIs are the fourth leading cause of hospitalization in people age 65 and above. Based on these findings, two Phase 3 studies are underway to determine whether RTB101 given for 16 weeks during winter cold and flu season decreases relative to placebo the percentage of elderly subjects with illnesses associated with RTIs."}
+{"text": "Objectives: Occupational mobility at various stages in the life course may have a cumulative influence on health outcomes in later life. This study aims to (1) systematically review the association between occupational mobility and chronic illness in late life; and (2) identify potential mechanisms underlying this relationship. Methods: A systematic review of literature was carried out by searching two databases (PubMed and SocIndex) and reference lists. Eligible studies examined associations between occupational mobility and at least one measure of chronic illness among adults aged 50 years or above. Occupational disruptions  were reviewed as special cases of occupational mobility. Results: Downward occupational mobility and mid-life occupational disruptions have been consistently shown to predict higher risk of chronic illness in older adults. Several potential mechanisms were identified from the literature: (1) health behaviors, including dietary practices and alcohol consumption; (2) psychosocial factors, including stress, stigma, job control, job demands, and job satisfaction; (3) economic factors, including financial incentives or constraints; and (4) other individual characteristics, including personality traits and coping skills. There is also evidence that the timing of job mobility and the duration of (each) occupation modify the association between occupational mobility and health in late life. Discussion: These findings suggest that experiencing involuntary occupational mobility at various stages in the life course can increase the risk of chronic illness in late life. Health professionals and policymakers should target more resources to disadvantaged older adults who experience involuntary occupational transition."}
+{"text": "Corneal blindness is one of the major causes of blindness worldwide, for which corneal transplantation has long been the only treatment method. In addition to penetrating keratoplasty, development of partial thickness corneal transplantation techniques including deep anterior lamellar keratoplasty (DALK), Descemet's stripping endothelial keratoplasty (DSEK), and Descemet's membrane endothelial keratoplasty (DMEK) allowed improved visual anatomical outcome. Keratoprosthesis including Boston keratoprosthesis (KPro) and osteo-odonto keratoprosthesis (OOKP) also enabled visual recovery in patients with serious ocular surface destruction. However, the demands for corneal transplant can never be met because of global shortage of donor corneal tissue.We have introduced in the call for papers for this special issue that various methods of corneal tissue engineering such as cultivation and expansion of corneal tissues using novel drugs and biomaterials have been studied. These novel methods are expected to allow the production of large amount of synthetic corneal tissues for transplantation without the risk of disease transmission. Further researches on corneal tissue engineering, i.e., cell therapy for corneal tissues including the epithelium, stroma, and endothelium; development of biomaterials, drugs, and imaging techniques that can be applied to corneal tissue engineering; application of artificial corneal tissue; and anterior segment reconstruction would provide even more improved visual and anatomical results.In this special issue, the authors contributed 4 original articles and 2 review papers regarding researches of corneal tissue engineering and its clinical application.The authors reported the results of their original researches on various topics in corneal tissue engineering: (1) outcomes of Descemet membrane endothelial keratoplasty for vitrectomized eyes with sutured posterior chamber intraocular lens; (2) generation of femtosecond laser-cut decellularized corneal lenticule using hypotonic trypsin-EDTA solution for corneal tissue engineering; (3) modern corneal eye-banking using a software-based IT management solution; and (4) preliminary investigation of the mechanical anisotropy of the normal human corneal stroma.This special issue also includes review articles on the following topics: (1) application of novel drugs for corneal cell regeneration and (2) from DMEK to corneal endothelial cell therapy: technical and biological aspects.We believe these articles will provide readers with valuable information on corneal tissue engineering and novel ideas for researches on related topics."}
+{"text": "Dengue prototype strains are widely used for virological study. The strains presented here have been cultured under different laboratory environments, resulting in accumulating genetic variations. Dengue prototype strains are widely used for virological study. The strains presented here have been cultured under different laboratory environments, resulting in accumulating genetic variations. We present the genomes of four serotypes of the dengue prototype strain that were continuously maintained in the laboratory. These genomes contain bases different from those of the original prototype strains in GenBank. Flaviviridae and the genus Flavivirus. Four serotypes of dengue virus are a cause of dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). The prototype strains of four dengue serotypes frequently used in the laboratory are DENV1 strain Hawaii, DENV2 strain 16681 and strain New Guinea C (NGC), DENV3 strain H87, and DENV4 strain H241. The prototype strains have been cultured and used for dengue study in laboratories since 1980 (Dengue virus (DENV) is the most prevalent arbovirus and is found mainly in tropical and subtropical regions. The virus belongs to the family Aedes albopictus cells by the cell culture laboratory of the Division of Dengue Hemorrhagic Fever Research . Five prototype strains were maintained in the laboratory for more than 10 years. The prototype strains were prepared for sequencing by using the 454 pyrosequencing GS FLX platform (Roche Applied Science) in the same run as that reported in our previous study  using BLASTn version 2.7.1+  database under the accession number"}
+{"text": "Infectious Diseases of Poverty claimed that undue influence on African programs by concepts developed by the Onchocerciasis Elimination Program of the Americas (OEPA) is detrimental to stopping mass drug administration (MDA) in Africa. This claim is made despite a record year for MDA stoppage in four African countries of >\u20093.5 million treatments in 2018, far exceeding any past OEPA or African Program for Onchocerciasis Control (APOC) stop MDA success.A recent article \u201cIs onchocerciasis elimination in Africa feasible by 2025: a perspective based on lessons learnt from the African control programmes\u201d in The online version of this article (10.1186/s40249-019-0558-0) contains supplementary material, which is available to authorized users. Please see Additional file Infectious Diseases of Poverty including the claims: (1) that the influence of the ongoing Onchocerciasis Elimination Program of the Americas (OEPA) is, \u201cimpeding progress towards decisions to stop intervention in many (African) areas that have reached the elimination point\u201d and (2) that the introduction of testing for antibody to the Onchocerca volvulus 16\u2009kDa antigen (OV16) in children  to assess for evidence of recent transmission \u201chas delayed progress with stopping treatment which according to APOC evaluations should already be feasible for millions of people.\u201d [Professor Dadzie with other distinguished directors of the former World Health Organization (WHO) African Regional Programs against River Blindness (the Onchocerciasis Control Programme in West Africa [OCP] and the African Programme for Onchocerciasis Control [APOC]) recently published an article in  claims:  that thetransmission suppression, at which point the adult Onchocerca volvulus worm population is in demise; (ii) transmission interruption determined by epidemiological and entomological studies of the Simulium vector black flies, at which time MDA may be halted; and lastly (iii) Post Treatment Surveillance (PTS) for 3\u20135\u2009years, after which evaluations must successfully demonstrate lack of recrudescence, at which time transmission elimination may be declared. (3) Decisions to stop MDA and PTS based on these WHO Guidelines require transmission monitoring in children. On this point, it should be recognized that it was the WHO Geneva 2001 guidelines (not OEPA) that stipulated what we agree is a quite challenging 0.1% threshold to measure [O. volvulus 150\u2009bp tandem repeat (O150) in pools of black fly heads (the threshold being <\u20091/2000 infective flies) rather than dissection. Because a laboratory was required for the PCR, in the mid-2000s OEPA successfully operationalized the use of OV16 antibody monitoring by Enzyme Linked Immunosorbant Assay (ELISA) testing of dried blood spots since it could be performed in the same facility. This test is currently known as the \u2018OEPA\u2019 OV16 ELISA [The OEPA programmatic model consists of five basic principles , 3: (1)  measure , 6, 7. T measure \u201310. Both16 ELISA . Under tThis five-step OEPA model had a positive influence in Africa due to two annual meetings that provided a forum for onchocerciasis warriors from six African countries  and six American ones  to exchange information. One of these meetings was the annual InterAmerican Conferences for Onchocerciasis , and the other was the annual Carter Center Program Review (held since 1996). On several occasions African country delegations attended IACO and at least one IACO an APOC Director (Dr. A. Seketeli) gave the keynote address. The Director of OEPA (Dr. M. Sauerbrey) attended at least one meeting of the APOC Technical Consultative Committee (TCC).The fruit of this African-American exchange first became apparent in 2006 when Sudan declared elimination of transmission of onchocerciasis as its goal. In doing so, Sudan embraced the 2001 WHO Geneva Elimination Guidelines and many OEPA principles to reorient its program. The national program independently took the decision to upgrade to OEPA\u2019s twice-per-year treatment strategy and successfully adapted it to the APOC Community Directed Treatment with Ivermectin (CDTI) framework. It expanded MDA to low prevalence (hypoendemic) communities included under OEPA but excluded under the APOC paradigm. A national lab was established at the Ministry of Health, and OEPA OV16 ELISA and O150 PCR were successfully deployed to allow a stop MDA decision in Abu Hamad in 2012 and completion of 3-year PTS . The AbuSimulium neavei foci. The UOEEAC defined guidelines for elimination in S. neavei areas that were ultimately incorporated into the 2016 WHO guidelines. Representatives from onchocerciasis programs in the Democratic Republic of Congo and the Republic of South Sudan regularly attend UOEEAC meetings to discuss establishing SIZs in shared (cross-border) transmission zones with Uganda. Since the Ugandan program launched its elimination policy, approximately 1.9 million ivermectin treatments have been halted in the country. Active transmission now only occurs in two of the original foci. The S. neavei vector has been eliminated from many foci. Six foci have been determined to have met the WHO criteria for elimination by successfully completing the 3-year PTS period; an estimated 1.15 million persons living in these districts are no longer at risk of acquiring onchocerciasis [In 2007, Uganda declared a goal of onchocerciasis transmission elimination from all its 16 active transmission zones (foci) just months after a high-level delegation went to Guatemala for the 2006 IACO. The 2018 publication describing the history of the Uganda program includes in its introduction a section entitled \u2018Inspiration from the Americas\u2019 . The UgaEthiopia is now in its sixth year of executing a national twice-per-year treatment policy to accelerate onchocerciasis transmission elimination. In 2017, at its third meeting, the Ethiopian Onchocerciasis Elimination Expert Advisory Committee (EOEEAC) met with representatives from the Sudan program to review binational PCR and OV16 data \u201318. OverAt its fifth meeting, the Nigeria Onchocerciasis Elimination Committee (NOEC) reviewed results of 2017 OV16/PCR assessments in Plateau and Nasarawa States and determined that the WHO Geneva guidelines for stopping ivermectin MDA had been met . It recoWe conclude by noting that 2018 was the most successful year ever for stopping MDA for onchocerciasis in Africa, and that the OEPA elimination model was important in helping that success. Last year 3.8 million ivermectin treatments for onchocerciasis were halted in Africa, 64% of the cumulative 5.9 million treatments that have been stopped since Sudan\u2019s initial Abu Hamad success in 2012. This is compared with under 1 million treatments stopped by OEPA in the Americas . These eAdditional file 1:Multilingual abstracts in the five official working languages of the United Nations. (PDF 321 kb)"}
+{"text": "Mitogen-Activated Protein Kinase (MAPK) cascades are conserved signaling modules that integrate multiple signaling pathways. One level of control on the activity of MAPKs is through their negative regulators, MAPK phosphatases (MKPs). Therefore, MKPs also play an integrative role for plants responding to diverse environmental stimulus; but the mechanism(s) by which these phosphatases contribute to specific signals remains largely unknown. In this review, we summarize recent advances in characterizing the biological functions of a sub-class of MKPs, dual-specificity phosphatases (DSPs), ranging from controlling plant growth and development to modulating stress adaptation. We also discuss putative regulatory mechanisms of DSP-type MKPs, which plants may use to control the correct level of responses at the right place and time. We highlight insights into potential regulation of cross-talk between different signaling pathways, facilitating the development of strategies for targeting such cross-talk and to help improve plant resistance against adverse environmental conditions without affecting the growth and development. To rapidly adapt to various environmental challenges, plants need to balance diverse signal inputs which involves crosstalk between different signaling pathways. A common strategy for integrating these signals is through use of shared components, including mitogen-activated protein kinase (MAPK) cascades that play essential roles in signal transduction and amplification for many distinct cellular responses. MAPK cascade modules are conserved in all eukaryotes and consist of three kinase components: MAPK kinase kinases (MAPKKKs) phosphorylate dual-specificity MAPK kinases (MAPKKs), which then phosphorylate and activate the terminal MAPKs in a Thr-X-Tyr activation loop  and metal-dependent protein phosphatases (PPMs), which are serine/threonine phosphatases, and tyrosine phosphatases (PTPs) Shi, . RepresePTPs are biochemically distinct protein phosphatases and include tyrosine specific phosphatases and dual-specificity (Ser/Thr and Tyr) phosphatases (DSPs)  phosphatases (DSPs) belong to a subfamily of the tyrosine phosphatases (PTPs) that can dephosphorylate both phosphoserine/phosphothreonine and phosphotyrosine within the activation loop of MAPKs , synthetic auxins and auxin transport inhibitors  and PDR9 genes were characterized, and these two genes encode ABC transporters implicated in the efflux of synthetic auxins  mutants, which display a defect in a microtubule-associated protein  in the putative kinase interaction motif (KIM) of MAPKs such that the mutation might interfere with interactions with the target MAPK(s). Therefore, it has been proposed that PHS1 may regulate multiple MAPKs; and a subset of its target kinases may be involved in the organization of cortical microtubules. To further investigate the mechanism underlying microtubule regulation, a screen for PHS1-interacting MAPKs was performed; and MPK12 and MPK18 were identified by yeast two-hybrid assays  was expressed in the background of phs1-5 to examine if the phosphatase-dead form of PHS1 functions as a dominant-negative microtubule destabilizer  which