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Implementation of Patient Safety and Patient-Centeredness Strategies in Iranian Hospitals. |
OBJECTIVE: To examine the extent of implementation for patient safety (PS) and patient-centeredness (PC) strategies and their association with hospital characteristics (type, ownership, teaching status, annual evaluation grade) in Iran. METHODS: A cross-sectional study through an adapted version of the MARQuIS questionnaire, eliciting information from hospital and nursing managers in 84 Iranian hospitals on the implementation of PS and PC strategies in 2009-2010. RESULTS: The majority of hospitals reported to have implemented 84% of the PS and 72% of the PC strategies. In general, implementation of PS strategies was unrelated to the type of hospital, with the exception of health promotion reports, which were more common in the Social Security Organization (SSO), and MRSA testing, which was reported more often in nonprofit hospitals. MRSA testing was also more common among teaching hospitals compared to non-teaching hospitals. The higher grade hospitals reported PS strategies significantly more frequently than lower grade hospitals. Overall, there was no significant difference in the reported implementation of PC strategies across general and specialized hospitals; except for the provision of information in different languages and recording of patient's diet which were reported significantly more often by general than specialized hospitals. Moreover, patient hotel services were more common in private compared to public hospitals. CONCLUSIONS: Despite substantial reporting of PS and PC strategies, there is still room for strengthening standard setting on safety, patient services and patient-centered information strategies in Iranian hospitals. To assure effective implementation of PS and PC strategies, enforcing standards, creating a PS and PC culture, increasing organizational responsiveness, and partnering with patients and their families need more attention. |
US Definitions, Current Use, and FDA Stance on Use of Platelet-Rich Plasma in Sports Medicine. |
With increased utilization of platelet-rich plasma (PRP), it is important for clinicians to understand the United States, the Food and Drug Administration (FDA) regulatory role and stance on PRP. Blood products such as PRP fall under the prevue of FDA's Center for Biologics Evaluation and Research (CBER). CBER is responsible for regulating human cells, tissues, and cellular and tissue-based products. The regulatory process for these products is described in the FDA's 21 CFR 1271 of the Code of Regulations. Under these regulations, certain products including blood products such as PRP are exempt and therefore do not follow the FDA's traditional regulatory pathway that includes animal studies and clinical trials. The 510(k) application is the pathway used to bring PRP preparation systems to the market. The 510(k) application allows devices that are "substantially equivalent" to a currently marketed device to come to the market. There are numerous PRP preparation systems on the market today with FDA clearance; however, nearly all of these systems have 510(k) clearance for producing platelet-rich preparations intended to be used to mix with bone graft materials to enhance bone graft handling properties in orthopedic practices. The use of PRP outside this setting, for example, an office injection, would be considered "off label." Clinicians are free to use a product off-label as long as certain responsibilities are met. Per CBER, when the intent is the practice of medicine, clinicians "have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects." Finally, despite PRP being exempted, the language in 21 CFR 1271 has caused some recent concern over activated PRP; however to date, the FDA has not attempted to regulate activated PRP. Clinicians using activated PRP should be mindful of these concerns and continued to stay informed. |
Clinical Effectiveness of Protein and Amino Acid Supplementation on Building Muscle Mass in Elderly People: A Meta-Analysis. |
OBJECTIVE: A major reason for the loss of mobility in elderly people is the gradual loss of lean body mass known as sarcopenia. Sarcopenia is associated with a lower quality of life and higher healthcare costs. The benefit of strategies that include nutritional intervention, timing of intervention, and physical exercise to improve muscle loss unclear as finding from studies investigating this issue have been inconsistent. We have performed a systematic review and meta-analysis to assess the ability of protein or amino acid supplementation to augment lean body mass or strength of leg muscles in elderly patients. METHODS: Nine studies met the inclusion criteria of being a prospective comparative study or randomized controlled trial (RCT) that compared the efficacy of an amino acid or protein supplement intervention with that of a placebo in elderly people (>/=65 years) for the improvement of lean body mass (LBM), leg muscle strength or reduction associated with sarcopenia. RESULTS: The overall difference in mean change from baseline to the end of study in LBM between the treatment and placebo groups was 0.34 kg which was not significant (P = 0.386). The overall differences in mean change from baseline in double leg press and leg extension were 2.14 kg (P = 0.748) and 2.28 kg (P = 0.265), respectively, between the treatment group and the placebo group. CONCLUSIONS: These results indicate that amino acid/protein supplements did not increase lean body mass gain and muscle strength significantly more than placebo in a diverse elderly population. |
Increased orbitofrontal cortex activation associated with "pro-obsessive" antipsychotic treatment in patients with schizophrenia. |
BACKGROUND: Patients with schizophrenia have an approximately 10-fold higher risk for obsessive-compulsive symptoms (OCS) than the general population. A large subgroup seems to experience OCS as a consequence of second-generation antipsychotic agents (SGA), such as clozapine. So far little is known about underlying neural mechanisms. METHODS: To investigate the role of SGA treatment on neural processing related to OCS in patients with schizophrenia, we stratified patients according to their monotherapy into 2 groups (group I: clozapine or olanzapine; group II: amisulpride or aripiprazole). We used an fMRI approach, applying a go/no-go task assessing inhibitory control and an n-back task measuring working memory. RESULTS: We enrolled 21 patients in group I and 19 patients in group II. Groups did not differ regarding age, sex, education or severity of psychotic symptoms. Frequency and severity of OCS were significantly higher in group I and were associated with pronounced deficits in specific cognitive abilities. Whereas brain activation patterns did not differ during working memory, group I showed significantly increased activation in the orbitofrontal cortex (OFC) during response inhibition. Alterations in OFC activation were associated with the severity of obsessions and mediated the association between SGA treatment and co-occurring OCS on a trend level. LIMITATIONS: The main limitation of this study is its cross-sectional design. CONCLUSION: To our knowledge, this is the first imaging study conducted to elucidate SGA effects on neural systems related to OCS. We propose that alterations in brain functioning reflect a pathogenic mechanism in the development of SGA-induced OCS in patients with schizophrenia. Longitudinal studies and randomized interventions are needed to prove the suggested causal interrelations. |
Salinity in Drinking Water and the Risk of (Pre)Eclampsia and Gestational Hypertension in Coastal Bangladesh: A Case-Control Study. |
BACKGROUND: Hypertensive disorders in pregnancy are among the leading causes of maternal and perinatal death in low-income countries, but the aetiology remains unclear. We investigated the relationship between salinity in drinking water and the risk of (pre)eclampsia and gestational hypertension in a coastal community. METHODS: A population-based case-control study was conducted in Dacope, Bangladesh among 202 pregnant women with (pre)eclampsia or gestational hypertension, enrolled from the community served by the Upazilla Health Complex, Dacope and 1,006 matched controls from the same area. Epidemiological and clinical data were obtained from all participants. Urinary sodium and sodium levels in drinking water were measured. Logistic regression was used to calculate odds ratios, and 95% confidence intervals. FINDINGS: Drinking water sources had exceptionally high sodium levels (mean 516.6 mg/L, S.D 524.2). Women consuming tube-well (groundwater) were at a higher disease risk than rainwater users (p<0.001). Adjusted risks for (pre)eclampsia and gestational hypertension considered together increased in a dose-response manner for increasing sodium concentrations (300.01-600 mg/L, 600.1-900 mg/L, >900.01 mg/L, compared to <300 mg/L) in drinking water (ORs 3.30 [95% CI 2.00-5.51], 4.40 [2.70-7.25] and 5.48 [3.30-9.11] (p-trend<0.001). Significant associations were seen for both (pre)eclampsia and gestational hypertension separately. INTERPRETATION: Salinity in drinking water is associated with increased risk of (pre)eclampsia and gestational hypertension in this population. Given that coastal populations in countries such as Bangladesh are confronted with high salinity exposure, which is predicted to further increase as a result of sea level rise and other environmental influences, it is imperative to develop and evaluate affordable approaches to providing water with low salt content. |
Chimaeric Virus-Like Particles Derived from Consensus Genome Sequences of Human Rotavirus Strains Co-Circulating in Africa. |