acts in the apical meristem to induce floral identity genes  treatment, including activation of MPK6 and MPK3, production of reactive oxygen species (ROS), accumulation of a subset of PAMP-regulated transcripts, and inhibition of seedling growth  DC3000 (hereafter referred to as DC3000)  dephosphorylates phospho-MPK3 and phospho-MPK6 ibr5-7 suppresses the chilling-induced defense responses of chs3-1  to stabilize CHS3 protein, thus increasing the accumulation of CHS3 . IBR5 interacts with and promotes the accumulation of SNC1  and DC3000 (avrRps4)  proteins. IBR5 plays a positive role in regulating R protein CHS3, as evidenced by that mutation of mkp1 mutant results in hypersensitivity to various genotoxic stresses , suggesting that MKP1 plays essential roles in genotoxic stress relief -induced nitric oxide (NO) production in guard cells , superoxide anion O2\u2212 and hydrogen peroxide levels in the TMKP1 transgenic seedlings  and downregulation of two ABA-repressed genes  , including hydrogen peroxide (H2O2), hydroxyl radical (HO.), singlet oxygen (1O2) and superoxide anion (mkp2 mutants was more severely inhibited by the oxidative agent methyl-viologen (MV) compared to wild type plants , mkp1 mutants produced more ROS than in wild type plants  are generated from partial reduction of oxygen  treatments , contributing to differences in amplitude and duration of signaling. Many examples have shown that the phosphatase activity of MKPs can be regulated by post-translational modification. Mammalian MKP1s (not an orthologue of plant MKP1s) and yeast Msg5 are phosphorylated by their own substrates MAPKs, and phosphorylation regulates not only the activities but also the abundance of the phosphatases, establishing an efficient negative feedback loop ; and phosphorylation of TMKP1 is required for the interaction , which was mainly localized in cytoplasm, the localization of both MAPKs also changed to the cytoplasm   substrates but decreases phosphatase activity on the phosphotyrosine of myelin basic protein (MBP), suggesting that calmodulin differentially regulates substrate specificity  but not CaMBDII mutant (W678R) can be activated by CaM, which indicates that CaMBDII plays a more important role than CaMBDI for the regulation of MKP1  binding proteins, where CaM is a CaThis review summarizes current knowledge of the roles of MKPs in multiple signaling pathways. MKPs are involved in many aspects of a plant's life cycle, including growth and development as well as the adaption to various biotic and abiotic stresses. As different signaling pathways integrate through MKPs, it is critical for MKPs to undergo precise regulation to generate correct biological outcomes. These investigations of regulatory mechanisms have provided insights into putative mechanisms that might explain how the phosphatases assist in producing specific signals. The potential combinatorial complexity of different transcriptional/post-transcriptional regulations, differential localization affecting subcellular pools of MAPKs, and the possibility to integrate information from other pathways may have profound effects on organizing the amplitude and duration of targeted kinases.As important as the MKPs appear to be, most of our knowledge regarding their functions is limited to their roles in negatively regulating MAPK signaling, and few other potential upstream and/or downstream targets have yet to be characterized. Genome-wide analyses will certainly facilitate a better understanding of MKPs-mediated signaling pathways by identification of both molecular players in the pathways as well as additional putative MKP targets. A better understanding of how plants coordinate and balance different signaling pathways in response to diverse environmental stimuli could lead to more rationally designed strategies for improving crop yield under changing environmental conditions. Promising results such as the deletion of MKP1 resulting in enhanced resistance to various biotic and abiotic stresses without compromising plant growth (Ulm et al., LJ and SP conceived the main subject of this review and wrote the manuscript. YC and LL provided the suggestions and revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Sleep is important for memory consolidation, hence the disruption of normal sleep patterns as a result of age-related changes in the circadian system could be one of the contributors to memory impairment among older adults. It is now well-established that light is the main environmental element that synchronizes circadian rhythms. An appropriate lighting condition can be considered as a non-pharmacological solution to improve the sleep quality of individuals and consequently their overall health and well-being. The present study investigates the effectiveness of two proposed whole-day lighting interventions (L1 and L2) applied by Tunable White Lighting Technology (TWLT) on sleep quality and cognitive performance in older adults. Both lighting interventions provide a high illuminance level (500 lux) in the morning and then the illumination is dimmed gradually throughout the day and reached 100 lux in the evening. However, while L1 offers a constant Correlated Color Temperature (CCT) of 2700K, during the L2 intervention, the CCT is changing in the range of 6500K \u2013 2700K from morning towards evening. Fifteen healthy older adults  participated in a 41-day counterbalanced crossover study. Participants were exposed to each lighting condition for 9 days. Actigraphy, standard questionnaires (PROMIS and PSQI), and tests (Trail Making Test (TMT) A & B and Digit Symbol Substitution Test (DSST)) were employed to measure sleep quality and cognitive performance before, during, and after lighting interventions. Significant improvements in sleep quality and cognitive performance were found for both lighting interventions with better outcomes for L2."}
+{"text": "Plant is endowed with sessile habit and nutrient acquisition mainly through the root organ, which also provides an excellent model to study stem cell fate and asymmetric division due to well-organized cell layers and relatively simple cell types in root meristem. Besides genetic material DNA wrapped around histone octamer, chromatin structure determined by chromatin modification including DNA methylation, histone modification and chromatin remodeling also contributes greatly to the regulation of gene expression. In this review, we summarize the current progresses on the molecular mechanisms of chromatin modification in regulating root development. The root system constitutes the underground world of a plant, and it takes charge of nutrient and water supply for the whole plant under normal and stress environments. The developmental status of the root system directly determines the plant survival and performance of leaves, stems, flowers, fruits, and seeds, which are closely related to animal and human life. Compared with the aerial part, the building unit of a root system is simple and mainly consists of primary and lateral roots (LRs) without substantial difference in appearance. An intact root system is derived from the tiny root apical meristem (RAM). Proliferation and differentiation of RAM give rise to different types of root cells and tissues.Transcription factors combined with phytohormones, small signaling molecules, and miRNAs play an essential role in regulating the stem cell fate and RAM maintenance during root development . For instance, active marker histone acetylation and repressive marker histone deacetylation are catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively  homologs , three Su(z)12 homologs , a single ESC homolog (FIE), and five p55 homologs (MSI1\u2013MSI5). PRC1 core subunits consist of two RING1 homologs (AtRING1a/b), three Psc homologs (AtBMI1a/b/c), a Pc equivalent (LHP1), and a plant-specific component EMF1, without the Ph counterpart  proteins associated with repressive genes and the trithorax group (TrxG) proteins associated with active genes  and atrichoblast/non-hair cell (N) in an alternative arrangement, providing a well-characterized system for studying the relationship between root epidermal cell fate decision and positional cue from underlying cortical cells /IAA14 (mIAA14) protein with enhanced inhibiting capacity on the downstream targets ARF7/19 , which is a core component of several HDAC corepressor complexes , resulting in formation of decreased CDF4 protein gradient from differentiated columella, CSCs to QC, which is opposite to the WOX5 protein gradient and permits the exit of stem cell descendants from the stem cell state  in roots  family ; it downregulates auxin maxima in roots, thereby inhibiting the establishment of founder cells during LR initiation  display a certain proportion of \u201cpkl-root\u201d phenotype , FUSCA3 (FUS3), LEAFY COTYLEDON2 (LEC2), and LEAFY COTYLEDON1 (LEC1)  and H3K4me3 through the CW domain or PHD domain and H3K27me3 through the PHD domain  and reduction in levels of gene repression mark H3K27me3 in seedling  and cysteine and tryptophan residue-containing domain (CW), which usually act as histone code reader modules, and the ethylene-responsive element binding factor-associated amphiphilic repression (EAR) domain that functions as a repressive motif to recruit corepressors  but is enhanced by GA biosynthesis inhibitor paclobutrazol  can recognize the active mark H3K4me3 through the PHD-domain and interact with the RAWUL domain of PRC1 RING-finger proteins through the PAL domain  and many additional types  pathway by directly targeting the chromatin of several PIN genes  and affecting auxin distribution. PLT2 overexpression can partially rescue a brm SCN defect  in distinct plants will deepen our understanding of root function and phylogenesis. Root developmental progresses is closely associated with stem cell fate transition during RAM differentiation, where the dynamic change and action mechanism of epigenetic marks in specific cell lineage need to be addressed.clf mutant with curly leaf, early flowering and homeotic conversion of floral organ /Cas (CRISPR-associated) system provides an extremely powerful and labor-saving tool for targeted gene editing. This tool can be used to target several genes simultaneously for fast and efficient generation of high-order mutants (Cong et al., D-HC and YH wrote the manuscript. CJ collected the raw materials. J-PS provided important suggestions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Family members and friends are the main providers of care for persons living with dementia. However, dementia caregivers are at greater risk than other caregivers of experiencing negative caregiving consequences. Despite the development of evidence-based programs to support dementia caregivers, few health or social service organizations offer any of these programs due, in part, to a lack of knowledge about their availability. Best Practice Caregiving is a newly launched website where professionals can get detailed information about these programs. Data collected to develop Best Practice Caregiving are analyzed for a sample of 42 evidence-based dementia caregiving programs to describe similarities and differences among programs including gaps in assistance available from these programs. Results show 64% of programs are delivered to caregivers only while the remaining are delivered to the caregiver and/or persons with dementia. Nearly half (43%) of the 42 programs are delivered in-person, 38% by phone, with 17% delivered all or in part online. Most programs are delivered by professionals (86%) followed by trained lay leaders (40%) and self-guided (12%). Most programs (95%) provide assistance with coping with illness/caregiving and the relationship of the dyad. Fewer than half of the programs assist caregivers with issues regarding finances (45%), end-of-life care (43%), and medical care (40%). Data from 233 delivery organizations show the most common challenge was getting caregivers to accept and complete the program (86%). Delivery sites reported more success with funding the program  than with marketing and recruiting participants (mean=6.7)."}
+{"text": "Type 2 diabetes mellitus (T2DM) and Heart Failure (HF) are two complex multifactorial diseases that can coexist and strongly amplify each other, suggesting overlapping mechanisms contributing to disease state. T2DM patients with HF have a higher risk of mortality and hospitalization for HF than HF patients without T2DM. Therefore, there is an increasing necessity to find new diagnostic instruments and treatments to improve clinical outcomes in T2DM subjects with HF , current research demonstrate many additional important and possibly beneficial direct effects of these drugs on endothelial cells and cardiomyocytes. SGLT2 inhibitors can normalize elevated sodium and calcium levels in cardiomyocytes through inhibition of the cardiac sodium-hydrogen exchanger, improve vascular function and activate anti-oxidant systems and intracellular stress signals such as AMPK and reduce inflammatory pathways. Further research will have to demonstrate to what extent these cellular cardiac mechanisms contribute to the large beneficial effects of SGLT2i's in clinical trials. Despa then goes on to describe that sodium is often increased in the failing and diabetic cardiac cell. Elevated intracellular sodium can then cause oxidative stress and augments the sarcoplasmic reticulum Ca2+ leak, thus amplifying the risk for arrhythmias and promoting heart dysfunction. Alterations in Na+ extrusion and/or Na+ uptake that underlie the [Na+]i increase in heart failure and diabetes are discussed, and emphasis is placed on the emerging role of Na+ -glucose cotransporters in the diabetic heart. Doliba et al. subsequently demonstrate the functional and energetics consequences of elevated sodium in the diabetic cardiomyocyte in their pioneering studies in this field. Their work clearly indicates that raising sodium in the cardiac cell will directly result in impaired mitochondrial function, possibly explaining the often observed energetic problems in the diabetic heart. These reviews all point to the importance of ionic homeostasis and disturbances in the setting of diabetic cardiomyopathy, cardiac arrhythmias, and the elevated incidence of heart failure in T2DM patients.Liu et al. evaluated the clinical effects of Black garlic in patients with ischemic heart failure. They found that black garlic treatment improved cardiac function in terms of left ventricular ejection fraction and the scores of quality of life (QOL) and decreased circulating BNP precursor N-terminal (Nt-proBNP) by increasing antioxidant levels.The article by Koyani et al. studied the effects of saxagliptin and sitagliptin (anti-hyperglycemic drugs that have been shown to inhibit dipeptidyl peptidase 4 -DPP4) in mouse ventricular cardiomyocytes. The authors showed that saxagliptin (but not sitagliptin) impaired Ca2+ transient relaxation and prolonged action potential duration in cardiomyocytes. They suggested that these results are linked to saxagliptin-DPP9 interaction and following impairment in Ca2+/calmodulin- dependent protein kinase II (CaMKII)- phospholamban (PLB) and protein kinase C (PKC) signaling.Trotta et al. investigated the anti-hypertrophic effect of the melanocortin receptor 5 (MC5R) stimulation in cardiomyocytes exposed to high glucose. The authors showed that MC5R agonists increased viability and reduced total protein in cell stimulated with high glucose via reduced GLUT1/GLUT4 ratio at the plasma membrane and increased intracellular phosphoinositide 3-kinase (PI3K) activity. In addition, MC5R stimulation showed beneficial effects on cardiac function and hypertrophy paralleled by significantly reduced blood glucose levels in a rat model of diabetes (streptozotocin-induced).We have arrived at exciting times in the world of diabetes and heart failure. At last, several novel antidiabetic drugs have shown large cardiovascular benefits in T2DM patients. Understanding the causal mechanism of these effects are now crucial in order to further our understanding of the interaction between diabetes and heart failure, possibly also offering new therapeutic strategies to combat heart failure in the absence of diabetes.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This study is a secondary analysis of the Outcome and Assessment Information Set (OASIS) and administrative billing records of 6,153 adults \u2265 65 years old who received home health (HH) from a not-for-profit HH agency in upstate New York in CY 2017. We evaluated the association between the use of home health services (HH) with the hazard of unplanned facility admissions among Medicare patients with and without Alzheimer\u2019s disease and related dementia (ADRD). Outcome was time from HH start of care to an unplanned facility admission of any type, including the hospital, nursing home, or rehabilitation facility. Independent variables included weekly intensity  of each discipline, including skilled nursing (SN), physical therapy (PT), occupational therapy (OT), social work (SW), and home health aide (HA), separately. ADRD was identified by diagnosis (ICD-10 codes) and cognitive impairment . In multivariable Cox Proportional hazard models that adjusted for time-varying effects of HH intensity, receiving the highest intensity of SN (3.3 visits of 2.78 hours per week) and PT (2.5 visits of 2 hours per week) was related to up to a 54% and 86% decrease, respectively, in the hazard of unplanned facility admission among patients with ADRD , and decreases of 56% and 90% respectively among patients without ADRD . This is the first study in the United States showing that receiving a sufficient amount and appropriate mix of HH services was associated with substantially reduced risk of unplanned facility admission among patients with ADRD by up to 86%."}