Rotavirus virus-like particles (RV-VLPs) are potential alternative non-live vaccine candidates due to their high immunogenicity. They mimic the natural conformation of native viral proteins but cannot replicate because they do not contain genomic material which makes them safe. To date, most RV-VLPs have been derived from cell culture adapted strains or common G1 and G3 rotaviruses that have been circulating in communities for some time. In this study, chimaeric RV-VLPs were generated from the consensus sequences of African rotaviruses (G2, G8, G9 or G12 strains associated with either P[4], P[6] or P[8] genotypes) characterised directly from human stool samples without prior adaptation of the wild type strains to cell culture. Codon-optimised sequences for insect cell expression of genome segments 2 (VP2), 4 (VP4), 6 (VP6) and 9 (VP7) were cloned into a modified pFASTBAC vector, which allowed simultaneous expression of up to four genes using the Bac-to-Bac Baculovirus Expression System (BEVS; Invitrogen). Several combinations of the genome segments originating from different field strains were cloned to produce double-layered RV-VLPs (dRV-VLP; VP2/6), triple-layered RV-VLPs (tRV-VLP; VP2/6/7 or VP2/6/7/4) and chimaeric tRV-VLPs. The RV-VLPs were produced by infecting Spodoptera frugiperda 9 and Trichoplusia ni cells with recombinant baculoviruses using multi-cistronic, dual co-infection and stepwise-infection expression strategies. The size and morphology of the RV-VLPs, as determined by transmission electron microscopy, revealed successful production of RV-VLPs. The novel approach of producing tRV-VLPs, by using the consensus insect cell codon-optimised nucleotide sequence derived from dsRNA extracted directly from clinical specimens, should speed-up vaccine research and development by by-passing the need to adapt rotaviruses to cell culture. Other problems associated with cell culture adaptation, such as possible changes in epitopes, can also be circumvented. Thus, it is now possible to generate tRV-VLPs for evaluation as non-live vaccine candidates for any human or animal field rotavirus strain. |
Infertility following retained products of conception: is it the surgical procedure or the presence of trophoblastic tissue? |
OBJECTIVE: To compare the reproductive outcome of women who underwent re-evacuation of the uterine cavity due to suspected retained products of conception (RPOC) and in whom trophoblastic tissue was confirmed by histopathologic examination to those with negative pathologic findings. STUDY DESIGN: We retrospectively reviewed all cases of women who underwent uterine re-evacuation due to suspected RPOC between January 2000 and December 2010. Reproductive outcomes were compared between women in whom trophoblastic tissue was confirmed by histopathologic examination and those with negative pathologic findings. RESULTS: A total of 240 patients underwent uterine re-evacuation due to suspected RPOC, of whom 162 (67.5%) had pathological examination positive for RPOC, and 78 (32.5%) had pathologically negative RPOC. The rate of a new infertility problem following resection of a positive pathologic finding was significantly higher compared with a negative finding (P=0.029). The mean time to conception was significantly longer after resection of a positive pathologic finding compared with a negative finding (P<0.001). A significantly higher rate of hypomenorrhea/amenorrhea was found following resection of a positive pathologic finding compared with a negative finding (P=0.017). CONCLUSION: RPOC-associated infertility is primarily related to the presence of trophoblastic tissue rather than the surgical intervention per se in the gravid uterus. |
Effects of a contraceptive containing drospirenone and ethinylestradiol on blood pressure, metabolic profile and neurohumoral axis in hypertensive women at reproductive age. |
The use of combined oral contraceptives is widespread among hypertensive women despite being associated with increased cardiovascular risk. Contraceptives containing drospirenone, which has antimineralocorticoid properties, may have a positive or neutral effect on neurohumoral activation and metabolic homeostasis of hypertensive women at reproductive age. OBJECTIVES: To evaluate the effect of combined oral contraceptive containing drospirenone+ethinylestradiol on the systemic blood pressure, metabolic variables and neurohumoral axis in hypertensive women in reproductive age. DESIGN: Prospective controlled trial with 56 hypertensive women allocated in two groups: 30 volunteers under oral combined contraceptive use and 26 volunteers using non-hormonal contraceptive methods. Subjects were tested before the introduction of the contraceptive method and 6 months after its use. For data acquisition, we used continuous non-invasive beat-to-beat blood pressure curve recordings and, for the biochemical and hormonal analyses two blood samples were obtained. Student's t test was used to determine differences between groups and moments and p<0.05 was considered statistically signi fi cant. RESULTS: Comparing antropometric and blood pressure measurements, cardiac sympatho-vagal modulation, baroreceptor sensitivity, metabolic and neurohumoral axis variables between baseline and after 6 months, no signi fi cant difference was detected in each group or between groups. Except serum triglyceride levels which increased in the group of women using EE+DRSP after 6 months of use. CONCLUSION: A contraceptive containing 20mcg of ethinyl estradiol and 3mg of drospirenone causes no signi fi cant changes in clinical and autonomic parameters, metabolic variables and neurohumoral axis of hypertensive women. |
Pregnancy outcome of non-anonymous oocyte donation: a case-control study. |
OBJECTIVE: To evaluate the maternal and neonatal outcome of non-anonymous oocyte donation compared to in vitro fertilization. Study design We compared 84 oocyte donation pregnancies with a 251 matched in vitro fertilization cohort. Maternal and neonatal outcomes were retrieved from a nationwide perinatal registry. Oocyte donation and in vitro fertilization pregnancies were matched for maternal age, study center, ZIP code and embryo transfer date. Both maternal and neonatal complications and outcome were compared between oocyte donation and in vitro fertilization with univariate and multivariate logistic regression analyses, adjusting for maternal age, donor age, socio-economic status, ethnicity, and parity. RESULTS: In total, 277 women underwent 541 oocyte donation cycles. The median recipient age was 34.9 years (IQR: 31.5-38.5), while the median donor age was 34.4 years (IQR: 31.7-37.0). Clinical pregnancy rate was 26.6%, which is comparable to standard in vitro fertilization treatment. Donor age in years (OR 0.93, 95% CI 0.88-0.99) and a previous pregnancy of the recipient (OR 1.69, 95% CI 1.02-2.78) were significantly associated with clinical pregnancy rate. Both singleton and multiple oocyte donation pregnancies were associated with pregnancy-induced hypertension compared with in vitro fertilization singleton and multiple pregnancies (OR 1.99, 95%CI 1.02-3.89, OR 6.43, 95% CI 1.67-24.72, respectively). No significant differences in neonatal outcome were observed. CONCLUSION: Oocyte donation pregnancies are associated with an increased incidence of pregnancy-induced hypertension compared with age-matched in vitro fertilization controls. However, no significant differences in neonatal outcome were observed between oocyte donation and in vitro fertilization. |
The Huntington's Disease-Related Cardiomyopathy Prevents a Hypertrophic Response in the R6/2 Mouse Model. |
Huntington's disease (HD) is neurodegenerative disorder for which the mutation results in an extra-long tract of glutamines that causes the huntingtin protein to aggregate. It is characterized by neurological symptoms and brain pathology that is associated with nuclear and cytoplasmic aggregates and with transcriptional deregulation. Despite the fact that HD has been recognized principally as a neurological disease, there are multiple epidemiological studies showing that HD patients exhibit a high rate of cardiovascular events leading to heart failure. To unravel the mechanistic basis of cardiac dysfunction in HD, we employed a wide range of molecular techniques using the well-established genetic R6/2 mouse model that develop a considerable degree of the cardiac atrophy at end stage disease. We found that chronic treatment with isoproterenol, a potent beta-adrenoreceptor agonist, did not change the overall gross morphology of the HD murine hearts. However, there was a partial response to the beta-adrenergenic stimulation by the further re-expression of foetal genes. In addition we have profiled the expression level of Hdacs in the R6/2 murine hearts and found that the isoproterenol stimulation of Hdac expression was partially blocked. For the first time we established the Hdac transcriptional profile under hypertrophic conditions and found 10 out of 18 Hdacs to be markedly deregulated. Therefore, we conclude that R6/2 murine hearts are not able to respond to the chronic isoproterenol treatment to the same degree as wild type hearts and some of the hypertrophic signals are likely attenuated in the symptomatic HD animals. |
Magnesium Protects Cognitive Functions and Synaptic Plasticity in Streptozotocin-Induced Sporadic Alzheimer's Model. |
Alzheimer's disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3beta at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3beta in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy. |
Antiinflammatory Effect of Phytosterols in Experimental Murine Colitis Model: Prevention, Induction, Remission Study. |
Phytosterols, besides hypocholesterolemic effect, present anti-inflammatory properties. Little information is available about their efficacy in Inflammatory Bowel Disease (IBD). Therefore, we have evaluated the effect of a mixture of phytosterols on prevention/induction/remission in a murine experimental model of colitis. Phytosterols were administered x os before, during and after colitis induction with Dextran Sodium Sulfate (DSS) in mice. Disease Activity Index (DAI), colon length, histopathology score, 18F-FDG microPET, oxidative stress in the intestinal tissue (ileum and colon) and gallbladder ileum and colon spontaneous and carbachol (CCh) induced motility, plasma lipids and plasma, liver and biliary bile acids (BA) were evaluated. A similar longitudinal study was performed in a DSS colitis control group. Mice treated with DSS developed severe colitis as shown by DAI, colon length, histopathology score, 18F-FDG microPET, oxidative stress. Both spontaneous and induced ileal and colonic motility were severely disturbed. The same was observed with gallbladder. DSS colitis resulted in an increase in plasma cholesterol, and a modification of the BA pattern. Phytosterols feeding did not prevent colitis onset but significantly reduced the severity of the disease and improved clinical and histological remission. It had strong antioxidant effects, almost restored colon, ileal and gallbladder motility. Plasmatic levels of cholesterol were also reduced. DSS induced a modification in the BA pattern consistent with an increase in the intestinal BA deconjugating bacteria, prevented by phytosterols. Phytosterols seem a potential nutraceutical tool for gastrointestinal inflammatory diseases, combining metabolic systematic and local anti-inflammatory effects. |
Efficacy Outcome Selection in the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials. |
OBJECTIVES:: The Therapeutic Hypothermia After Pediatric Cardiac Arrest trials will determine whether therapeutic hypothermia improves survival with good neurobehavioral outcome, as assessed by the Vineland Adaptive Behavior Scales Second Edition, in children resuscitated after cardiac arrest in the in-hospital and out-of-hospital settings. We describe the innovative efficacy outcome selection process during Therapeutic Hypothermia After Pediatric Cardiac Arrest protocol development. DESIGN/SETTING:: Consensus assessment of potential outcomes and evaluation timepoints. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: We evaluated practical and technical advantages of several follow-up timepoints and continuous/categorical outcome variants. Simulations estimated power assuming varying hypothermia benefit on mortality and on neurobehavioral function among survivors. Twelve months after arrest was selected as the optimal assessment timepoint for pragmatic and clinical reasons. Change in Vineland Adaptive Behavior Scales Second Edition from prearrest level, measured as quasicontinuous with death and vegetative status being worst-possible levels, yielded optimal statistical power. However, clinicians preferred simpler multicategorical or binary outcomes because of easier interpretability and favored outcomes based solely on postarrest status because of concerns about accurate parental assessment of prearrest status and differing clinical impact of a given Vineland Adaptive Behavior Scales Second Edition change depending on prearrest status. Simulations found only modest power loss from categorizing or dichotomizing quasicontinuous outcomes because of high expected mortality. The primary outcome selected was survival with 12-month Vineland Adaptive Behavior Scales Second Edition no less than two SD below a reference population mean (70 points), necessarily evaluated only among children with prearrest Vineland Adaptive Behavior Scales Second Edition greater than or equal to 70. Two secondary efficacy outcomes, 12-month survival and quasicontinuous Vineland Adaptive Behavior Scales Second Edition change from prearrest level, will be evaluated among all randomized children, including those with compromised function prearrest. CONCLUSIONS:: Extensive discussion of optimal efficacy assessment timing, and of the advantages versus drawbacks of incorporating prearrest status and using quasicontinuous versus simpler outcomes, was highly beneficial to the final Therapeutic Hypothermia After Pediatric Cardiac Arrest design. A relatively simple, binary primary outcome evaluated at 12 months was selected, with two secondary outcomes that address the potential disadvantages of primary outcome. |
Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone. |
Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4'-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases. |
Dipeptidyl peptidase-4 (DPP-4): localization and activity in human and rodent islets. |
Dipeptidyl peptidase 4 (DPP-4) was recently found to be expressed in human and mouse islets with different expression pattern. However, whether species-dependent expression pattern is a generalized phenomenon and whether islet DPP-4 activity is regulated are not known. This study was conducted to investigate DPP-4 localization in several different species, and to examine the impact of glucose, incretin hormones, and insulin on islet DPP-4 activity. It was shown by immuofluorescent staining that there were two distinct species-specific expression pattern of islet DPP-4. The enzyme was expressed exclusively in alpha-cells in human and pig islets, but primarily in beta-cells in mouse and rat islets. INS-1 832/13 cells also expressed DPP-4, and inhibition of DPP-4 enhanced insulin secretion in the presence of glucagon-like peptide-1 (GLP-1) in the cells. DPP-4 activity was remarkably robust when cultured with high glucose, incretin hormones, and insulin in mouse and human islets as well as INS-1 832/13 cells and islet DPP-4 activity and expression pattern was not altered in double incretin receptor knockout mice, compared to wild type mice. We conclude that islet DPP-4 is species-specifically expressed in alpha-cell and ss-cell dominant patterns in several species and both patterns remained robust in enzyme activity during short-term metabolic challenge. |
Negative Regulation of Grb10 Interacting GYF Protein 2 on Insulin-Like Growth Factor-1 Receptor Signaling Pathway Caused Diabetic Mice Cognitive Impairment. |
Heterozygous Gigyf2+/- mice exhibits histopathological evidence of neurodegeneration such as motor dysfunction. Several lines of evidence have demonstrated the important role of insulin-like growth factor-1 receptor (IGF1R) signaling pathway in the neuropathogenic process of cognitive impairment, while decreased Grb10-Interacting GYF Protein 2 (GIGYF2) expression can alter IGF1R trafficking and its downstream signaling pathways. Growth factor receptor-bound protein 10 (Grb10), a suppressor of IGF1R pathway, has been shown to play a critical role in regulating diabetes-associated cognitive impairment. It remains unknown whether endogenous GIGYF2 expression contributes to the development of diabetes-associated cognitive impairment. Using streptozotocin (STZ)-induced diabetic mice model, we first demonstrated that a significantly increased level of GIGYF2 expression was correlated with a significant decrease in the expression of phosphorylated IGF1R as well as the phosphorylation of AKT and ERK1/2, two signaling pathways downstream of IGF1R, in the hippocampus of diabetic mice. On the contrary, in situ knockdown of GIGYF2 expression in hippocampus resulted in increased expression of phosphorylated IGF1R expression and correspondingly reversed the down-regulation of ERK1/2 phsophorylation but had no obvious effect on Grb10 expression. Functionally, knockdown of GIGYF2 expression markedly ameliorated diabetes-associated cognitive dysfunction as well as the ultrastructural pathology and abnormal neurobehavioral changes. These results suggest that increased expression of GIGYF2 might contribute to the development of diabetes-associated cognitive disorder via negatively regulating IGF1R signaling pathway. Therefore, down-regulation of GIGYF2 expression may provide a potential novel approach to treat diabetes-associated cognitive impairment caused by aberrant IGF1R signaling pathway. |
An examination of camptocormia assessment by dynamic quantification of sagittal posture. |
Objective: Camptocormia is a disabling pathology of the axial system that debilitates patients in their daily life. To date, there have been no studies evaluating the impact of camptocormia on walking performance. This study presents a new method for assessing sagittal posture under walking conditions in patients with camptocormia. Design: The severity of camptocormia was evaluated by measuring sagittal inclination, represented indirectly by the horizontal distance between the C7 and S1 markers (C7 sagittal arrow; C7-SAR). Sagittal inclination was measured under various behavioural conditions using clinical, radiological and kinematic approaches. Patients: Forty-three patients were included in the study (17 with Parkinson's disease and 26 with idiopathic camptocormia). Results: Under static conditions, C7-SAR could be assessed using different methods. During walking, there was a dramatic increase in C7-SAR values. Correlation analysis revealed a relationship between functional impairment and dynamic C7-SAR values, but not with radiological C7-SAR values. Patients with Parkinson's disease behaved differently from idiopathic patients, suggesting the involvement of different underlying physiopathological mechanisms. Conclusion: Monitoring sagittal inclination during walking is more accurate than radiological measurements to determinine the detrimental effects of camptocormia and its consequences for quality of life. |