+{"text": "The oomycete-specific ITS primers published by Oomycetes, which probably results in a lower proportion of this group in metabarcoding studies. We hereby provide the updated figure (Figure Closer examination revealed that the sequence of primer ITS1oo in Figure PageBreak"}
+{"text": "Therapeutic strategies to restore hearing and balance in mouse models of inner ear disease aim to rescue sensory function by gene replacement, augmentation, knock down or knock out. Modalities to achieve therapeutic effects have utilized virus-mediated transfer of wild type genes and small interfering ribonucleic acids; systemic and focal administration of antisense oligonucleotides (ASO) and designer small molecules; and lipid-mediated transfer of Cas 9 ribonucleoprotein (RNP) complexes. This work has established that gene or drug administration to the structurally and functionally immature, early neonatal mouse inner ear prior to hearing onset is a prerequisite for the most robust therapeutic responses. These observations may have significant implications for translating mouse inner ear gene therapies to patients. The human fetus hears by gestational week 19, suggesting that a corollary window of therapeutic efficacy closes early in the second trimester of pregnancy. We hypothesize that fetal therapeutics deployed prior to hearing onset may be the most effective approach to preemptively manage genetic mutations that cause deafness and vestibular dysfunction. We assert that gene therapy studies in higher vertebrate model systems with fetal hearing onset and a comparable acoustic range and sensitivity to that of humans are an essential step to safely and effectively translate murine gene therapies to the clinic. Gene replacement, augmentation, knock down and knock out strategies have been elucidated to ameliorate the effects of deleterious mutations that cause hearing loss and vestibular dysfunction in mouse models of human inner ear disease. Table Vglut3 knockout mouse after round window membrane inoculation at postnatal day 1\u20133 , compound action potentials (CAP) and acoustic startle -mediated gene transfer to the sensory epithelium by delivery through the round window membrane  introduces a cryptic splice site in exon 3 of the PDZ  domain scaffolding protein, harmonin and generates a frameshift with premature stop codon. The splicing machinery strongly prefers the cryptic splice site though wild type splicing is not precluded. The Ush1c c.G216A knock-in mouse accurately models the hearing and vestibular abnormalities seen in USH1C patients  to interfere with pre-mRNA splicing from the cryptic splice site and enhance wild type splicing. ASO therapy restored functionally relevant levels of protein expression, improved hair cell survival, rescued ABR thresholds at low and intermediate frequencies, and corrected vestibular dysfunction . The French-Acadian mutation  of the transmembrane channel-like 1 (TMC1) gene is dominantly inherited and causes progressive hearing loss in mice  from 8 kHz to 22.6 kHz  thresholds, a sensitive measure of outer hair cell function  protein joins SANS cause Usher syndrome type 1G (Ush1g) characterized by congenital profound sensorineural hearing loss and vestibular dysfunction at birth with onset of retinitis pigmentosa by adolescence -GFP at P2.5 improved stereociliary bundle morphology in auditory and vestibular hair cells. In addition, Sans rescued mechanoelectrical transduction currents in inner and outer hair cells, modestly improved ABR thresholds from 5 kHz to 15 kHz, and completely restored vestibular function measured by circling behavior and vestibulo-ocular reflex (VOR) testing  designed against the Beethoven allele was delivered by lipid-mediated transfer to the mouse inner ear at P0\u2013P2 -GFP mouse cochlea at 6 weeks of age to test the efficiency of inner ear genome editing in adult hair cells. Encouragingly, GFP expression was perturbed in 25% of the adult, Atoh1-GFP hair cells /Cas9 nuclease genome editing system further validates the early neonatal window of efficacy while offering potential for adult inner ear genetic modulation. The The literature discussed thus far demonstrates that AAV-, ASO- and CRISPR/Cas9 RNP-based therapies achieve maximal benefit for recessively and dominantly inherited forms of deafness and vestibular dysfunction when initiated from P0\u2013P5. Furthermore, initiating therapeutic strategies after P5 shows reduced efficacy or the elimination of therapeutic benefit entirely Table . The thoClarin 1 is expressed in inner and outer hair cells as well as spiral ganglion neurons in the mouse cochlea  mouse under the control of the Atoh1 3\u2019 enhancer/\u03b2-globin basal promoter sequence  family are potent transcriptional repressors of Atoh1 expression preventing hair cell fate commitment  is one of four connexins expressed in the inner ear that link all supporting cells with adjacent epithelial cells but not hair cells  and the auditory sensory epithelium degrades at P18  and the EP was significantly improved (n = 5 mutant mice). An alternative model system was developed due to the difficulty in obtaining sufficient numbers of mutant mice for extensive analysis. A plasmid encoding four short hairpin RNAs (shRNAs) against Cx-30 was electroporated into wild type mice at E11.5 that knocked down Cx-30, elevated ABR thresholds to over 90 dB SPL from 4 KHz to 20 KHz, and depleted the EP. Co-electroporation of a shRNA-resistant sequence encoding Cx-30 along with the shRNAs against wild type Cx-30 in wild type mice resulted in improved ABR thresholds and EP  is a nuclear-localized, long noncoding RNA robustly expressed in a diverse array of tissues that is nonessential for mouse pre- and postnatal development (Zhang et al., MALAT1 RNA effectively reduced expression in most mouse tissues analyzed (Wheeler et al., MALAT1 ASO into the E13-E13.5 mouse amniotic cavity reduced MALAT1 RNA abundance in the inner ear through P15 establishing that the ASO gains entry into embryonic tissues and exerts its bioactive effects through the second postnatal week (Depreux et al., Ush1c mutant mice generated correctly spliced harmonin RNA in the inner ear at P22 (Depreux et al., While direct injection of bioactive reagents into the developing inner ear is formally a plausible gene therapy strategy, it is unlikely that targeted injections will be conducted into the human otic vesicle which first forms by GA 6 not long after most pregnancies are first verified (Streeter, The therapeutic modulation of inner ear gene expression by systemic and focal injections of bioactive reagents has defined authentic gene therapy strategies in mouse models of hearing loss and vestibular dysfunction. The literature establishes that therapeutic intervention in the functionally immature mouse inner ear by 5 days postnatal age leads to optimal recovery of hearing and balance. This early neonatal window of therapeutic efficacy holds irrespective of the molecular strategy, delivery modality, or viral vector serotype deployed. Moreover, a corollary prenatal window of therapeutic efficacy in humans is predicted to close by 19 weeks of GA before the onset of fetal hearing. The efficacy of fetal gene therapy to preemptively correct deleterious genetic mutations in the organogenesis stage mouse embryo before the onset of inner ear disease is an emerging research focus that has promising potential. The process of defining and validating fetal and postnatal gene therapies will be critically enhanced by rigorous evaluation in higher vertebrate model systems in which the fetal onset of hearing is a defining feature.LW, JK and JB identified the need for a comprehensive review of the literature on gene therapy to treat inner ear disease. LW, JK and JB compiled the necessary literature and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Kweni, Cengkir, Palmer and Kent). Near infrared spectral data were collected and recorded as absorbance (Log(1/R)) data in wavelength range of 1000\u20132500 nm. Those spectral data are potential to be re-used and analysed for the prediction of mango quality attributes in form of vitamin C, soluble solids content (SSC) and total acidity (TA). Spectra data can be corrected and enhanced using several algorithms such as multiplicative scatter correction (MSC) and de-trending (DT). Prediction models can be established using common regression approach like partial least square regression (PLSR).Presented dataset contains spectral data on near infrared region for a total of 186 intact mango fruit samples from 4 different cultivars ( Spectra/R in wavSpectra data set were then used to establish prediction model for the determination of inner quality attributes on intact mangos using regression approach. One of the most promising and common regression method in NIRS practices is partial least square regression (PLSR) . This me22.1The NIR instrument used to obtain spectral data is Fourier transform near infrared (FT-NIR) (Thermo Nicolet Antaris II TM). It was configured and controlled under integrated software Thermo Integration\u00ae and Thermo Operation\u00ae. The workflow has been developed and set up to run specified tasks for spectra data acquisition of intact mango samples. High resolution measurement with integrating sphere was chosen as a basic measurement ..spa) and comma separated value (.csv). Standard laboratory method also prepared for inner quality attributes measurements of mango as vitamin C, soluble solids content (SSC) and total acidity (TA). Hand held refractometer  was used for SSC, automatic titrator equipment  for TA and standard manual titration method for vitamin C measurement respectively. The centrifuge was also used to obtain clarified sample juice and separate suspended solids.Sample naming and labelling was required automatically for each spectra acquisition in order to distinct all 186 mango samples. Background spectra correction was carried out every hour automatically. Spectra data were recorded in form of absorbance (Log(1/R)) in wavelength range from 1000 to 2500 nm and saved in two different file extension formats: Nicolet  [Once after spectra data acquisitions are completed, fruit samples were directly sliced and some part of mango pulp were taken. To measure vitamin C, a total 5g of mango pulp samples were macerated, mixed and homogenized with addition of 20 ml of meta-phosphoric acid into a beaker to prevent oxidation. Distilled water were added until 50 ml of volume was reached. Vitamin C was obtained and quantified based on its reaction with the ass (FM) .oBrix while automatic titration method with 0.1 N NaOH to an end point of pH 8.1 was used to measure TA of intact mango and expressed as mg\u2219100g\u22121 fresh mass [On the other hand, SSC and TA quality attributes were measured by making another juices from 20 g of pulp sample and maximum of 100 ml distilled water. A little filtered juice was squeezed and dropped into a hand-held refractometer to record SSC in form of esh mass ,6. Descr2.4The Unscrambler X 10.1 software  with network client license.It is highly recommended to perform spectra correction and enhancement prior to prediction model development. There are several methods and approaches that can be used to enhance spectra data, among of them are Multiplicative scatter correction (MSC) and de-trending (DT). Spectra enhancements were used to correct additive and multiplicative effects in the spectra. The MSC and DT spectra corrections were carried out using 2.5The main part of NIRS application is to develop models used to predict desired quality attributes of intact mango simultaneously. Prediction models were constructed to reveal information about mango quality attributes buried in absorbance spectra data. These models were developed commonly by regressing spectra data (as X variable) and actual measured quality attributes (as Y variable) through multivariate analysis. Partial least squares regression (PLSR) was applied to develop those models and validated using full cross validation approach.2) between predicted and measured quality attributes, prediction error which is defined as the root mean square error (RMSE) and the residual predictive deviation (RPD), defined as the ratio between standard deviation (SD) of the population's actual value of Vitamin C, SSC and TA, and the RMSE of predicted quality attributes. The higher value of RPD, the greater probability of models to predict desired quality parameters or chemical constituent of samples dataset accurately [The prediction performances were evaluated by means of these following statistical parameters: the coefficient of correlation (r) and determination (Rcurately ."}
+{"text": "Two multimetric indices have been developed to help address fish community (reservoir fish assemblage index [RFAI]) and individual population quality (sport fishing index [SFI]) in Tennessee River reservoirs. The RFAI, with characteristics similar to the index of biotic integrity (IBI) used in stream fish community determinations, was developed to monitor the existing condition of resident fish communities. The index, which incorporates standardized electrofishing of littoral areas and experimental gill netting for limnetic bottom-dwelling species, has been used to determine residential fish community response to various anthropogenic impacts in southeastern reservoirs.The SFI is a multimetric index designed to address the quality of the fishery for individual resident sport fish species in a particular lake or reservoir[4]. The SFI incorporates measures of fish population aspects and angler catch and pressure estimates. This paper proposes 70% of the maximum RFAI score and 10% above the average SFI score for individual species as \u201cscreening\u201d endpoints for balanced indigenous populations (BIP) or adverse environmental impact (AEI). Endpoints for these indices indicate: (1) communities/populations are obviously balanced indigenous populations (BIP) indicating no adverse environmental impact (AEI), or are \u201cscreened out\u201d; (2) communities/populations are considered to be potentially impacted; and (3) where the resident fish community/population should be considered adversely impacted. Suggestions are also made concerning how examination of individual metric scores can help determine the source or cause of the impact."}