The Prevalence and Factors for Cancer Screening Behavior among People with Severe Mental Illness in Hong Kong. |
OBJECTIVES: Screening is useful in reducing cancer incidence and mortality. People with severe mental illness (PSMI) are vulnerable to cancer as they are exposed to higher levels of cancer risks. Little is known about PSMI's cancer screening behavior and associated factors. The present study examined the utilization of breast, cervical, prostate, and colorectal cancer screening among PSMI in Hong Kong and to identify factors associated with their screening behaviors. METHOD: 591 PSMI from community mental health services completed a cross-sectional survey. RESULTS: The percentage of cancer screening behavior among those who met the criteria for particular screening recommendation was as follows: 20.8% for mammography; 36.5% for clinical breast examination (CBE); 40.5% for pap-smear test; 12.8% for prostate examination; and 21.6% for colorectal cancer screening. Results from logistic regression analyses showed that marital status was a significant factor for mammography, CBE, and pap-smear test; belief that cancer can be healed if found early was a significant factor for pap-smear test and colorectal screening; belief that one can have cancer without having symptoms was a significant factor for CBE and pap-smear test; belief that one will have a higher risk if a family member has had cancer was a significant factor for CBE; and self-efficacy was a significant factor for CBE and pap-smear test behavior. CONCLUSIONS: Cancer screening utilization among PSMI in Hong Kong is low. Beliefs about cancer and self-efficacy are associated with cancer screening behavior. Health care professionals should improve the knowledge and remove the misconceptions about cancer among PSMI; self-efficacy should also be promoted. |
Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjogren's syndrome: results of a large multicentre study. |
Objectives: To determine the clinical and laboratory differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjogren's syndrome (pSS), in a large Italian multicentre cohort. Method: Patients were selected according to the following criteria: fulfilling the American-European classification criteria for pSS, serum cryoglobulin and gammaglobulin levels evaluated, and lack of hepatitis C virus (HCV) infection. Multinomial analyses were performed by distinguishing three groups of pSS: (i) purpura associated with cryoglobulinaemic vasculitis (CV), (ii) purpura associated with hypergammaglobulinaemic vasculitis (HGV), and (iii) pSS patients without purpura (pSS controls). Patients with purpura but without cryoglobulins or hypergammaglobulinaemia were excluded. Results: A total of 652 patients were enrolled in this study. Group 1/CV comprised 23/652 patients (3.53%), group 2/HGV 40/652 patients (6.13%), and group 3/pSS controls 589/652 (90.34%). The three groups were found to be significantly different from each other (post-estimation test: group 1/CV vs. group 3/pSS controls: p < 0.0001; group 1/CV vs. group 2/HGV: p = 0.0001; group 2/HGV vs. group 3/pSS controls: p = 0.0003), thus confirming the different phenotypes of purpura in pSS.Multivariate analyses revealed that peripheral neuropathy (p < 0.001), low C4 (p < 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.02), and the presence of anti-SSB/La antibodies (p = 0.02) characterized CV whereas rheumatoid factor (p = 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.01), and anti-SSA/Ro antibodies (p = 0.049) were significantly associated with HGV. Lymphoma was associated only with CV. Conclusions: HGV is a cutaneous vasculitis, related to a benign B-cell proliferation, whereas CV is a systemic immune complex-mediated vasculitis with complement activation and a higher risk of lymphoma, thus confirming CV but not HGV as a prelymphomatous condition in pSS. |
Incidence of Incisional Hernia after Cesarean Delivery: A Register-Based Cohort Study. |
OBJECTIVE: To estimate the incidence of incisional hernias requiring surgical repair after cesarean delivery over a 10-year period. METHODS: This population- and register-based cohort study identified all women in Denmark with no history of previous abdominal surgery who had a cesarean delivery between 1991 and 2000. The cohort was followed from their first until 10 years after their last cesarean delivery within the inclusion period or until the first of the following events: hernia repair, death, emigration, abdominal surgery, or cesarean delivery after the inclusion period. For women who had a hernia repair, hospital records regarding the surgery and previous cesarean deliveries were tracked and manually analyzed to validate the relationship between hernia repair and cesarean delivery. Data were analyzed with a competing risk analysis that included each cesarean delivery. RESULTS: We identified 57,564 women who had had 68,271 cesarean deliveries during the inclusion period. During follow-up, 134 of these women had a hernia requiring repair. Of these 68 (51% [95% CI 42-60%]) were in a midline incision although the transverse incision was the primary approach at cesarean delivery during the inclusion period. The cumulated incidence of a hernia repair within 10 years after a cesarean delivery was 0.197% (95% CI 0.164-0.234%). The risk of a hernia repair was higher during the first 3 years after a cesarean delivery, with an incidence after 3 years of 0.157% (95% CI 0.127-0.187%). CONCLUSIONS: The overall risk of an incisional hernia requiring surgical repair within 10 years after a cesarean delivery was 2 per 1000 deliveries in a population in which the transverse incision was the primary approach at cesarean delivery. |
Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved. |
Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response to oncogenic stress and constitutes an efficient barrier to tumour progression. We have recently proposed that OIS may be involved in the pathogenesis of thyroid carcinoma by restraining tumour progression as well as the transition of well differentiated to more aggressive variants. Here, an OIS inducible model was established and used for dissecting the molecular mechanisms and players regulating senescence in human primary thyrocytes. We show that oncogenic RAS induces senescence in thyrocytes as judged by changes in cell morphology, activation of p16INK4a and p53/p21CIP1 tumour suppressor pathways, senescence-associated beta-galactosidase (SA-beta-Gal) activity, and induction of proinflammatory components including IL-8 and its receptor CXCR2. Using RNA interference (RNAi) we demonstrate that p16INK4a is necessary for the onset of senescence in primary thyrocytes as its depletion rescues RAS-induced senescence. Furthermore, we found that IL-8/CXCR2 network reinforces the growth arrest triggered by oncogenic RAS, as its abrogation is enough to resume proliferation. Importantly, we observed that CXCR2 expression coexists with OIS markers in thyroid tumour samples, suggesting that CXCR2 contributes to senescence, thus limiting thyroid tumour progression. |
Therapeutic effect of a TM4SF5-specific monoclonal antibody against colon cancer in a mouse model. |
Transmembrane 4 superfamily member 5 protein (TM4SF5) is presumed to serve as a molecular target to prevent or treat hepatocellular carcinoma (HCC) and colon cancer in a mouse model. Previously, we reported the efficacy of anti-cancer peptide vaccine targeting TM4SF5. In addition, we reported an anti-proliferative effect of anti-TM4SF5 monoclonal antibody in HCC. Here, we investigated expression of TM4SF5 in 45 primary colon cancer tissues. Almost all of the colon cancer tissues expressed TM4SF5 based on immunohistochemistry using anti-TM4SF5 monoclonal antibody. The treatment of human colon cancer cells with anti-TM4SF5 antibody reduced growth of TM4SF5 expressing cells and enhanced expression of E-cadherin and beta-catenin. Using mouse colon cancer models, we then evaluated the in vivo anti-cancer effect of anti-TM4SF5 antibody. Injection of the antibody significantly reduced growth of tumors priorly established by subcutaneous injection of human colon cancer cells HT-29 in a xenograft setting. We obtained similar results with mouse colon cancer cell line CT-26 in an allograft setting. Therefore, we suggest that the TM4SF5-specific monoclonal antibody has a therapeutic effect against colon cancer. |
Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism. |
Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated. The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues. Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics. These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP. |
PssP2 Is a Polysaccharide Co-Polymerase Involved in Exopolysaccharide Chain-Length Determination in Rhizobium leguminosarum. |
Production of extracellular polysaccharides is a complex process engaging proteins localized in different subcellular compartments, yet communicating with each other or even directly interacting in multicomponent complexes. Proteins involved in polymerization and transport of exopolysaccharide (EPS) in Rhizobium leguminosarum are encoded within the chromosomal Pss-I cluster. However, genes implicated in polysaccharide synthesis are common in rhizobia, with several homologues of pss genes identified in other regions of the R. leguminosarum genome. One such region is chromosomally located Pss-II encoding proteins homologous to known components of the Wzx/Wzy-dependent polysaccharide synthesis and transport systems. The pssP2 gene encodes a protein similar to polysaccharide co-polymerases involved in determination of the length of polysaccharide chains in capsule and O-antigen biosynthesis. In this work, a mutant with a disrupted pssP2 gene was constructed and its capabilities to produce EPS and enter into a symbiotic relationship with clover were studied. The pssP2 mutant, while not altered in lipopolysaccharide (LPS), displayed changes in molecular mass distribution profile of EPS. Lack of the full-length PssP2 protein resulted in a reduction of high molecular weight EPS, yet polymerized to a longer length than in the RtTA1 wild type. The mutant strain was also more efficient in symbiotic performance. The functional interrelation between PssP2 and proteins encoded within the Pss-I region was further supported by data from bacterial two-hybrid assays providing evidence for PssP2 interactions with PssT polymerase, as well as glycosyltransferase PssC. A possible role for PssP2 in a complex involved in EPS chain-length determination is discussed. |
Expression of XPG Protein in the Development, Progression and Prognosis of Gastric Cancer. |
BACKGROUND: Xeroderma pigmentosum group G (XPG) plays a critical role in preventing cells from oxidative DNA damage. This study aimed to investigate XPG protein expression in different gastric tissues and in patients with diverse prognoses, thus providing insights into its role in the development, progression and prognosis of gastric cancer (GC). METHODS: A total of 176 GC, 131 adjacent non-tumour tissues, 53 atrophic gastritis (AG) and 49 superficial gastritis (SG) samples were included. Immunohistochemical staining was used to detect XPG protein expression. RESULTS: XPG expression was significantly higher in GC tissues compared with adjacent non-tumour tissues. In the progressive disease sequence SG-->AG-->GC, XPG expression was significantly higher in AG and GC compared with SG. Analysis of clinicopathological parameters and survival in GC patients demonstrated a significant association between XPG expression level and depth of tumour invasion, macroscopic type, Lauren's classification, smoking, Helicobacter pylori infection and family history. Cox multivariate survival analysis indicated that patients with positive XPG expression had significantly longer overall survival (P = 0.020, HR = 0.394, 95%CI 0.179-0.866), especially in aged younger than 60 years (P = 0.027, HR = 0.361, 95%CI 0.147-0.888) and male patients (P = 0.002, HR = 0.209, 95%CI 0.077-0.571). CONCLUSIONS: This study demonstrated that XPG protein expression was related to the development, progression and prognosis of GC, and might thus serve as a potential biomarker for its diagnosis and prognosis. |
Host Genetic Background Influences the Response to the Opportunistic Pseudomonas aeruginosa Infection Altering Cell-Mediated Immunity and Bacterial Replication. |
Pseudomonas aeruginosa is a common cause of healthcare-associated infections including pneumonia, bloodstream, urinary tract, and surgical site infections. The clinical outcome of P. aeruginosa infections may be extremely variable among individuals at risk and patients affected by cystic fibrosis. However, risk factors for P. aeruginosa infection remain largely unknown. To identify and track the host factors influencing P. aeruginosa lung infections, inbred immunocompetent mouse strains were screened in a pneumonia model system. A/J, BALB/cJ, BALB/cAnNCrl, BALB/cByJ, C3H/HeOuJ, C57BL/6J, C57BL/6NCrl, DBA/2J, and 129S2/SvPasCRL mice were infected with P. aeruginosa clinical strain and monitored for body weight and mortality up to seven days. The most deviant survival phenotypes were observed for A/J, 129S2/SvPasCRL and DBA/2J showing high susceptibility while BALB/cAnNCrl and C3H/HeOuJ showing more resistance to P. aeruginosa infection. Next, one of the most susceptible and resistant mouse strains were characterized for their deviant clinical and immunological phenotype by scoring bacterial count, cell-mediated immunity, cytokines and chemokines profile and lung pathology in an early time course. Susceptible A/J mice showed significantly higher bacterial burden, higher cytokines and chemokines levels but lower leukocyte recruitment, particularly neutrophils, when compared to C3H/HeOuJ resistant mice. Pathologic scores showed lower inflammatory severity, reduced intraluminal and interstitial inflammation extent, bronchial and parenchymal involvement and diminished alveolar damage in the lungs of A/J when compared to C3H/HeOuJ. Our findings indicate that during an early phase of infection a prompt inflammatory response in the airways set the conditions for a non-permissive environment to P. aeruginosa replication and lock the spread to other organs. Host gene(s) may have a role in the reduction of cell-mediated immunity playing a critical role in the control of P. aeruginosa infection. These results now provide a basis for mapping genomic regions underlying host susceptibility to P. aeruginosa infection. |
5-Alpha-reductase inhibitors in diseases of the prostate. |
PURPOSE OF REVIEW: To summarize the history of the use of 5-alpha-reductase inhibitors in the treatment of urologic diseases and discuss the current practices and indications for therapy. RECENT FINDINGS: 5-Alpha-reductase inhibitors (5-ARIs) are indicated in the treatment of benign prostatic hyperplasia (BPH) with obstructive urinary symptoms to reduce symptoms, reduce the risk of acute urinary retention, and reduce the risk of needing surgical management for this condition. These drugs have also been employed in the treatment of recurrent and refractory hematuria of prostatic origin because of their effect on the androgen-mediated angiogenic pathways in the prostate. Data support the use of 5-ARIs for this indication, though this is off-label use. There is no role for the use of 5-ARIs in primary prostate cancer chemoprevention and they may increase the risk of developing high-grade prostate cancer. Current investigations are underway to determine the efficacy of 5-ARIs in the secondary treatment of localized prostate cancer as adjunctive therapy, which may decrease the likelihood of prostate cancer progression and increase the likelihood that patients will remain on active surveillance. SUMMARY: 5-ARIs have significantly impacted the medical treatment of urologic disease, in particular BPH, and prostatic hematuria. Their use in the secondary treatment of prostate cancer is currently under investigation. |
Comparison of Shockwave Lithotripsy and Flexible Ureteroscopy for the Treatment of Kidney Stones in Patients with Solitary Kidney. |
INTRODUCTION AND OBJECTIVES: To compare the outcomes of these minimally invasive procedures in this patient population. PATIENTS AND METHODS: The database of our institution has been retrospectively reviewed and medical records of urolithiasis patients with a solitary kidney who underwent F-URS or SWL between January 2009 and December 2012 were examined. Retreatment rates, complications, changes in estimated glomerular filtration rates (eGFR) and chronic kidney disease (CKD) stages, and stone-free rates were compared between the two groups. RESULTS: Stones of 48 patients (mean age: 48.8+/-15.4, range: 14-76) with solitary kidneys were treated with SWL (n=30, 62.5%) or F-URS (n=18, 37.5%). Patient demographics and stone related parameters were similar. The most common stone location was pelvis in the SWL group (36.6%) whereas it was pelvis and a calyx in the F-URS group (38.8%). Complications and success rates were similar in both groups, however patients in the SWL group needed more sessions to achieve stone clearance (2.2+/-0.89 vs. 1.06+/-0.24, p=0.0001). Preoperative and postoperative eGFR and CKD stage changes were also similar. CONCLUSION: Both SWL and F-URS are effective and safe techniques, which can be used for the treatment of stones in patients with solitary kidney. However, patients treated with SWL need more sessions to achieve stone clearance. |
Rhodiola Rosea for Mental and Physical Fatigue in Nursing Students: A Randomized Controlled Trial. |
BACKGROUND: Fatigue is one of many unintended consequences of shift work in the nursing profession. Natural health products (NHPs) for fatigue are becoming an increasingly popular topic of clinical study; one such NHP is Rhodiola rosea. A well-designed, rigorously conducted randomized controlled trial is required before therapeutic claims for this product can be made. OBJECTIVE: To compare the efficacy of R. rosea with placebo for reducing fatigue in nursing students on shift work. DESIGN: A parallel-group randomized, double-blinded, placebo-controlled trial of 18-55 year old students from the Faculty of Nursing from the University of Alberta, participating in clinical rotations between January 2011 and September 2011. INTERVENTIONS: Participants were randomized to take 364 mg of either R. rosea or identical placebo at the start of their wakeful period and up to one additional capsule within the following four hours on a daily basis over a 42-day period. OUTCOMES: The primary outcome was reduction in fatigue over the 42-day trial period measured using the Vitality-subscale of the RAND-36, cross-validated by the visual analogue scale for fatigue (VAS-F). Secondary outcomes included health-related quality of life, individualized outcomes assessment, and adverse events. RESULTS: A total of 48 participants were randomized to R. rosea (n = 24) or placebo (n = 24). The mean change in scores on the Vitality-subscale was significantly different between the study groups at day 42 in favor of placebo (-17.3 (95% CI -30.6, -3.9), p = 0.011), The mean change in scores on the VAS-F was also significantly difference between study groups at day 42 in favour of placebo (1.9 (95% CI 0.4, 3.5), p = 0.015). Total number of adverse events did not differ between R. rosea and placebo groups. CONCLUSION: This study indicates that among nursing students on shift work, a 42-day course of R. Rosea compared with placebo worsened fatigue; however, the results should be interpreted with caution. TRIAL REGISTRATION: Clinicaltrials.gov NCT01278992. |