+{"text": "To assess the link between the risks of most frequent cancer sites in Poland and selected socioeconomic variables that potentially affect health outcomes throughout the life course.p\u00a0<\u00a00.05 (two-tailed tests).This is a cross-sectional ecological study. Incidence of lung, breast, and colon cancer by voivodeships in 2014 was calculated based on Polish National Cancer Registry. Socioeconomic variables in individual voivodeships were assessed based on Polish Social Cohesion Survey for 2015. Spearman\u2019s rank correlation coefficient was used to test the association of incidence rates and socioeconomic variables. The significance level was set at Statistically significant negative correlation exists between: (1) friend-/neighbour-based social capital and colon and breast cancer, (2) association-based social capital and lung cancer, (3) high religiousness and lung and breast cancer, and (4) income poverty and breast cancer. Statistically significant positive correlation exists between: (1) social isolation, living conditions poverty, poverty resulting from the lack of budget balance, and lung cancer; (2) low/no involvement in religious activity and lung and breast cancer.Our findings support public health concerns over the implication of socioeconomic environment for cancer. Cancer is one of the major contributors to health burden worldwide. In 2012 14.1 million new cases and 8.2 million deaths were reported. Lung, breast and colorectal were the most frequently diagnosed cancers  have rarely been analysed. Only one study, performed in the Opole province, found statistically significant positive correlation between unemployment rate and lung cancer incidence rates among male population  is conceptualized as an area-level attribute. Socioeconomic determinants are conceptualized as a group attribute that affects all individuals living within the community and the interest is drawing inferences regarding differences between areas.http://onkologia.org. Data storage enables analysis of cancer incidence and mortality by type of cancer (classified according to ICD-10), age, sex and voivodeship, as well as creating custom reports. The average completeness of the Cancer Registry in Poland has been continuously improving and is currently estimated to be 94% .The cancer risk in each of 16 Polish voivodeships was calculated as incidence rates and expressed as the number of newly registered cases of cancer in 2014 per a population of 100,000. The absolute numbers of newly registered cases of lung, breast and colon cancer in Poland by voivodeships were retrieved from the Polish National Cancer Registry (NCR). NCR is a principal data source for cancer incidence in the Polish population. Healthcare providers are legally obliged to provide annual reports to NCR about every case of cancer diagnosed within the Polish population. Principles of data collecting and institutions responsible for cancer registries in Poland are specified in two acts: the Act on Public Statistics and the Act on the Health Care Information System and an ordinance issued on the basis of the said Act. The unit responsible for the registry is the National Cancer Registration Office, which is an organizational unit of the Cancer Centre and Institute of Oncology. New cases of cancer are collected via specific cancer registration forms (MZ/N-1a form) and each voivodeship is obliged to deliver the data to a shared NCR database. The data is validated using rules enforced to the system. An online database is available at Area-based socioeconomic measurements were retrieved from the Polish Social Cohesion Survey for the year 2015 . The effect of potential confounders such as sex, age and completeness of cancer registration distribution across regions was accounted for by Spearman\u2019s partial rank correlation. The basis for the evaluation of the completeness of cancer registration in particular voivodeships was the ratio of mortality to incidence (M/I\u2013Index) calculated for each cancer site in the same period of time  was used to examine the link between incidence rates of particular types of cancer and socioeconomic determinants. A significance level of The ranking of voivodeships according to incidence rates of particular cancers differs considerably Table\u00a0. The higSocial isolation, social capital, religious activity and poverty in individual voivodeships is presented in Table\u00a0Voivodeships showed wide disparities in social capital levels. The lowest ratio for high degree of association-based social capital was recorded in Pomeranian, Swietokrzyskie (16%), Lodz (14%) and Warmian-Masurian (13%), whereas the highest in Podlaskie (31%), Opole (25%) and Lublin (24%). The share of persons with high level of familial capital was lowest in West Pomeranian (19%) and highest in Swietokrzyskie (34%), Opole (31%), Lesser Poland (31%), Subcarpathian (31%), Lublin (31%). The lowest value for the indicator for high level of friends- and neighbours-based social occurred in Kuyavian-Pomeranian (21%), Lodz and Lower Silesian (23%), the highest in Lesser Poland (34%), Subcarpathian (33%) and Swietokrzyskie (32%).The attitude to faith varied from one voivodeship to another. Percentage of people who declared to be \u201cprofound believers\u201d was highest in Opole (16%), Subcarpathian (15%), Podlaskie (15), Lublin (14%), and lowest\u2014in Lubusz (6%), Lodz (7%), Kuyavian-Pomeranian (7%), and West-Pomeranian (7%). In 7 voivodeships the percentage of religiously uncommitted and nonclerical people is lower than the mean for entire Poland (39%), voivodeships with the topmost percentage of religiously uncommitted inhabitants are West Pomeranian (56%), Warmian-Masurian (54%) and Lubusz (50%).Income poverty affects inhabitants of Lublin (27%), Swietokrzyskie (24%) and Subcarpathian (21%) more often, whereas those residing in the southwest part of Poland are at a lower risk: Silesian (7%), Lubusz, Opole, Lower Silesian (11%). The same value (11%) was observed in the Mazovian voivodeship as well. Voivodeship proved to have a different impact on the risk of living conditions poverty than on income poverty. The highest rates of living conditions poverty were recorded in Warmian-Masurian (12%), West Pomeranian (12%), \u015awi\u0119tokrzyskie (11%) and \u0141\u00f3d\u017a (11%), and the lowest in Podlaskie (5%), Greater Poland (6%) and Silesian (7%). Poverty in terms of lack of budget balance more often affects the West Pomeranian households (18%). Other voivodeships with high shares of households experiencing difficulties with balancing their budgets included Lubusz (15%), Lodz (15%), Pomeranian (14%) and Warmian-Masurian (14%). The lowest values were reported in Subcarpathian (6%) and Podlaskie (7%).p\u00a0=\u00a00.007), (2) two types of poverty: living conditions poverty  and poverty following a lack of budget balance , and (3) low/no involvement in religious activity . A statistically significantly strong negative correlation was found between risk of lung cancer and: (1) high level of association-based social capital , and (2) high religiousness . After age and sex adjustment the Spearman\u2019s correlation coefficients remained similar, with the exception of correlation with association-based social capital which was stronger after correcting for sex . Adjustment for completeness of cancer registry strengthened the positive association between lung cancer incidence and low/no involvement in religious activity , and made the negative associations between lung cancer incidence, family based social capital and friend- and neighbour-based social capital stronger and statistically significant . After adjustment for completeness of cancer registry the correlations between lung cancer incidence, living conditions poverty and association-based social capital were no longer statistically relevant.The relevance and magnitude of associations between cancer risk and socioeconomic variables varies greatly by cancer site Table\u00a0. Spearmap\u00a0=\u00a00.04), (2) high level of friend- and neighbour-based social capital , and (3) high religiousness , and positively related to low/no involvement in religious activity . After sex, age and completeness of data adjustment the correlations between breast cancer incidence and socioeconomic variables were not substantially modified, only correlation with income poverty became statistically insignificant.The risk of breast cancer was statistically significantly negatively related to: (1) income poverty . Adjustment for age, sex and data completeness produced fairly similar coefficients.The only statistically relevant for colon cancer was a negative correlation between colon cancer risk and high level of friend- and neighbour-based social capital  imply that a low income situation (determined by revenue) does not necessarily signify other poverty forms. Time factor is, therefore, extremely important, because poor living conditions and budget difficulties result from unfavourable income situation continuing for a longer period. The strong relationship with material situation  observed for association-based capital and social isolation suggests a coexistence of these factors. All of these determinants were correlated with lung cancer risk. However, the question whether poverty caused social isolation and low level of association-based social capital, or if, conversely, social isolation and low level of association-based capital caused poverty, is still to be answered.These results should be interpreted in light of relationships that may exist between the socioeconomic variables selected to the analysis. Theoretically these determinants have different meaning, but there are correlations between them, except for relationships between income poverty and other socioeconomic determinants, various forms of social capital, as well as social isolation and informal social capital . Lack of correlation between income poverty and other poverty forms and strong correlation between living conditions poverty and poverty following a lack of budget balance  is well known and repeatedly discussed  and influencing health care accessibility, use of cancer screening programmes and effective treatments. National policy actions which can have an important effect on the magnitude of social inequalities in cancer incidence might significantly reduce the burden and disparities in various populations and geographic areas. Our study showed that the relevance and magnitude of associations between socioeconomic variables and cancer risk vary greatly by cancer site. It provides important additional information about how socioeconomic mechanisms work. Social and economic inequalities can be avoided; therefore their limitation constitutes an achievable goal and an ethical imperative."}
+{"text": "Overall growth and development of a plant is regulated by complex interactions among various hormones, which is critical at different developmental stages. Some of the key aspects of plant growth include seed development, germination and plant survival under unfavorable conditions. Two of the key phytohormones regulating the associated physiological processes are gibberellins (GA) and abscisic acid (ABA). GAs participate in numerous developmental processes, including, seed development and seed germination, seedling growth, root proliferation, determination of leaf size and shape, flower induction and development, pollination and fruit expansion. Despite the association with abiotic stresses, ABA is essential for normal plant growth and development. It plays a critical role in different abiotic stresses by regulating various downstream ABA-dependent stress responses. Plants maintain a balance between GA and ABA levels constantly throughout the developmental processes at different tissues and organs, including under unfavorable environmental or physiological conditions. Here, we will review the literature on how GA and ABA control different stages of plant development, with focus on seed germination and selected abiotic stresses. The possible crosstalk of ABA and GA in specific events of the above processes will also be discussed, with emphasis on downstream stress signaling components, kinases and transcription factors (TFs). The importance of several key ABA and GA signaling intermediates will be illustrated. The knowledge gained from such studies will also help to establish a solid foundation to develop future crop improvement strategies. Overall growth and different developmental stages of plants are under strict regulation by several classes of plant hormones. Hormone molecules are present at low concentrations in plants, and they function either at the sites of synthesis or after they are transported to different tissues  of crop plants  enzyme  and abscisic aldehyde oxidase (AAO), respectively  and AAO3 (AAO3/ABA3/LOS5) were upregulated in Arabidopsis. Furthermore, transcript levels of NCED3, ABA3/LOS5, and AAO3 were induced by abiotic stresses  catalyze the deactivation reaction resulting in phaseic acid (PA) and dihydro phaseic acid (DPA) as the main ABA catabolites  and in turn regulate transcription of several downstream ABA-responsive genes  infection in rice by Teijiro Yabuta and co-workers  was the result of an investigation of fungal  from the precursor compound geranylgeranyl diphosphate (GGDP), which is aided by terpene synthases (TPSs), cytochrome P450 monooxygenases (P450s), and 2-oxoglutarate\u2013dependent dioxygenases (2ODDs)  and ent-kaurene synthase (KS), which are located in the plastids are responsible for the first few steps of GA biosynthesis (conversion of GGDP to ent-kaurene). Then two P450 enzymes, namely, ent-kaurene oxidase (KO) and ent-kaurenoic acid oxidase (KAO) convert ent-kaurene to GA12. Finally, three active GAs are formed by reactions catalyzed by GA 20-oxidase (GA20ox) and GA 3-oxidase (GA3ox), that belong to 2ODDs  showed drought tolerance phenotype and overexpression of GA20ox confers drought sensitivity in Arabidopsis  genes and growth arrest by activating a basic leucine zipper transcription factor, ABSCISIC ACID INSENSITIVE 5 (ABI5)  and activates a GA catabolic gene (GA2ox2) indirectly  and represses an ABA catabolic gene (CYP707A2)  which acts downstream to PIL5, leads to repression of GA biosynthesis and activation of ABI3 and ABI5  which leads to increased dormancy   and hence increases the ABA level whereas it decreases the GA level by repressing GA biosynthesis genes in Arabidopsis seeds  lead to changes in the plant response and therefore alter the balance of endogenous levels of GA and ABA. High temperature induces ABA biosynthesis genes   module , which results in stabilization of the receptor. Conversely, opposite effect has been shown by GA by inhibiting rice SnRK2  has a link between GA and ABA signaling in rice via SnRK2-APC/CCYP707A1 and CYP707A2)  -domain containing transcription factors (ATFs), Arabidopsis ABA-INSENSITIVE 4 (ABI4) and rice OsAP2-39, have key roles in the antagonistic crosstalk between ABA and GA. ABI4 positively regulates primary seed dormancy by downregulating GA biosynthesis and by inhibiting ABA catabolic genes  and indirectly repressing GA biosynthesis genes (GA3ox1 and GA20ox1) , B3 domain factors LEC2, and FUSCA3 (FUS3)  and modulating expression of GA metabolic genes   as well as signaling cascades that regulate downstream target genes (of different classes) further add to the complexity of the already elaborate cellular communication network. This has been highlighted here with the examples of ABA and GA metabolism and their regulation. Selected genes that play significant roles in the regulation of seed dormancy and germination and various abiotic stresses were also discussed. It is evident that several positive and negative regulators of ABA and GA have direct or indirect impacts on germination and abiotic stresses. Many transcription factors and signaling components of these two phytohormones help to maintain an intricate balance between endogenous levels of bioactive ABA and GA. Furthermore, studies have identified several ABA and GA crosstalk points showing positive and negative regulation of different molecular modules associated with their metabolism and signaling. There are a few open questions that can help in formulating the future research directions. Despite the fact that there are some studies on ABA transport in different cell types and tissues, there might be many unknown pathways/transporters that are yet to be explored. Moreover, very few reports on the transport mechanism of GA are available. The antagonistic roles of GA and ABA in controlling developmental processes have been established by several pieces of evidence; however, there could be synergistic crosstalk between GA and ABA in some instances whose underlying molecular mechanisms remain undiscovered. Although several target genes of a few TFs have been established  (Yaish et al., BV and PK conceived the idea and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Escherichia coli (aEPEC) has been increasing worldwide. Here, we report the draft whole-genome sequences of 10 aEPEC strains isolated in Brazil.The number of diarrhea cases caused by