Radiation Therapy Remains The Key Cost Driver Of Oncology Inpatient Treatment. |
Abstract Objective: Current radiation therapy capacities in Serbia and most of Eastern Europe are heavily lagging behind population needs. Primary study aim was assessment of direct costs of cancer medical care for patients suffering from cancer with assigned radiotherapy based treatment protocols. Identification of key cost drivers and trends during 2010-2013 comparing brachytherapy and teleradiotherapy was secondary objective of the study. Methods: Retrospective, bottom-up database analysis was conducted on electronic discharge invoices. Payer's perspective has been adopted and one year long time horizon. Total sample size was 2544 patients during four years long observation period (2010-2013). Sample consisted of all patients with confirmed malignancy disorder receiving inpatient radiation therapy in a large university hospital. Results: Diagnostics and treatment cost of cancer in the largest Western Balkans market of Serbia were heavily dominated by radiation therapy related direct medical costs. Total costs of care as well as mean cost per patient were steadily decreasing due to budget cuts caused by global recession. Paradox is that at the same time budget share of radiotherapy increased for almost 15% and in value based terms for euro 109 per patient (in total euro 109,330). Second ranked cost drivers were nursing care and imaging diagnostics. Costs of high-tech visualising examinations were heavily dominated by nuclear medicine tests. Conclusion: Budget impact of radiation oncology to the large tertiary care university clinics of the Balkans is likely to remain significant in future. Brachytherapy exhibited slow growth pattern while teleradiotherapy remained stable in terms of value based turnover of medical services. Upcoming heavy investment into national network of radiotherapy facilities will emphasize the unsatisfied needs. Huge contemporary budget share of radiotherapy coupled with rising cancer prevalence brings this issue into the hot spot of the ongoing cost containment efforts by local governments. |
Discovery of New Imidazole Derivatives Containing the 2,4-Dienone Motif with Broad-Spectrum Antifungal and Antibacterial Activity. |
A compound containing an imidazole moiety and a 2,4-dienone motif with significant activity toward several fungi was discovered in a screen for new antifungal compounds. Then, a total of 26 derivatives of this compound were designed, synthesized and evaluated through in vitro and in vivo antifungal activity assays. Several compounds exhibited improved antifungal activities compared to the lead compound. Of the derivatives, compounds 31 and 42 exhibited strong, broad-spectrum inhibitory effects toward Candida spp. In particular, the two derivatives exhibited potent antifungal activities toward the fluconazole-resistant isolate C. albicans 64110, with both having MIC values of 8 microg/mL. In addition, they had significant inhibitory effects toward two Gram-positive bacteria, Staphylococcus aureus UA1758 (compound 31: MIC = 8 microg/mL; compound 42: MIC = 4 microg/mL) and Staphylococcus epidermidis UF843 (compound 31: MIC = 8 microg/mL; compound 42: MIC = 8 microg/mL). The results of an animal experiment indicated that both compounds could improve the survival rate of model mice infected with ATCC 90028 (fluconazole-susceptible isolate). More importantly, the two compounds exhibited notable in vivo effects toward the fluconazole-resistant C. albicans isolate, which is promising with regard to the clinical problem posed by fluconazole-resistant Candida species. |
Anti-Fibrosis Effect of Scutellarin via Inhibition of Endothelial-Mesenchymal Transition on Isoprenaline-Induced Myocardial Fibrosis in Rats. |
Scutellarin (SCU) is the major active component of breviscapine and has been reported to be capable of decreasing myocardial fibrosis. The aim of the present study is to investigate whether SCU treatment attenuates isoprenaline-induced myocardial fibrosis and the mechanisms of its action. Rats were injected subcutaneously with isoprenaline (Iso) to induce myocardial fibrosis and rats in the SCU treatment groups were intraperitoneally infused with SCU (10 mg.kg-1.d-1 or 20 mg.kg-1.d-1, for 14 days). Post-treatment, cardiac functional measurements and the left and right ventricular weight indices (LVWI and RVWI, respectively) were analysed. Pathological alteration, expression of type I and III collagen, Von Willebrand factor, alpha-smooth muscle actin, cluster of differentiation-31 (CD31), and the Notch signalling proteins (Notch1, Jagged1 and Hes1) were examined. The administration of SCU resulted in a significant improvement in cardiac function and decrease in the cardiac weight indices; reduced fibrous tissue proliferation; reduced levels of type I and III collagen; increased microvascular density; and decreased expression of alpha-smooth muscle actin and increased expression of CD31, Notch1, Jagged1 and Hes1 in isoprenaline-induced myocardial fibrosis in rats. Our results suggest that SCU prevents isoprenaline-induced myocardial fibrosis via inhibition of cardiac endothelial-mesenchymal transition potentially, which may be associated with the Notch pathway. |
Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin. |
The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport. |
Five New Iridoids from Roots of Salvia digitaloides. |
Five new iridoids, salvialosides A-E (compounds 1-5), together with fifty known compounds were isolated from the roots of Salvia digitaloides. The structures of the new compounds were completely elucidated using a combination of 2D NMR techniques (COSY, NOESY, HMQC and HMBC) and HR-ESI-MS analyses. The known compounds were identified by comparison of their spectroscopic and physical data with those reported in the literature. |
Significance of Pulmonary Arterial Pressure as a Prognostic Indicator in Lung-Dominant Connective Tissue Disease. |
BACKGROUND: Lung-dominant connective tissue disease (LD-CTD) is a new concept for classifying the subset of patients with interstitial pneumonia who have clinical features suggesting an associated CTD, but whose features fall short of a clear diagnosis of CTD under the current rheumatologic classification systems. The impact of mean pulmonary arterial pressure (MPAP) in LD-CTD has not been sufficiently elucidated. OBJECTIVES: To evaluate the survival impact of MPAP measured during the initial evaluation in patients with LD-CTD. METHODS: We retrospectively analyzed the initial evaluation data of 100 LD-CTD patients undergoing pulmonary function test, 6-min walk test (6MWT), and right heart catheterization (RHC). RESULTS: The mean MPAP was 16.2+/-4.4 mm Hg, and 18 patients had MPAP>/=20 mm Hg. A univariate Cox proportional hazard model showed that MPAP and several variables have a statistically significant impact on survival. With stepwise, multivariate Cox proportional analysis, MPAP (HR = 1.293; 95% CI 1.130-1.480; p<0.001) and mean forced vital capacity (FVC) % predicted (HR = 0.958; 95% CI 0.930-0.986; p = 0.004) were shown to be independent determinants of survival. CONCLUSIONS: Higher MPAP and lower %FVC at the initial evaluation were significant independent prognostic factors of LD-CTD. MPAP evaluation provides additional information of disease status and will help physicians to predict mortality in LD-CTD. |
Impact of alpha-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel. |
To better understand the molecular basis of the enhanced cell killing effected by the combined modality of paclitaxel and 212Pb-trastuzumab (Pac/212Pb-trastuzumab), gene expression in LS-174T i.p. xenografts was investigated 24 h after treatment. Employing a real time quantitative PCR array (qRT-PCR array), 84 DNA damage response genes were quantified. Differentially expressed genes following therapy with Pac/212Pb-trastuzumab included those involved in apoptosis (BRCA1, CIDEA, GADD45alpha, GADD45gamma, GML, IP6K3, PCBP4, PPP1R15A, RAD21, and p73), cell cycle (BRCA1, CHK1, CHK2, GADD45alpha, GML, GTSE1, NBN, PCBP4, PPP1R15A, RAD9A, and SESN1), and damaged DNA repair (ATRX, BTG2, EXO1, FEN1, IGHMBP2, OGG1, MSH2, MUTYH, NBN, PRKDC, RAD21, and p73). This report demonstrates that the increased stressful growth arrest conditions induced by the Pac/212Pb-trastuzumab treatment suppresses cell proliferation through the regulation of genes which are involved in apoptosis and damaged DNA repair including single and double strand DNA breaks. Furthermore, the study demonstrates that 212Pb-trastuzumab potentiation of cell killing efficacy results from the perturbation of genes related to the mitotic spindle checkpoint and BASC (BRCA1-associated genome surveillance complex), suggesting cross-talk between DNA damage repair and the spindle damage response. |
Th1 Stimulatory Proteins of Leishmania donovani: Comparative Cellular and Protective Responses of rTriose Phosphate Isomerase, rProtein Disulfide Isomerase and rElongation Factor-2 in Combination with rHSP70 against Visceral Leishmaniasis. |
In visceral leishmaniasis, the recovery from the disease is always associated with the generation of Th1-type of cellular responses. Based on this, we have previously identified several Th1-stimulatory proteins of Leishmania donovani -triose phosphate isomerase (TPI), protein disulfide isomerase (PDI) and elongation factor-2 (EL-2) etc. including heat shock protein 70 (HSP70) which induced Th1-type of cellular responses in both cured Leishmania patients/hamsters. Since, HSPs, being the logical targets for vaccines aimed at augmenting cellular immunity and can be early targets in the immune response against intracellular pathogens; they could be exploited as vaccine/adjuvant to induce long-term immunity more effectively. Therefore, in this study, we checked whether HSP70 can further enhance the immunogenicity and protective responses of the above said Th1-stimulatory proteins. Since, in most of the studies, immunogenicity of HSP70 of L. donovani was assessed in native condition, herein we generated recombinant HSP70 and tested its potential to stimulate immune responses in lymphocytes of cured Leishmania infected hamsters as well as in the peripheral blood mononuclear cells (PBMCs) of cured patients of VL either individually or in combination with above mentioned recombinant proteins. rLdHSP70 alone elicited strong cellular responses along with remarkable up-regulation of IFN-gamma and IL-12 cytokines and extremely lower level of IL-4 and IL-10. Among the various combinations, rLdHSP70 + rLdPDI emerged as superior one augmenting improved cellular responses followed by rLdHSP70 + rLdEL-2. These combinations were further evaluated for its protective potential wherein rLdHSP70 + rLdPDI again conferred utmost protection ( approximately 80%) followed by rLdHSP70 + rLdEL-2 ( approximately 75%) and generated a strong cellular immune response with significant increase in the levels of iNOS transcript as well as IFN-gamma and IL-12 cytokines which was further supported by the high level of IgG2 antibody in vaccinated animals. These observations indicated that vaccine(s) based on combination of HSP70 with Th1-stimulatory protein(s) may be a viable proposition against intracellular pathogens. |
CCR5 Gene Editing of Resting CD4 T Cells by Transient ZFN Expression From HIV Envelope Pseudotyped Nonintegrating Lentivirus Confers HIV-1 Resistance in Humanized Mice. |
CCR5 disruption by zinc finger nucleases (ZFNs) is a promising method for HIV-1 gene therapy. However, successful clinical translation of this strategy necessitates the development of a safe and effective method for delivery into relevant cells. We used non-integrating lentivirus (NILV) for transient expression of ZFNs and pseudotyped the virus with HIV-envelope for targeted delivery to CD4+ T cells. Both activated and resting primary CD4+ T cells transduced with CCR5-ZFNs NILV showed resistance to HIV-1 infection in vitro. Furthermore, NILV transduced resting CD4+ T cells from HIV-1 seronegative individuals were resistant to HIV-1 challenge when reconstituted into NOD-scid IL2rgammac null (NSG) mice. Likewise, endogenous virus replication was suppressed in NSG mice reconstituted with CCR5-ZFN-transduced resting CD4+ T cells from treatment naive as well as ART-treated HIV-1 seropositive patients. Taken together, NILV pseudotyped with HIV envelope provides a simple and clinically viable strategy for HIV-1 gene therapy. |
Large-Scale Brain Systems and Subcortical Relationships: Practical Applications. |
This article describes an interactive paradigm for understanding brain functioning. This model requires both explicit and implicit learning processes. This paradigm is illustrated through the interpretation of practical examples of behavior. Applications of current neuropsychological tests are presented within this interactive paradigm. The development of new neuropsychological tests is presented, as derived from experimental test paradigms that evaluate implicit learning processes. |
Large-Scale Brain Systems and Subcortical Relationships: The Vertically Organized Brain. |
This article reviews the vertical organization of the brain. The cortico-basal ganglia and the cerebro-cerebellar circuitry systems are described as fundamental to cognitive and behavioral control. The basal ganglia anticipate and guide implicitly learned behaviors on the basis of experienced reward outcomes. The cerebellar-cortical network anticipates sensorimotor outcomes, allowing behaviors to be adapted across changing settings and across contexts. These vertically organized systems, operating together, represent the underpinning of cognitive control. The medial temporal lobe system, and its development, is also reviewed in order to better understand how brain systems interact for both implicit and explicit cognitive control. |
The Small-World Organization of Large-Scale Brain Systems and Relationships With Subcortical Structures. |
Brain structure and function is characterized by large-scale brain systems. However, each system has its own "small-world" organization, with sub-regions, or "hubs," that have varying degrees of specialization for certain cognitive and behavioral processes. This article describes this small-world organization, and the concepts of functional specialization and functional integration are defined and explained through practical examples. We also describe the development of large-scale brain systems and this small-world organization as a sensitive, protracted process, vulnerable to a variety of influences that generate neurodevelopmental disorders. |
Structure and Function of Large-Scale Brain Systems. |
This article introduces the functional neuroanatomy of large-scale brain systems. Both the structure and functions of these brain networks are presented. All human behavior is the result of interactions within and between these brain systems. This system of brain function completely changes our understanding of how cognition and behavior are organized within the brain, replacing the traditional lesion model. Understanding behavior within the context of brain network interactions has profound implications for modifying abstract constructs such as attention, learning, and memory. These constructs also must be understood within the framework of a paradigm shift, which emphasizes ongoing interactions within a dynamically changing environment. |
Atypical parietal lobe activity to subliminal faces in youth with a family history of alcoholism. |
Abstract Background: Adults with alcohol use disorders (AUDs) show different behavioral and neurological functioning during emotional processing tasks from healthy controls. Adults with a family history (FHP) of AUD also show different activation in limbic brain areas, such as the amygdala. However, it is unclear if this pattern exists during adolescence before any episodes of heavy alcohol use. Objectives: We hypothesized that the amygdalar response to subliminally-presented fearful faces would be reduced in FHP adolescents compared to peers who were family history negative (FHN) for AUD. Method: An adapted Masked Faces paradigm was used to examine blood oxygen level-dependent response to subliminal fearful vs. neutral faces in 14 FHP (6 females, 8 males) and 15 FHN (6 females, 9 males) youth, ages 11-15 years. Both FHP and FHN youth had no history of heavy alcohol consumption. Results: A significant difference was seen between groups in the left superior parietal lobule FHN youth showed deactivation to fearful and neutral masked faces compared to baseline, whereas FHP youth showed deactivation only to fearful masked faces. No significant differences in amygdalar activation were seen between groups. Conclusion: The left superior parietal lobule is part of the fronto-parietal network, which has been implicated in attentional control. Lack of reduced neural activity to neutral faces among FHP youth may represent differences in suppressing attention networks to less salient emotional stimuli, or perhaps, a higher threshold of saliency for emotional stimuli among at-risk youth. |
Editorial: Unlocking the Potential of Stem Cells in Cell Therapy, Drug Delivery and Drug Discovery. |
In metazoans, adult, tissue-specific stem cells function to naturally replace and regenerate components of organ systems during life. The restorative power of adult stem cells has been best exploited clinically in bone marrow transplantation to treat blood cancers and other disorders. With the discovery and characterisation of other adult stem cell types and pluripotent stem cells capable of generating all tissues in the body, it has been postulated that stem cells may be of utility in replacing other tissues which have stopped functioning due to age or disease. However, the potential application of stem cells to regenerative medicine is vast and more multi-faceted than simply furnishing replacement tissue in failing organ systems. In this minithematic issue of Current Drug Delivery, we explore these other applications focusing on current knowledge about the regulation of stem cells, its implications for pathogenesis in cancer and cell therapy and how stem cells may be used as drug delivery agents and as tools in disease modelling and drug discovery. Adult stem cell function during homeostasis and in response to periods of physiological demand relies on strict intrinsic regulation interwoven with complex extrinsic signals emanating from the micro-environment (or 'niche'). That proper adult stem cell function in vivo is dependent on its niche was the concept first invoked in the blood system in the 1970s and is an idea that has gained considerable traction in this and other tissue systems more recently. The overall complexity of adult stem cell niches is gradually being understood at the level of cellular constituents and molecular pathways controlling their behaviour. In addition to its purely supportive role as a habitat for the stem cell, it is responsible for secreting growth factors and other regulatory proteins that extrinsically regulate stem cell functionality. Crawford and colleagues review the role of pigment epitheliumderived factor (PEDF), a critical regulator of neural stem cell self-renewal in the neural stem cell niche. The authors explore the potential therapeutic role of PEDF where its opposing positive effect on stem cell behaviour and powerful