atypical enteropathogenic  Escherichia coli (aEPEC) has been increasing worldwide. Here, we report the draft whole-genome sequences of 10 aEPEC strains isolated in Brazil. These sequences will provide an important source for future studies concerning aEPEC pathogenicity and genetic markers of potentially virulent strains.The number of diarrhea cases caused by atypical enteropathogenic  Escherichia coli (EPEC), which is one of the diarrheagenic E. coli pathotypes. EPEC is subdivided into typical EPEC (tEPEC) and atypical EPEC (aEPEC) based on the presence of the EPEC adherence factor (EAF) plasmid in the former group and its absence in the latter group  lesions in the intestinal epithelium, in which intimate adherence between bacteria and host cells occurs \u20138. The g\u2013The number of cases of diarrhea caused by aEPEC has increased even in industrialized countries. This information reveals the need for a thorough knowledge of the genetic traits of aEPEC organisms and their mechanisms of pathogenicity in order to develop appropriate control strategies , 10, 11.The 10 aEPEC strains we sequenced were isolated from feces of children under 5\u2009years old during epidemiological studies carried out in S\u00e3o Paulo, Brazil (1985 to 1986 and 1989 to 1990) by the Laboratory of Microbiology of the Universidade Federal de S\u00e3o Paulo (UNIFESP) and in Salvador (2003 to 2004) by the Laboratory of Bacteriology of the Butantan Institute , 13. Allde novo assembly and annotation of the genomes were performed using the software SPAdes version 3.9.1 (with the \u2013careful flag) (DNA extraction was performed using the QIAamp DNA minikit (Qiagen) according to the manufacturer\u2019s instructions. DNA libraries from each aEPEC genome were prepared using the Nextera XT library prep kit  and sequenced at MicrobesNG  on the Illumina HiSeq 2500 platform using 2- \u00d7 250-bp paired-end reads, achieving between 34 and 157\u00d7 depth . Trimmomul flag) , respectThese sequences will provide an important source for futures studies concerning aEPEC pathogenicity and genetic markers of potentially virulent strains. Furthermore, these data will permit comparative studies to be carried out with aEPEC strains isolated in Brazil and others isolated in different countries.PRJNA490882, and the whole-genome shotgun sequences were deposited in the GenBank database under the accession numbers shown in The reads used for assembly of the 10 aEPEC genomes were deposited in the Sequence Read Archive (SRA) at the National Center for Biotechnology Information (NCBI) under the accession number"}
+{"text": "This paper focus to examine the best molecular interaction between Polyamide Thin Film Composite (PA TFC) layers with different properties of the support membrane. The support membrane of Nylon 66 (N66) and Polyvinylidene fluoride (PVDF) was chosen to represent the hydrophilic and hydrophobic model respectively in the Molecular Dynamic (MD) simulation. The Condensed-Phase Optimized Molecular Potential for Atomistic Simulation Studies (COMPASS) force field was used with the total simulation runs were set 1000 picoseconds run production ensembles. The temperature and pressure set for both ensembles were 298 K and 1 atm respectively. The validity of our model densities data was check and calculated where the deviation must be less than 6%. The comparison between hydrophobic and hydrophilic of the support membrane data was examined by the distance and magnitude of intensity of the Radial Distribution Function (RDF's) trends. The interactions of binary system (MPD/TMC) were comparing with both the tertiary system, (N66/MPD/TMC) and (PVDF/MPD/TMC)[10]. Where:N (MPD) \u2013 C (TMC): Intermolecular interaction (crosslink) between nitrogen in the MPD molecules with carbon in the TMC group There were also interactions detected between TMC-subtracts presented inwhich contributes to the better attachment of TFC layer onto support membrane. Where:Cl (TMC) \u2013 O (N66): Intermolecular interaction between chlorides in the MPD molecules with the oxygen atom in the N66 group.O (TMC) \u2013 H (N66): Intermolecular interaction between oxygen in the MPD molecules with the hydrogen atom in the N66 group.Cl (TMC) \u2013 F (PVDF): Intermolecular interaction between chlorides in the MPD molecules with the fluorine atom in the PVDF group.Cl (TMC) \u2013 H (PVDF): Intermolecular interaction between chlorides in the MPD molecules with the hydrogen atom in the PVDF group.2All simulations were performed using Material Studio (version 7.0) software from Accelrys, Inc. Models were firstly undergoing the geometry optimization and then the energy started to minimized. The molecules of the models chosen represent in"}
+{"text": "Bos gaurus hubbacki), locally known as the seladang, from two captive centers. Thirty fecal samples of Malayan gaur were collected from Jenderak Selatan Wildlife Conservation Center (Pahang) and the Sungkai Wildlife Reserve (Perak) for DNA extraction and amplification with polymerase chain reactions. DNA sequences were then analyzed using neighbor joining (NJ) and maximum parsimony (MP) methods. Based on the 652 base pairs obtained, we found seven variable characters with a value of 1%. The genetic distance between the two captive centers was 0.001. Haplotype analyses detected only four haplotypes between these two captive centers. Both NJ and MP trees demonstrate that all individuals in the Jenderak and Sungkai captive centers are in the same clade. Genetic variation of the Malayan gaur in these centers is considered low, possibly because individuals share the same common parent. This sequence variation data are of paramount importance for designing a proper breeding and management program of the Malayan gaur in the future.This article contains data of the sequence variation in the mitochondrial DNA D-loop region of the Malayan gaur ( Specifications tableValue of the data\u2022The data presented here provide sequence variations of Malayan gaur in captivity.\u2022Genetic relationships among captive Malayan gaur individuals.\u2022Revealing inbreeding in which they might share the same common parent.\u2022The data are useful for decision-making in the breeding and management program of the Malayan gaur.1We present D-loop region sequence data 2The DNA chromatograms  of the s"}
+{"text": "Scientific Reports 10.1038/s41598-018-35051-w, published online 12 November 2018Correction to: This Article contains typographical errors in the Results section where,20), Marinimicrobium, Marinobacter and Acinetobacter (Table 1). A decrease in biodiversity is observed as the salinity of the lagoons increase (Table 1), revealing the higher salinity tolerance of Marinimicrobium and Marinobacter species compared to that of Halomonas and Acinetobacter species here reported.\u201d\u201cMassive parallel sequencing of 16S ribosomal RNA gene amplicons showed that more than 60% of the sequences found in the lagoons belonged to only four main OTUs , specifically to the Class Gammaproteobacteria: Halomonas (found worldwideshould read:20), Marinimicrobium, Marinobacter and Acinetobacter (Table 2). A decrease in biodiversity is observed as the salinity of the lagoons increase (Table 2), revealing the higher salinity tolerance of Marinimicrobium and Marinobacter species compared to that of Halomonas and Acinetobacter species here reported.\u201d\u201cMassive parallel sequencing of 16S ribosomal RNA gene amplicons showed that more than 60% of the sequences found in the lagoons belonged to only four main OTUs , specifically to the Class Gammaproteobacteria: Halomonas (found worldwide"}
+{"text": "As the age of the US population increases, so does cognitive impairment (CI); therefore early detection of CI is critical for ensuring its appropriate management. As part of a NINDS Consortium to detect CI and dementia in primary care (DetectCID), we are implementing and evaluating a brief 2-step CI detection paradigm (MyCog), that can be delivered in clinics with diverse populations via the electronic health record (step 1) and iPad (step 2). We conducted focus groups with 25 clinicians and administrative leaders from academic and community primary care practices to 1) understand how CI is being assessed, and 2) evaluate the feasibility of implementing the MyCog paradigm into existing primary care workflows. Several key themes emerged from the discussions. No proactive detection strategy for CI was regularly used outside of the Medicare Annual Wellness Visits (AWV); variable assessments including the Minicog, MoCA, or MMSE were used to fulfill the AWV requirement. Regarding the feasibility of our MyCog Paradigm, our 2-step process was positively received, with the brief case-finding step 1 satisfying AWV requirements and replacing the longer assessments currently being used. Clinicians preferred that step 2 be self-administered due to limited clinician time for wellness visits, and highlighted logistical challenges such as room availability and storage and maintenance of the iPad. Overall, clinicians felt that the identification of CI was valuable and supported standardization, but indicated regular case finding was unlikely without clear guidance on clinical decision-making."}
+{"text": "TOX3 (16q) at 1.5% frequency, as well as for CCND2 (12p) and ANXA11 (10q) at 1% frequency, in addition to the well-known targets ERBB2 (17q) and MYC (8q). Focal amplifications with \u226515 or \u22655 additional copies of at least one of these regions were associated with a poor overall survival among patients with stage I-III MSS CRCs . All high-level amplifications were focal and had a more consistent relationship with gene expression than lower amplitude and/or broad-range amplifications, suggesting specific targeting during carcinogenesis. Genome-wide, copy number driven gene expression was enriched for pathways characteristic of the CMS2-epithelial/canonical subtype, including DNA repair and cell cycle progression. Furthermore, 50% of upregulated genes in CMS2-epithelial/canonical MSS CRCs were driven by CNAs, an enrichment compared with the other CMS groups, and associated with the stronger correspondence between CNAs and gene expression in malignant epithelial cells than in the cells of the tumor microenvironment . In conclusion, we identify novel recurrent amplifications with impact on gene expression in CRC and provide the first evidence that CMS2 may have a stronger copy-number related genetic basis than subtypes more heavily influenced by gene expression signals from the tumor microenvironment.About 80% of colorectal cancers (CRCs) have chromosomal instability, which is an integral part of aggressive malignancy development, but the importance of specific copy number aberrations (CNAs) in modulating gene expression, particularly within the framework of clinically relevant molecular subtypes, remains mostly elusive. We performed DNA copy number profiling of 257 stage I-IV primary CRCs and integrative gene expression analysis in 151 microsatellite stable (MSS) tumors, focusing on high-level amplifications and the effect of CNAs on the characteristics of the gene expression-based consensus molecular subtypes (CMS). The results were validated in 323 MSS tumors from TCGA. Novel recurrent high-level amplifications  with a major impact on gene expression were found for  BRAF mutation in CMS1 and KRAS mutation in CMS3, and the low frequency of somatic copy number aberrations (CNAs) in MSI is well established. However, little is in general known about the genetic basis for the distinct gene expression-based subtypes.Colorectal cancers (CRC) can be classified into four biologically distinct and clinically relevant consensus molecular subtypes (CMS) based on their global gene expression patterns . A few gChromosomal instability is an integral part of canonical CRC pathogenesis, and the majority of CRCs are characterized by a large burden of CNAs. Chromosomal instability is associated with poor patient prognosis  and resiERBB2 amplification, is a druggable target, and the HERACLES trial demonstrated a 30% response rate to dual HER2 blockade in the 5% subpopulation of HER2 positive and KRAS wild-type metastatic cancers  samples on gene expression (or among top five samples on gene expression when fewer than five samples displayed amplification). Similar correspondence analyses were also performed for recurrent high-level amplifications, defined as \u226515 additional copies in >1 tumor. For selected amplified genes the gene expression was additionally assessed by Wilcoxon tests .p\u2009<\u20090.05 and fold change\u2009>\u20091.2) and calculated the proportion of upregulated genes that overlapped with in cis genes. To control for the potential impact of different numbers of samples in the subtypes, we performed random sampling (n\u2009=\u20091000) of 20 tumors from each CMS group and repeated analyses for each iteration. Enrichment was assessed in pairwise comparisons among the subtypes. For a gene to be assessed in the in cis analysis, at least three tumors had to be found in the copy number gain and copy number neutral group. For robustness, the analysis was done in three different ways: (i) by identifying significant in cis genes  for the 40 tumors (20 tumors in each of the subtypes included in the pairwise comparison) and performing differential expression analysis  for the 20 versus 20 tumors per re-sampling, (ii) by identifying significant gain/upregulated genes for the 40 tumors per re-sampling and using the differential expression results from the original analyses including all samples, and (iii) by identifying significant in cis genes for the 40 tumors and randomly sampling 250 genes from the original differential expression results. Furthermore, to test if the variable number of genes that were differentially upregulated in each subtype affected the analysis we also performed repeated (n\u2009=\u20091000) re-samplings of 250 genes from the original gain/upregulated gene list and among the genes originally found to be upregulated in each CMS group (CMSx versus remaining CMS classified tumors).To investigate a potential enrichment of genes with in cis-association (gain/upregulation) among upregulated genes in each of the four CMSs we identified differentially expressed genes between each subtype and the remaining subtypes using limma  were used for integration analyses with CNAs. Prior to data integration, the same fraction of low-variance genes as in the inhouse dataset was excluded prior to Wilcoxon-testing. The amplification analyses  were performed on 320 out of 323 tumors due to segmentation failure in 3 samples.Gene expression data from four different colon cancer cell populations"}
+{"text": "To determine how intrusion of O2 into iron mound sediments influences microbial community composition and Fe metabolism, we incubated samples of these sediments in a column format. O2 was only supplied through the top of the columns, and microbiological, geochemical, and electrochemical changes at discrete depths were determined with time. Despite the development of dramatic gradients in dissolved Fe(II) concentrations, indicating Fe(II) oxidation in shallower portions and Fe(III) reduction in the deeper portions, microbial communities varied little with depth, suggesting the metabolic versatility of organisms in the sediments with respect to Fe metabolism. Additionally, the availability of O2 in shallow portions of the sediments influenced Fe metabolism in deeper, O2-free sediments. Total potential  measurements at discrete depths in the columns indicated that Fe transformations and electron transfer processes were occurring through the sediments and could explain the impact of O2 on Fe metabolism past where it penetrates into the sediments. This work shows that O2 availability (or lack of it) minimally influences microbial communities, but influences microbial activities beyond its penetration depth in AMD-derived Fe(III) rich sediments. Our results indicate that O2 can modulate Fe redox state and solubility in larger volumes of iron mound sediments than only those directly exposed to O2.Fe(III)-rich deposits referred to as \u201ciron mounds\u201d develop when Fe(II)-rich acid mine drainage (AMD) emerges at the terrestrial surface, and aeration of the fluids induces oxidation of Fe(II), with subsequent precipitation of Fe(III) phases. As Fe(III) phases accumulate in these systems, O Centuries of coal extraction in the Appalachian region of the United States has left a legacy of acid mine drainage (AMD), which remains the region\u2019s greatest threat to surface water quality . The maj2, while Fe(II) oxidation might occur under conditions of severe O2 depletion .(DOCX)Click here for additional data file.S2 Fig]. Values in parentheses in depth legend indicate Shanon Indices of microbial communities at each of those depths. Values in parentheses of axis labels indicate the percentage of variation explained by a PCo.Appl Environ Microbiol 2007; 73: 1576\u20131585.(DOCX)Click here for additional data file."}