anti-angiogenic effect on cancers make it possible for it to operate as a selective drug in cancer while sparing or possibly boosting normal tissue function through harnessing endogenous stem cell function. It has also become increasingly clear how crucial the stem cell-niche collaboration is to the maintenance of normal tissue function: in the blood system the potentially dire consequences of disturbing particular constituents of the niche are evident in decreased stem cell function and the emergence of pre-cancerous and cancerous conditions in mouse models and select clinical syndromes. The niche may also provide a sanctuary that protects already existent cancer from the effects of treatment (e.g. chemotherapy), and enables eventual disease relapse. Bartos and Dubielecka-Szczerba explore how one potential component of the niche - actin cytoskeleton- is impacted by the Bcr-abl oncogene in chronic myeloid leukaemia, leading to drug and therapy resistance. Pluripotent stem cells, derived from the embryo (embryonic stem cells) or by reprogramming somatic cells to an embryonic state (induced pluripotent stem cells), and adult stem cells may impact cellular therapy in two distinct ways. As alluded to, they may directly replace damaged tissues in organ transplantation related strategies (see review by Stewart for examples using pluripotent stem cell derived tissue). Less well established but becoming more appreciated is that stem cells can function and act as drug delivery modalities, facilitating tissue replacement without formally integrating or replacing tissue. A case in point is mesenchymal stem/stromal cells (MSCs), which as English and colleagues discuss, have potent immune modulatory function that could be deployed to facilitate acceptance of allogeneic organ transplantation or to ameliorate graft versus host disease, a potentially fatal side-effect of allogeneic bone marrow transplantation (for another example, see Falanga and colleagues review of the use of MSCs to treat chronic wounds). Shinya Yamanaka was awarded the Nobel Prize in Physiology and Medicine in 2012 for discovering induced pluripotent stem cells (iPSCs), underscoring their potential to revolutionise therapies for a plethora of debilitating and fatal diseases via cell replacement therapy or drug discovery. For example, the capacity to make iPSCs from a somatic cell of a patient afflicted with a given disease offers an unprecedented opportunity to peer into the evolution of that disease by essentially rewinding its history in vitro and modelling the earliest pathological steps associated with it, with an ultimate view of identifying drug targets for treatment. Stewart reviews and explains progress made to date with disease specific iPSCs in this context set against a historical perspective of the pluripotent stem cell biology field. Finally, translating the potential of pluripotent stem cell derived tissue or adult stem cells (e.g. MSCs) into both safe and effective clinical therapies in any setting involving administration of cellular products requires adherence to Good Manufacturing Practice (GMP) supervised by the Food and Drug Administration (FDA) regulatory framework in the United States and by the European Medicines Agency (EMA) in Europe. Falanga and colleagues outline the laborious yet essential strategy required to establish a GMP lab for these purposes and describe their experience with using the laboratory to manipulate MSCs that will encourage chronic wound healing. |
Annexin A8 Is a Prognostic Marker and Potential Therapeutic Target for Pancreatic Cancer. |
OBJECTIVES: We investigated whether annexin A8 (A-A8), a Ca-binding protein overexpressed in pancreatic cancer, plays a role in cell growth and migration and investigated its association with pancreatic cancer prognosis. METHODS: Clinicopathological features and associations between increased A-A8 expression (determined by immunohistochemistry) and histologic grade were studied in a tissue microarray of 90 patients with resected stage I/II pancreatic cancer. We investigated A-A8's effect on cell migration, proliferation, and colony formation in 2 pancreatic cancer cells (BXPC-3 and Panc-1). Statistical analyses included Fisher exact test, t test, analysis of variance, and survival analysis. RESULTS: Western blot showed increased A-A8 expression in human pancreatic cancer cells, with A-A8 knockdown in BXPC-3 and Panc-1 cells demonstrating decreased cell viability (P = 0.017 and P = 0.001), migration (2.5 vs 0.9 mm and 1.6 vs 1 mm at 96 hours; P = 0.048 and P = 0.004), and colony formation (approximately 75% and 40% from scramble; P </= 0.01), respectively. In our tissue microarray, A-A8 expression increased 5.9-fold (r = 0.31; P = 0.019) from low- to high-grade tumors, correlating with tumor grade (r = 0.23; P = 0.027). In addition, high A-A8 expression was associated with a decreased 5-year survival (P = 0.042). CONCLUSIONS: Our study is the first showing that increased A-A8 expression is associated with poor prognosis in early-stage pancreatic cancer, thus supporting its further investigation as a future therapeutic target and prognostic marker. |
Prevalence of Behcet's disease in the province of Brescia in northern Italy. |
Interferon alfa-associated depression in patients with Behcet's syndrome: a prospective controlled study. |
Anti-cytokine biologic treatment beyond anti-TNF in Behcet's disease. |
Unmet therapeutic needs in Behcet's disease have drawn recent attention to biological agents targeting cytokines other than TNF. The anti-IL-17 antibody secukinumab and the anti-IL-2 receptor antibody daclizumab were not superior to placebo for ocular Behcet's in randomised controlled trials, comprising 118 and 17 patients, respectively. The anti-IL-1 agents anakinra and canakinumab and the anti-IL-6 agent tocilizumab were given to isolated refractory disease patients, who were either anti-TNF naive (n=9) or experienced (n=18). No new safety signals were reported. Although a potential for bias to report positive effects and underreport negative cases may exist, Anakinra was partially effective, whereas disease remission was noted after canakinumab in some anti-TNF resistant patients. Tocilizumab appeared effective for neuro-Behcet's, but not for mucocutaneous manifestations. Finally, in a pilot study of 7 patients with relapsing posterior uveitis refractory to azathioprine and/or cyclosporine, the anti-IL-1beta antibody Gevokizumab was beneficial. Collectively, it seems that IL-1 and IL-6 are promising targets in patients refractory or intolerant to other regimens including anti-TNFs. However, controlled studies are surely needed. |
Gastrointestinal manifestations of Behcet's disease: advances in evaluation and management. |
Behcet's disease is a chronic, recurrent, inflammatory disorder characterized by orogenital ulcers and skin lesions; serious manifestations also include ocular, large vessel, gastrointestinal and neurological involvement. Genetic and unknown environmental factors customise the wide clinical expression of the disease. Gastrointestinal involvement is not unusual, albeit with a highly variable frequency among different ethnic populations. However, given the fact that gastrointestinal symptoms such as reflux, bleeding, diarrhoea are common in the general population, their clinical significance needs to be carefully interpreted. Apart from mouth the ileocecal area is typically involved, but inflammatory and/or vasculitic lesions may affect any part of the gastrointestinal tract. Complications such as perforation carry high morbidity rates and even mortality. Herein, we review all available information pertinent to gastrointestinal involvement of Behcet's disease and discuss the published advances in evaluation and its empirical management, including anti-TNF biologic therapies. |
Behcet's syndrome: a critical digest of the 2013-2014 literature. |
This review focuses on the recent research on the epidemiology, outcome measures, immunopathogenesis, genetics, clinical manifestations and management of Behcet's syndrome (BS). A systematic review of outcomes and outcome measures used in BS points out to a need for reliable and validated outcome measures that would be widely used by researchers. Despite novel methods of analyses and cheaper and more sophisticated technologies are yielding new genetic associations and molecular pathways in BS, HLA-B51 still shows the strongest link. The MHC class I amino acid residues, GIMAP, the neuromodulin pathway, complement component copy variations, microRNA polymorphisms and DNA methylation abnormalities are examples. IL-27, 33 and 37 may also play important roles in the pathogenesis. Clinical studies have shown that the fluorescein angiography scoring system could be a useful tool to discern active inflammation in eye disease from the quiescent phase, the cumulative risk for recurrence of any vascular event was 38% at 5 years in a large vascular cohort and significant correlations between dural sinus thrombosis and pulmonary artery involvement, a retrospective survey of patients with parenchymal NBS revealed a 30% relapse rate and 10% mortality of 10% after a median follow-up of 73 months, and quantitative measurement of the brainstem atrophy using MRI was correlated with clinical symptoms. Studies on the management of BS showed that continuous use of colchicine may not prevent the development of organ involvement at the long-term, remission of uveitis may persist after withdrawal of infliximab, refractory intestinal involvement may respond to infliximab, immunosuppressive treatment is important in reducing complications of endovascular stent grafting for aortic pseudoaneurysm and intravitreal steroid implants or injections may be considered in refractory uveitis. |