+{"text": "Mission: to urge all relevant entities within the international cardiac surgery, industry and government sectors to commit to develop and implement an effective strategy to address the scourge of rheumatic heart disease in the developing world through increased access to life-saving cardiac surgery. Twelve years after cardiologists and cardiac surgeons from all over the world issued the Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa, calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and rheumatic heart disease, and to periodically review progress made and challenges that remain,2Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open-heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality.Elimination of RHD and relief from its debilitating consequences can only occur through interdisciplinary effort, as outlined in the Cairo Accord.Progress in the prevention of RHD has been slow during the past 15 years,6Although there is one cardiac centre per 120 000 people in the United States, there is only one centre per 33 million in Africa. Furthermore, RHD is not restricted to sub-Saharan Africa. India, Pakistan, China and Indonesia together account for 72% of the mortality rate of RHD cases worldwide.2We strongly endorse the position that building local capacity is the best solution for this serious public health problem. Many lives have been saved by humanitarian \u2018fly-in\u2019 missions, but these efforts are neither sustainable nor cost effective. The non-governmental organisations associated with these programmes are shifting focus towards building long-term partnerships with host countries to develop autonomous local services with government buy-in.It is not sufficient for governments and non-governmental organisations to support the training of cardiologists and cardiac surgeons from these regions at high-income country facilities, because they will not be trained in most of the pathologies awaiting them in their own countries and will be unfamiliar with resource-constrained circumstances.There is an urgent need for a concerted effort by all stakeholders to address the plight of the poor in these regions, who need cardiac surgery. As signatories and endorsing organisations of the Cape Town Declaration, we propose a comprehensive solution with two principal aims.Aim 1: To establish an international working group  of individuals from cardiac surgery societies and representatives from industry, cardiology and government to evaluate and endorse the development of cardiac care in low- to middle-income countries.It is proposed that the international coalition will have two representatives from each of the major cardiac surgery societies , and ideally, two additional committed members. There will be at least one representative from industry and at least one appointee to represent cardiology/the World Heart Federation. The responsibilities of the coalition will include establishing criteria for centres for clinical care and training as well as selecting and endorsing the centres. The coalition will derive metrics of quality and performance for the endorsed centres of training and clinical care and will encourage standardisation of care to the extent possible.The coalition will advocate mutually agreed policies and prescriptions to relevant governmental bodies. In addition, the coalition will engage with industry and private sources of philanthropy for financial assistance with large-scale initiatives.Aim 2: To advocate for the training of cardiac surgeons and other key specialised caregivers at identified and endorsed centres in lowto middle-income countries.The case has been made above for critical providers obtaining training in settings and conditions and dealing with the cardiac pathologies that they will be encountering in their practice in their countries of origin.It is preferred that centres endorsed by this coalition be based on an alliance of four stakeholders: a programme initiator , an audited training centre in a low- to middle-income country, a committed partner institution in a high-income country, and a consortium of industry that would sign on as benefactors to the specific programme. Because regional centres in low- to middleincome countries typically operate within a resource-scarce environment, resulting in lower case numbers than needed for the training of outside residents, a facilitated capacity increase to help achieve higher case numbers would benefit all participants.Summary: It is imperative that action be taken urgently. A nucleus of one to three centres should be identified and endorsed, with co-ordination by global stakeholders, as quickly as possible. The implementation of this initiative will only be made possible by the endorsement of all the relevant cardiothoracic societies and agencies subscribing to clearly defined targets and timelines, and committing appropriate resources. The time to act is now.For Cardiothoracic Societies Joseph Bavaria Friedhelm Beyersdorf R Morton Bolman, III Kumud Dhital Robert SD Higgins James Kirklin Robert Kleinloog Bongani Mayosi Juan Mejia Jose Pomar Karen Sliwa Shinichi Takamoto Wei Wang David Wood Charles Yankah , Ghana/Germany]Liesl Zuhlke Humanitarian and government organisations Alain Carpentier Sylvain Chauvaud Afksendiyos Kalangos Richard Kamwi Ren\u00e9 Pr\u00eatre Nicole Sekarski Magdi Yacoub Industry and health economy representatives Iraj Abedian Francois Bonnici Lenias Hwenda Sidhant Jena Samukeliso Dube Jacques Kpodonu  Salah Malek Markus Stirner-Schilling Patrice Matchaba Lee Chuen Neng Michael P Phalen Tim Ring Kathryn Gleason Devi Prassad Shetty Alistair Simpson Raenette Taljaard Helmut Straubinger Barry Wilson For major journals and publications Friedhelm Beyersdorf Sampath Kumar Dan Ncayiyana JP van Niekerk G Alexander Patterson Marko Turina David Williams Other signatory delegates to the Cape Town Dialogue Elena Aikawa (USA)Masanori Aikawa (USA)Henning Rud Andersen (Denmark)Manuel Antunes Eduardo Becerra (Chile)Solomon Benatar (South Africa/Canada)Richard Bianco (USA)Bojan Biocina (Croatia)Carlijn Bouten (Netherlands)Abdelmalek Bouzid (Algeria)Luke Brewster (USA)Johan Brink (South Africa)Taweesak Chotivatanapong (Thailand)Patrick Commerford (South Africa)David Cooper (USA)John Curci (USA)Manfred Deutsch (Austria)Richard Daly (USA)Frederick C de Beer (USA)Norberto de Vega (Spain)Howard Eisen (USA)Max Emmert (Switzerland)Giuseppe Faggian Volkmar Falk (Germany)Ted Feldman (USA)Giovanni Ferrari (USA)Teddy Fischlein (Germany)Robert Frater (USA)Glen Gaudette (USA)Gino Gerosa Bernard Gersh (USA)Allan Glanville Craig Goergen (USA)Claudia Goettsch (Germany)Mervyn Gotsman (Israel)Martin Grabenwoeger (Austria)Andrea Griesmacher (Austria)Christian Hagl (Germany)Ulf Hedin (Sweden)Simon Hoerstrup (Switzerland)Saeid Hosseini (Iran)Joshua Hutcheson (USA)Willie Koen (South Africa)Gennadiy Khubulava (Russia)Robin Kleinloog (South Africa)Walter Klepetko (Austria)Michael Knaut (Germany)Theodoros Kofidis (Singapore)Guenther Laufer (Austria)Nicolas l\u2019Heureux (France)Georg Lutter (Germany)Simon Maltais (USA)Simon Matskeplishvili (Russia)Jo Meinhart (Austria)Ana Olga Mocumbi (Mozambique)Elmi Muller (South Africa)Mathias Mueller (Austria)Paul Mohacsi (Switzerland)Ivan Netuka (Czech Republic)Mpiko Ntsekhe (South Africa)Minoru Ono (Japan)Otmar Pachinger (Austria)Timothy Pennel (South Africa)Olga Plattner (Austria)Bruno Podesser (Austria)Darshan Reddy (South Africa)Bruno Reichart (Germany)Hermann Reichenspurner (Germany)Hector Sanchez (Argentina)Jacques Scherman (South Africa)Stephan Schueller (United Kingdom)Jim Schurman (USA)Rainald Seitelberger (Austria)Toshi Shinoka (USA)Agneta Simionescu (USA)Dan Simionescu (USA)Francis Smit (South Africa)Ulrich Steinseifer (Germany)Cynthia St Hilaire (USA)Justiaan Swanevelder (South Africa)Hendrik Treede (Germany)Nir Uriel (USA)Devagourou Velayodamu (India)David Vorp (USA)Susan Vosloo (South Africa)Beath Walpoth (Switzerland)Georg Wieselthaler (USA)Mike Wolf (USA)Andreas Zuckermann (Austria)"}
+{"text": "The use of video-recording offers important advantages in observing and assessing the relationships between specific behaviors in health care settings. The purpose of this systematic review is to investigate and synthesize the methodological characteristics of studies using video-technology for measuring interactions between the older persons with dementia and staff in long-term care facilities. We searched Medline, Embase and CINHAL databases for published articles in English using a video-recording method for both staff and persons with dementia. Quantitative research design studies  were included. Among 5,605 searched papers, a total of 20 studies were selected for this review. Situations of video-recording were providing personal care (n=12), mealtime (n=6), and conversation (n=3). Concepts of measuring by video-recording were classified into two groups: 1) Staff [care practice by staff (n=13) and communication by staff (n=11)] and 2) residents . This review demonstrates that video technologies are actively used to evaluate the relationship between quality of care and health outcomes of the elderly with dementia in many international nursing studies. This study provides the foundation for a future research using video-recording technologies to examine the interactions and relationship between staff and the residents in long-term care settings."}
+{"text": "We detected 2936 large and rare CNVs events . Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes . Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10\u201320%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany ( Gallstones disease (GSD) is a multifactorial chronic metabolic disease characterized by the development of calculi inside the gallbladder composed mainly by cholesterol. GSD features a long silent progression where the accumulation of stones in the affected gallbladder can lead to clinical symptoms such as recurrent episodes of intense abdominal pain (biliary colic) and major complications, like obstruction and infection of the biliary tree (cholestasis and cholangitis), acute pancreatitis, and gallbladder cancer . At leasABCG5/8 gene  ATP8B1) gene [RB1) gene [HNF1A) gene [SULT2A1) gene [APOL1 and APOL2) involved in lipid transport. In addition, we note that the 23 candidate genes were enriched with 7 genes extremely intolerant to loss-of-function genetic variation  and variants within these genes are rarely found in the general population [The observed associations could not be attributed to one CNV nor to an specific gene and thus CNVs may confer risk to GSD through multiple highly rare and penetrants events. In an effort to identify genes with the strongest potential to be involved in the development of GSD by a CNV-related mechanism, we highlight 23 genes involved in lipid metabolic process, which are expressed in the small intestine and exclusively affected by CNV in cases. Direct functional links between the candidate genes and the etiology of GSD is available for: the lipid transporter ATPase phospholipid transporting 8B1, (B1) gene , the RB B1) gene , the hep1A) gene , the bilA1) gene , and thepulation . We hypoAs suggested by CNVs overlapping nonlipid metabolic process genes that are expressed in the small intestine Fig.\u00a0 and the In summary, our study provides the first evidence of association of CNVs with GSD and will contribute to better understand the etiology of this complex and common metabolic disorder.Supplementary Material"}
+{"text": "Investigators from Calico Life Sciences LLC and AbbVie report the effects of a novel drug targeting the genetic basis of Vanishing White Matter Disease (VWMD). Investigators from Calico Life Sciences LLC and AbbVie report the effects of a novel drug targeting the genetic basis of Vanishing White Matter Disease (VWMD). VWMD is caused by homozygous or compound heterozygous variants in any of five genes . Collectively the five genes encode a portion of the eukaryotic translation inhibition factor 2 (eIF2) termed eIF2B that is required for normal protein translation. VWMD-causing variants are though to cause a partial reduction in eIF2B activity. Prior studies by members of the group from Calico Life Sciences had shown that ISR-inhibitor (ISRIB), a small molecule, was able to activate and stabilize eIF2B [COMMENTARY. VWMD is a chronic, episodic and progressive leukoencephalopathy with highly variable presentation. Features include essentially normal early life development followed by progressive ataxia, cognitive impairment, and spasticity. In 1997 Van Der Knapp et al., proposed four criteria for diagnosis (1) essentially normal initial motor and cognitive development, (2) chronic, progressive deterioration that often follows a mild infection or head trauma, 3) progressive cerebellar ataxia and spasticity are prominent features; epilepsy and optic atrophy may be present; cognitive impairments are less significant than motor impairments and (4) MRI findings are symmetric, with white matter signal intensity similar to cerebrospinal fluid on multiple sequences [ progressWhen clinical suspicion is high, the diagnosis of VWMD is confirmed by genetic testing for homozygous or compound heterozygous variants in genes encoding the five eIF2B subunits. Normal protein expression requires function of eIF2B to extend translated RNA sequences . While tThe other important function of eIF2B is regulation of the integrated stress response (ISR), a reprogramming of protein expression that is common for a variety of cellular stress signals. ISR both shuts down normal protein expression, and activates specific transcription factors to help protect a stressed cell. Prior work demonstrated that suppression of eIF2B activates the ISR. ISRIB efficiently activates and stabilizes eIF2B to block the ISR .VWMD is caused by diminished eIF2B activity and often worsens in the setting of illness, which may be related to improper regulation of the ISR. The current investigation examined whether ISRIB can utilize the hypoactive eIF2B found in VWMD to properly inhibit the ISR. The authors selectively edited the eIF2B gene with CRISPR-Cas9 in otherwise normal cells to recreate patient derived mutations. Cells were then treated with ISRIB. Consistent with a properly inhibited ISR, global protein expression was increased and ISR-specific transcription factors were decreased [The author(s) have declared that no competing interests exist."}
+{"text": "A 78-year-old patient with a recent history of transitory ischemic attack with right upper extremity weakness was referred for computed tomographic angiography (CTA) of the neck arteries. No significant stenosis was found, but systematic 3D study of the circle of Willis Figure  revealedThe vocable of \u201cfetal posterior cerebral artery\u201d (FPCA) encompasses a group of developmental variants of the posterior cerebral artery (PCA) in which a significant portion of the distal PCA remains perfused through a branch of the internal carotid artery (ICA).When a FPCA variant is present, thromboembolism in the ICA may result in paradoxical PCA territory infarction  .During the choroidal stage of embryogenesis (at five weeks of gestation) the anterior brain circulation is constituted by two main branches of the ICA: the rostral branch (rICA) and the caudal branch (cICA) which prefigures the future posterior communicating artery (PcoA).The rICA feeds the anterior carotid artery (ACA) and the anterior choroidal artery (AchoA) and the cICA feeds the posterior choroidal artery (PchoA) and the future P1 segment of the PCA.During growth of the posterior cerebrum, cerebellum and brainstem acceleration arises in the development of the posterior arterial network. It progressively becomes independent from the anterior circulation and the primitive transitory carotid-basilar anastomoses completely regress.Different scenarios explain the pattern of the future definitive PCA. Most commonly Figure  the middAnother scenario produces the common FPCA variants Figure , C and DA third but extremely rare scenario called the \u201ctrue fetal PCA\u201d variant Figure  is repor"}
+{"text": "The Research article \u201cJurassic-Cretaceous boundary bioevents and magnetochrons: A stratigraphic experiment\u201d , describes the Lower Cretaceous 2016 Chronostratigraphic Database (LOK2016CS). This database comprises the first and last occurrences of key fossil ranges in forty-one global stratigraphic sections (Table 1). This data has been published by qualified biostratigraphers in selected worldwide sections that have been carefully measured, collected and fossil species consistently identified. Regional reference sections and approved or proposed Global Boundary Stratotype Section and Point (GSSP) are included. This data set is composed of lowermost and uppermost positions of species measured in meters or feet by the research team in each section, which represent the first and last occurrences of the species. These data sets were composited into the numerical age chart, LOK2016CS (Table 2), by graphic correlation. The 2016 Geologic Time Scale was the X-axis section on the first X/Y plot so that the numerical ages were calibrated consistently with that scale. The numerical ages of each event estimate the First and Last Appearance Datums  within the geographic area encompassed by the sampled sections."}
+{"text": "Cardioglossa schioetzi and Leptodactylodon bicolor (both in the Arthroleptidae), in and around Ngel Nyaki Forest Reserve on the Mambilla Plateau in eastern Nigeria. The landscape comprises continuous forest on steep slopes and small riparian forest fragments in a grassland matrix. While increased fragmentation is well documented for these and other forests in the mountains of Cameroon and Nigeria over the past century, there are no previous assessments of the impact of forest fragmentation on montane amphibian populations in this region. Our estimates of genetic diversity are similar across populations within each species with levels of heterozygosity values consistent with local population declines. Except for a pair of populations (C. schioetzi) we did not observe genetic differentiation between forest and riparian forest fragment populations, nor across sites within continuous forest (L. bicolor). Our results demonstrate recent gene flow between forest fragments and the adjacent protected forests and suggest that small forest corridors connecting these may lessen the genetic consequences of at least 30 years of intense and severe fragmentation in Ngel Nyaki.Amphibians are the vertebrate group with the highest number of species threatened with extinction, and habitat loss and fragmentation are considered to be among the leading causes of their declines and extinctions. Little is known of the population biology of amphibian species inhabiting montane forests in Central and West Africa, where anthropogenic activities such as farming and cattle raising are major threats to native biodiversity. We used Amplified Fragment Length Polymorphisms (AFLPs) to assess the population genetic structure of two poorly known species,  Globally, amphibians face the most extreme population declines of all major vertebrate groups \u20133. ContrAs is the case with many other taxa, habitat fragmentation likely has long-term effects on the genetic viability of amphibian populations because of the combined effects of reduced population size and increased isolation . IncreasTo begin to redress the paucity of population genetics studies of African amphibians, we focused on populations of frogs within the forests of the Nigerian Highlands of the Cameroon Volcanic Line . This isCardioglossa schioetzi and Leptodactylodon bicolor, are endemic to the montane forests of Cameroon and Nigeria, they are small (<30 mm snout\u2013vent length), have stream-adapted tadpoles, and live in leaf litter and rocky areas . Our results suggest that despite considerable habitat degradation  gene flow is still occurring (or occurred recently) among forest patches in two Afromontane frog species. This illustrates the importance of these degraded riparian forest fragments to amphibian communities.In Nigeria and all along the Cameroon Volcanic Line ,89, as eS1 FigK based on the Ln(K) K = 5, whereas graph B) and bar plot D) show the better K based on Evanno\u2018s method \u0394K = 2. Each vertical bar represents an individual for which is shown the proportional genetic assignment to each cluster.Graph A) and bar plot C) depict the optimal (TIF)Click here for additional data file.S2 FigK based on the Ln(K) K = 7, whereas graph (B) and bar plot (D) show the better K based on Evanno\u2018s method \u0394K = 2. Each vertical bar represents an individual for which is shown the proportional genetic assignment to each cluster.Graph (A) and bar plot (C) depict the optimal (TIF)Click here for additional data file.S1 TableTogether, the two preferred primer combinations ESP1B/MSP3 and ESP1B/MSP6 yielded 275 loci for the 198 samples representing both species.(XLSX)Click here for additional data file."}
+{"text": "Of 103 serum samples collected from dogs in South Korea, 3 (2.9%) were positive for severe fever with thrombocytopenia syndrome virus (SFTSV) and 22 (21.4%) were positive for antibodies against SFTSV. A dog-derived isolate of SFTSV clustered with many South Korea SFTSV strains in the Japanese clade. Phenuiviridae family (previously Bunyaviridae), causes severe fever with thrombocytopenia syndrome (SFTS) in China, Japan, and the Republic of Korea (South Korea) (Severe fever with thrombocytopenia syndrome virus (SFTSV), a new tickborne phlebovirus of the Haemaphysalis longicornis tick is the main vector for SFTSV, promoting its circulation and transmission , obtained from dog 16, a German shepherd; dog 22, a Belgian Malinois; and dog 56, a German shepherd were positive for the small (S [346 bp]), medium (M [859 bp]), and L  segments of SFTSV by reverse transcription PCR (the L segment of dog 16 was not amplified). The sequences of the SFTSV S, M, and L segments differed from each other. The results of phylogenetic analysis of partial S, M, and L segments showed that sequences of SFTSV obtained from dogs were more related to strains from Japan than to strains from China . MoreoveWe used Vero cells to isolate the virus from positive serum. We observed cytopathic effect in only 1 of 3 positive samples. The results of phylogenetic analysis of the complete S segment indicated that the SFTSV strain isolated from dog 22 had not previously been isolated; this strain clustered with many SFTSV strains from South Korea and Japan .H. longicornis ticks are the main vector of SFTSV and the dominant tick species collected from vegetation and animals in South Korea (The detection rates of SFTSV RNA and antibodies in our study were 2.9% and 21.4%, respectively, which were higher than those observed in shelter dogs in South Korea (Although we isolated only a few SFTSV strains from animals and our results could not represent all characteristics of SFTSV, our findings could indicate that SFTSV might not be host-specific and that various SFTSV clades circulate and are distributed in South Korea. Further studies continuously surveilling animals for SFTSV, along with whole-genome analysis of dog-derived Korean isolates of SFTSV, would help clarify the mechanisms of transmission and molecular evolution of SFTSV.Additional information for severe fever with thrombocytopenia syndrome virus in dogs, South Korea."}
+{"text": "We analyze possible future trends in dissolved inorganic nitrogen (DIN) export by world rivers and associated emissions of nitrous oxide (N2O). Our scenarios either assume that current trends continue or that nitrogen (N) inputs to aquatic systems are reduced as a result of changes in agriculture practices and fuel combustion technologies. The results indicate that moderate changes in the human diet in North America and Europe, reducing worldwide fertilizer use by only 16%, relative to Business-as-Usual (BAU) levels, may reduce DIN export rates to the North Atlantic and European Seas by about one third and associated N2O emissions by 36 to 77%. We furthermore calculate that relatively large reductions in NOy deposition rates in Europe (of about 80%) may reduce DIN export by rivers by a moderate 8% or less, relative to BAU levels. The potential effect of reduced NOy deposition on riverine DIN export is moderate, because most N in European rivers stems from agriculture, and not from fuel combustion. Nevertheless, the calculated 9% reduction (relative to BAU) in DIN inputs to the North Sea as a potential side effect of air pollution control may help achieve the international policy targets for reduced N inputs to the North Sea."}
+{"text": "Scientific Reports 10.1038/s41598-018-28912-x, published online 17 July 2018Correction to: The original version of this Article contained errors.In the Abstract,\u201cThe clean and stable experimental platform permits the visualisation of the structure and orientation of microvilli present at the apical cell membrane under standard laboratory conditions together with registering subcellular details within a microvillus.\u201dnow reads:\u201cThe clean and stable experimental platform permits the visualisation of the structure and orientation of microvilli present at the apical cell membrane under standard laboratory conditions together with registering topographical features within a microvillus.\u201dIn the main text,24), which are visible in the zoomed-in phase image  and in the overlay image .\u201d\u201cIn particular, we observe lateral striations running along the length of the microvillus unit (previously observed only using high-resolution electron microscopy at cryogenic temperaturesnow reads:24), which are visible in the zoomed-in phase image  and in the overlay image .\u201d\u201cIn particular, we observe lateral striations along the entire length of the microvillus unit (previously observed only using high-resolution electron microscopy at cryogenic temperaturesThese errors have now been corrected in the PDF and HTML versions of the Article."}
+{"text": "Transforming nursing home (NH) cultures\u2014from impersonal institutions to enriching communities where residents and employees thrive\u2014requires multifaceted change. NHs deploy an array of culture change (CC) practices, in three core domains: resident-centered care, staff empowerment, and physical environment. This study uses novel data on CC practice from a nationally representative panel of NHs  surveyed in 2009/2010 and 2016/2017. To understand how changes in practice adoption may relate to quality changes we linked longitudinal data on the CC practice domain scores for resident-centered care, staff empowerment, and physical environment and on NH deficiencies relating to health and quality of life (QoL) and combined these with Certification and Survey Provider Enhanced Reporting baseline data. Multinomial logistic regressions incorporating survey weights and inverse probability of weight (to address CC selection) estimated the relative risk ratios (RRR) of increased CC practice corresponding with NHs having fewer or no change in deficiencies, versus increased deficiencies. NHs with much increase in staff empowerment scores had a higher likelihood of no change (compared to an increase) in health deficiencies  and severe health deficiencies . With a RRR of 1.63, NHs with any improvement in resident-centered care scores appeared to have a higher likelihood of no change (compared to an increase) in QoL deficiencies but statistical significance was not reached (p=0.11). This study provides some support for the benefits of CC practices, and in particular, supports the importance of staff empowerment practices in NHs."}
+{"text": "Studies of aging rarely include the older adults themselves in the process of conceptualizing questions, implementing the research, and evaluating the results. To provide opportunities for community members to become engaged in research, researchers and community stakeholders developed \u201cEngaging Older Adult Learners as Health Researchers (ENGOAL).\u201d This program educates older adults from underserved and underresourced communities about geriatric health and research methods, enabling them to become Research Partners. Two cohorts of African-American seniors (N=21) aged 53-79 have participated or are currently participating in six months of weekly classes followed by 4-6 months of research apprenticeships. Content and structure of classes  will be described. Challenges and successes in providing research apprenticeships  will be discussed."}
+{"text": "KRT17 has been described in multi-layered epithelia as well as in tumors derived from these cells. In cancers arising from KRT17 negative single layered epithelia neo-expression of KRT17 has been associated with tumor progression. To obtain more insight into the biology of kidney cancers we have investigated KRT17 expression by immunohistochemistry in normal kidney, in papillary preneoplastic lesions and in 151 papillary and 692 conventional renal cell carcinomas placed on tissue microarray. We found a positive staining in ureteric bud and collecting duct cells in foetal kidney, in all papillary preneoplastic lesions and also in 77% of the 151 papillary renal cell tumors indicating a continuos KRT17 expression during tumor development. The neo-expression of KRT17 in conventional renal cell carcinomas, which derives from KRT17 negative proximal tubules showed a significant correlation with postoperative tumor relapse . In conclusion, the continuous expression of KRT17 from emerging fetal kidney tubules and microscopic pre-neoplastic lesions towards papillary renal cell tumors and its neo-expression in aggressive growing conventional renal cell carcinomas reflects the multiple function of KRT17 in kidney cancers with distinct natural history. This should be taken into account in clinical managements and therapy.Expression of KRT8 and KRT18 in their normal state, but this may change during inflammation, regeneration and also during tumor development. Kidney tubular cells may switch on KRT7 and KRT19, sometimes also KRT17 in addition to the expression of KRT8 and KRT18KRT7, KRT17 and KRT19 appears parallel to the reduction in degree of differentiation. KRT7 and KRT19 are upregulated during renal epithelial injury and repair leading to more plasticity of cells involved in the regeneration processes KRT8 and KRT18 expression to KRT7 and KRT19 is associated with structural remodelling of end stage kidney and increased frequency of tumors expressing both KRT7 and KRT19KRT17 in the biology of kidney cancer is not yet known. Two earlier studies on the keratin expression in distinct types of renal cell cancer using the E3 clone from DAKO did not find KRT17 expression in conventional, chromophobe and papillary renal cell tumors or renal oncocytoma Keratins are intermediate filaments playing a crucial role in the integrity and mechanical stability of single epithelial cells and epithelial tissues. The expression of keratins is regulated in a tissue-type and differentiation-specific manner KRT17 a member of type I acidic epithelial keratin family was first identified in skin basal cell epithelioma and it is considered to be a basal/myoepithelial cell keratin KRT17 occurs in complex, multilayered epithelia and it is largely retained during neoplastic transformation leading to several types of cancer derived from such epithelial cells KRT17 expression has also been detected in several tumors of non-epithelial type but not in their tissue of origin. These studies demonstrated a correlation between neo-expression of the KRT17 and tumor progression KRT17 in fetal development, regeneration and tumorigenesis and on the other hand in the progression of frankly malignant cancers.KRT17 in the biology of renal tumors we applied immunohistochemistry to a large panel of conventional RCC and papillary RCT as well as to preneoplastic lesions (PNL) associated with papillary RCT. In our study we used an antibody arised against the N-terminal protein fragment of KRT17 instead of the E3 clone from DAKO .In attempt to learn about the involvement of We have enrolled tumor samples from consecutively operated patients without selection, who undervent radical or partial nephrectomy due to kidney cancer between 2000 and 2013 at the Department of Urology, Medical School, University of Pecs, Hungary. The only criteria was the availability of clinical data, follow-up and paraffin embedded tumor material. Data on regular follow-up and tumor-specific death were obtained from the Registry of the Department of Urology. Follow-up was defined as time from operation until the last recorded control in 2018, or cancer-specific death. Patients who died from causes other than RCC were excluded from this analysis. Preoperative clinical staging included abdominal and chest computed tomography (CT) scans. Bone scans and brain CT scans were obtained only when clinically indicated. The presence of nodal metastases was confirmed by histological, whereas that of distant metastases by radiographic examination. During the postoperative period patients were surveyed every 6 months by abdominal ultrasound scans, serum creatinine and eGFR measurements, and every year by CT scans. Histological diagnoses were performed by a genitourinary pathologist (GK) according to the Heidelberg and TNM classification systems Haematoxylin and eosin stained slides were reviewed to select the representative paraffin blocks and tumor areas for TMA construction. From each tumor minimum three core biopsies with a diameter of 0.6 mm were placed in the recipient block using a Manual Tissue Arrayer . For marking the TMAs fetal and adult kidney biopsies were included.0C in a moist chamber with rabbit polyclonal anti-KRT17 antibody  at 1:500 dilution. Horse-radish-peroxydase conjugated anti-rabbit, anti-mouse secondary antibody  was applied for 30 minutes at room temperature and the bound antibody was visualized with AEC (Amino-ethyl-carbazol) . Tissue sections were counterstained with Mayer's haematoxylin. In negative control the primary antibody was omitted. The slides were evaluated twice at different times by two of the authors . The staining intensities were scored as low, medium or high. As we did not find substantial differences between weak or strong KRT17 expression and conventional RCC progression, we have evaluated all staining intensity as positive.Paraffin blocks of fetal and adult kidneys, pre-neoplastic lesions and TMAs were used for immunohistochemistry. After deparaffinisation and rehydration the 4 um thick sections were subjected to heat-induced epitope retrieval in citrate buffer, pH 6.0 in 2100-Retriever . Endogenous peroxidase activity and unspecific binding sites were blocked with 3% hydrogen peroxide containing 1% normal horse serum for 15 minutes at room temperature. Slides were incubated overnight at 4KRT17 expression, clinical and pathological parameters were calculated using the \u03c72 test. The effects of the different variables  on the survival of the patients were estimated by Kaplan-Meier analyses. Comparisons of survival curves were made using the Log rank test. Univariate and multivariate survival analyses were performed using the Cox regression model. Patients that were alive and disease-free were censored. Differences were considered significant at p < 0.05.Data analyses were performed using a SPSS Statistics software package version 25 . Correlations between KRT17 first appeared in the ureteric bud and collecting duct of fetal kidney , the average follow-up was 60.6\u00b133.2 months. Out of the 692 patients 108 (16%) developed metastasis during the follow-up and died due to metastatic cancer. The clinical parameters and correlation with KRT17 expression is shown in Table KRT17 staining which showed a significant correlation with cancer specific death, tumor size, T-stadium, grade and stage. The Kaplan-Meier analysis indicated that patients with KRT17 positive tumor have a significantly shorter survival than those with negative tumor . The KRT17 expression was an independent negative survival factor indicating a nearly three times higher risk of disease relapse and cancer specific death .To estimate the role of KRT17 has other functions as well. KRT17 plays a role in fetal epidermal development and in cell proliferation during wound healing by regulation of protein synthesis through intracellular signaling pathways KRT17 knockout mouse embryos show a delay in closure of surface ectoderm wounds KRT17 binds and sequester TRADD (TNFRSF1A associated via death domain), a mediator of programmed cell death signaling and protects the cells from apoptosis KRT17 null keratinocytes are sensitive to TNF mediated apoptosis KRT17 expression in embryonic ectoderm reflects its commitment towards distinct epithelial lineages and that the program of gene expression characteristic of wound-activated adult keratinocyte may have a relationship to that executed by epithelial cells at specific stages of embryonic development CD44+/KRT17+ cells have stemlike properties, including the capacity for cell renewal and in vivo tumorigenicity Beyond its role to maintain cellular integrity of multi-layered epithelia KRT17 is expressed in simple (one-layered) epithelial cells of fetal and adult kidney. Each PNL of embryonal origin as well as 77% of papillary RCT showed the KRT17 positivity irrespectively of cell type. Taking into account that only 5% of papillary RCTs developed metastasis during 5-year follow-up (data not shown), the role of KRT17 in the progression of papillary RCT can be excluded. Rather, the expression of KRT17 in fetal kidney suggests that it may play a role in the cell specific differentiation of tubular cells similarly to its role in fetal epidermal development KRT17 is associated with the development of PNL and subsequently of papillary RCT. This finding indicates a molecular relationship between kidney development and papillary RCT tumorigenesis. The developmental sequences outlined by KRT17 expression support our hypothesis on the unique natural history of papillary RCT We showed in this study that KRT17 is a basal/myoepithelial cell keratin the expression of which depends on the position of cells in complex multiplayer human epithelia KRT17 has been described in bladder carcinoma, keratoacanthoma and squamous cell carcinoma, oral squamous cell carcinoma, premalignant and malignant squamous lesions of the cervix, all derived from multilayer epithelial cells KRT17 has also been found in several other types of cancer such as gastric adenocarcinoma, ovarian and breast carcinoma, papillary thyroid carcinoma but not in their corresponding normal tissue KRT17 in these cases showed a significant correlation with tumor progression and metastasis. We have identified KRT17 expression in conventional RCCs as an independent negative survival factor indicating a higher risk for postoperative tumour relapse and cancer specific death of patients. Conventional RCC derives from KRT17 negative proximal tubules of the kidney, which suggests that KRT17 has not been involved in the development of conventional RCC. Rather, the neo-expression of KRT17 in conventional RCC can be used as a predictive biomarker similar to gastric, ovarian or breast carcinoma KRT17 in gastric cancer cells inhibited cell proliferation both in vitro and in vivo conditions, reduced the migration of tumor cells and induced apoptosis by BCL2 expression. They also showed that silencing KRT17 leads to cell-cycle arrest at G1/S phase of tumor cells. The clinical, pathological as well as experimental data strongly suggest the involvement of KRT17 neo-expression in tumor progression.Expression of KRT17 is expressed in a single-layered epithelia, and that papillary RCT and conventional RCC have distinct natural history. The continuous expression of KRT17 from fetal kidney tubules towards papillary RCT in adult confirm the relationship between fetal kidney development and tumorigenesis of papillary RCT. And finally, the neo-expression of KRT17 in aggressive growing conventional RCC is significantly associated with postoperative tumor relapse. The multiple functions of KRT17 in kidney cancers unequivocally delineates papillary RCTs and conventional RCCs with distinct natural history, which should be taken into account in clinical managements and therapy.The key novel findings of this study are, that"}
+{"text": "Ligand binding to death receptors activates apoptosis in cancer cells. Stimulation of death receptors results in the formation of intracellular multiprotein platforms that either activate the apoptotic initiator Caspase-8 to trigger cell death, or signal through kinases to initiate inflammatory and cell survival signalling. Two of these platforms, the Death-Inducing Signalling Complex (DISC) and the RIPoptosome, also initiate necroptosis by building filamentous scaffolds that lead to the activation of mixed lineage kinase domain-like pseudokinase. To explain cell decision making downstream of death receptor activation, we developed a semi-stochastic model of DISC/RIPoptosome formation. The model is a hybrid of a direct Gillespie stochastic simulation algorithm for slow assembly of the RIPoptosome and a deterministic model of downstream caspase activation. The model explains how alterations in the level of death receptor-ligand complexes, their clustering properties and intrinsic molecular fluctuations in RIPoptosome assembly drive heterogeneous dynamics of Caspase-8 activation. The model highlights how kinetic proofreading leads to heterogeneous cell responses and results in fractional cell killing at low levels of receptor stimulation. It reveals that the noise in Caspase-8 activation\u2014exclusively caused by the stochastic molecular assembly of the DISC/RIPoptosome platform\u2014has a key function in extrinsic apoptotic stimuli recognition. Death receptors are targets of novel cancer therapeutics. Most of them signal through flexible multiprotein platforms to either activate apoptotic or necroptotic cell death, or propagate cell survival and pro-inflammatory signals. We focused our study on the role of dynamic assembly and composition of these platforms in the initiation of cell death at the single cell level. Since the assembly is slow through the competitive nature of protein binding within the platforms core we developed a stochastic mathematical model of the death inducing signalling platform. Our model provided an explanation for delayed cell death and fractional killing upon the death receptor stimulation. Additionally, we found that the variability in the cell death response arises through the random assembly initiates a slow noise-prone ramp activation of initiator Caspase-8 spontaneously triggering the apoptotic cascade. Our computational simulations predicted high variation in the time required for cell death induction at the single cell level and highlighted a significant role of death receptor clustering in effective Caspase-8 activation. Our knowledge and data driven model captures detailed processes governing the early events of cell death initiation and can be used to guide the development of more rational combinational treatments against cancer. Apoptotic signalling cascades are designed to irreversibly lead to cell death once specific death thresholds are overcome ,2. Activin vivo studies have shown that fractional death resistance has no direct association with the amount of DRs expressed on the plasma membrane  is the total number of receptors per cell  and Caspase 6 (Casp6) which is triggered by stochastically activated Casp8. Pro-forms of both caspases form stable dimers at physiological concentrations . By cleaAll protein concentrations and parameters used in the model are provided in Tables D and E of Materials and Methods file .in vitro [The estimated weight of the RIPoptosome after short DR-targeted stimulation may exceed 2MDa ,24,29. Tin vitro , howeverThe composition and the time evolution of individual RIPoptosomes within single cell differed from one to another. Consequently, the size and, therefore, molecular weight of those RIPoptosomes varies as well. As an example, we display the composition change in a few randomly chosen RIPoptosomes over the first 20 min with 1 min step interval , S2 Fig.FADD recruitment to the fraction of the high molecular weight complexes is persistently increasing with post treatment time . Our simOn the contrary, ProCasp8 recruitment in the single cell is most abundant in the RIPoptosome of the lower molecular weight . The binMolecular fluctuations in the RIPoptosome composition within single cells cause the fluctuations in the active Casp8 abundance . StochasAveraged over the population the Casp8 activation time course demonstrated high dependence on the dose of the DL as well as the clustering capacity . Thus, eAs expected, the overall variability in the Casp8 activation is a function of the treatment dose . DespiteNext we studied the downstream caspase cleavage cascade, the second deterministic modelling module , which fkcat). Ubiquitination of active Casp3, which is set by XIAP, will attract proteasomal complex leading to Casp3 degradation. However, application of proteasome inhibitors does not stabilise the pool of active Casp3 and consequently does not result in reduced Casp3 proteasomal degradation. Instead, Casp3 catalytic activity is absolutely required for its own proteasomal degradation [kcat needs to be significantly higher (1.75 min-1) from the general  ubiquitin-dependent degradation rate (0.04 min-1) [kcat value    and ODE integration as well as semi-stochastic hybrid model was implemented in the MATLAB 2017b environment see also .S1 Figet al., 2014). Distribution for ligand free (in blue) and ligand bound receptors (in pink) in stimulated cells are followed separately. Distribution of bound receptors was approximated by splines (in red). Distribution for the trimeric Vesicular Stomatitis Virus G protein (VSVG) (in yellow) was used for the peaks calibration. Numbers above the peaks represent amount of monomeric receptor per corresponding cluster and red dots below represent the trimeric receptor complexes. The table demonstrates the conversion of the frequencies into the percentage of clusters from the total DR pool.Experimental frequency distribution of the TNFR1 cluster size on the cellular membrane of unstimulated (black line) and TNF\u03b1 stimulated HeLa cells derived by Super-resolution PALM microscopy (Fricke (TIF)Click here for additional data file.S2 FigModel generated individual RIPoptosome growth over first 20 min after DR stimulation with 5ng/mL of DL assuming receptor clustering scenario. Plots show eight individual RIPoptosomes randomly chosen from different randomly selected cells.(TIF)Click here for additional data file.S3 FigPopulation average Casp8 activation per cell simulated with model under receptor clustering and disrupted receptor clustering assumption upon stimulation with 5, 7.5, 50 and 250 ng/mL of the DL. Single cell trajectories have been averaged over 100 cells in each represented condition.(TIF)Click here for additional data file.S4 FigAverage FADD abundance per origin simulated for culture of 600 HeLa cells with clustering scenario (A) and without clustering (B) for low (5 ng/mL) and high (50 ng/mL) concentrations of the DL. (C) and (D) represent corresponding quantities for average abundance of ProCasp8 together with DED1-DED2.s.(TIF)Click here for additional data file.S5 FigResult of semi-stochastic model  and full stochastic model  simulation for 20 HeLa cells with clustering scenario for 50 ng/mL concentration of the DL.(TIF)Click here for additional data file.S1 File(PDF)Click here for additional data file.S1 Appendix(M)Click here for additional data file."}
+{"text": "Moringa oleifera,\u201d published in this journal  [I read with interest the article by Omabe et al., entitled \u201cAnion Gap Toxicity in Alloxan Induced Type 2 Diabetic Rats Treated with Antidiabetic Noncytotoxic Bioactive Compounds of Ethanolic Extract of Alloxan is one of the oldest chemicals to induce experimental diabetes. It induces type 1 diabetes through a single dose administration in laboratory animals. Alloxan acts in two ways: it selectively inhibits glucose-induced insulin secretion through specific inhibition of glucokinase, the glucose sensor of the beta cell, and it causes a state of insulin-dependent diabetes through its ability to induce reactive oxygen species (ROS) formation, resulting in the selective necrosis of pancreatic beta cells , 3. TherIn the article by Omabe et al., type 2 diabetes has been induced by a single intraperitoneal injection of alloxan, which is not correct due to its mechanism of action."}