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The procofactor, factor VIII, is activated by thrombin or factor Xa-catalyzed cleavage at three P1 residues: Arg-372, Arg-740, and Arg-1689. The catalytic efficiency for thrombin cleavage at Arg-740 is greater than at either Arg-1689 or Arg-372 and influences reaction rates at these sites. Because cleavage at Arg-372 appears rate-limiting and dependent upon initial cleavage at Arg-740, we investigated whether cleavage at Arg-1689 influences catalysis at this step. Recombinant B-domainless factor VIII mutants, R1689H and R1689Q were prepared and stably expressed to slow and eliminate cleavage, respectively. Specific activity values for the His and Gln mutations were approximately 50 and approximately 10%, respectively, that of wild type. Thrombin activation of the R1689H variant showed an approximately 340-fold reduction in the rate of Arg-1689 cleavage, whereas the R1689Q variant was resistant to thrombin cleavage at this site. Examination of heavy chain cleavages showed approximately 4- and 11-fold reductions in A2 subunit generation and approximately 3- and 7-fold reductions in A1 subunit generation for the R1689H and R1689Q mutants, respectively. These results suggest a linkage between light chain cleavage and cleavages in heavy chain. Results obtained evaluating proteolysis of the factor VIII mutants by factor Xa revealed modest rate reductions (<5-fold) in generating A2 and A1 subunits and in cleaving light chain at Arg-1721 from either variant, suggesting little dependence upon prior cleavage at residue 1689 as compared with thrombin. Overall, these results are consistent with a competition between heavy and light chains for thrombin exosite binding and subsequent proteolysis with binding of the former chain preferred.

Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.

Bone hemangiomas are extremely rare in the ribs, with only a handful of cases reported in the literature. A case of a rib hemangioma is presented in which the pre-resection diagnosis was an aggressive chest wall tumor. The plain film, CT, MRI and bone scan features of the lesion were reviewed with the pathological correlation. On imaging, the lesion was expansile and lytic, and it also had fine bony trabeculae. The lesion also demonstrated growth beyond a disrupted bony cortex, suggesting malignancy. This case report adds to the literature on this rare condition and discusses the issues in the diagnosis of chest wall tumors.

A robust and straightforward method for on-site determination of radon-222 activity concentrations in water is presented. The methodical approach is based on the principle of liquid-gas-membrane extraction. An extraction module, which consists of hollow polypropylene fibres, allows radon stripping from the water of interest into a connected closed air-loop. The resulting radon-in-air activity concentration, which can easily be reconverted into the original radon-in-water activity concentration is measured by means of a standard mobile radon-in-air monitor. The experimental set-up allows radon detection in discrete water samples as well as continuous water pump streams. The technique, covering a wide activity concentration range, is in particular advantageous for measurements of radon-in-water in the field or on research cruises.

The proteomic response of recombinant Escherichia coli producing human glucagon-like peptide-1 was analyzed by two-dimensional gel electrophoresis. Protein spots in two-dimensional gel could be identified by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and their expression profiles were compared with those of nonproducing cells. Thirty-five intracellular proteins exhibited differential expression levels between the production and control strains. These changes reflected physiological responses to heterologous peptide production in recombinant E. coli. Specifically, physiological changes included the down-regulation of proteins involved in the central carbon metabolism, biosynthesis of cellular building blocks and peptides, and up-regulation of cell protection proteins and some sugar transport proteins. This comprehensive analysis would provide useful information for understanding physiological alterations to heterologous peptide production and for designing efficient metabolic engineering strategies for the production of recombinant peptides in E. coli.

We recently have reported that ghrelin modulates adult hippocampal neurogenesis. However, there is a possibility that the action of ghrelin on hippocampal neurogenesis could be, in part, due to the ability of ghrelin to stimulate the GH/insulin-like growth factor (IGF)-1 axis, where both GH and IGF-1 infusions are known to increase hippocampal neurogenesis. To explore this possibility, we assessed the impact of ghrelin on progenitor cell proliferation and differentiation in the dentate gyrus (DG) of spontaneous dwarf rats (SDRs), a dwarf strain with a mutation of the GH gene resulting in total loss of GH. Double immunohistochemical staining revealed that Ki-67-positive progenitor cells and doublecortin (DCX)-positive neuroblasts in the DG of the SDRs expressed ghrelin receptors. We found that ghrelin treatment in the SDRs significantly increased the number of proliferating cell nuclear antigen- and BrdU-labeled cells in the DG. The number of DCX-labeled cells in the DG of ghrelin-treated SDRs was also significantly increased compared with the vehicle-treated controls. To test whether ghrelin has a direct effect on cognitive performance independently of somatotropic axis, hippocampus-dependent learning and memory were assessed using the Y-maze and novel object recognition (NOR) test in the SDRs. Ghrelin treatment for 4 weeks by subcutaneous osmotic pump significantly increased alternation rates in the Y-maze and exploration time for novel object in the NOR test compared to vehicle-treated controls. Our results indicate that ghrelin-induced adult hippocampal neurogenesis and enhancement of cognitive function are mediated independently of somatotropic axis.

The perception of drivers regarding risk-taking behaviour is widely varied. High-risk drivers are the segment of drivers who are disproportionately represented in the majority of crashes. This study examines the typologies of drivers in risk-taking behaviour, the common high-risk driving errors (speeding, close following, abrupt lane-changing and impaired driving), their safety consequences and the technological (ITS) devices for their detection and correction. Limiting the driving degree of freedom of high-risk drivers is proposed and its benefits on safety as well as traffic operations are quantified using VISSIM microscopic traffic simulation at various proportions of high-risk drivers; namely, 4%, 8% and 12%. Assessment of the safety benefits was carried out by using the technique of simulated vehicle conflicts which was validated against historic crashes, and reduction in travel time was used to quantify the operational benefits. The findings imply that limiting the freedom of high-risk drivers resulted in a reduction of crashes by 12%, 21% and 27% in congested traffic conditions; 9%, 13% and 18% in lightly congested traffic conditions as well as 9%, 10% and 17% in non-congested traffic conditions for high-risk drivers in proportions of 4%, 8% and 12% respectively. Moreover, the surrogate safety measures indicated that there was a reduction in crash severity levels. The operational benefits amounted to savings of nearly 1% in travel time for all the proportions of high-risk drivers considered. The study concluded that limiting the freedom of high-risk drivers has safety and operational benefits; though there could be social, legal and institutional concerns for its practical implementation.

Vegetable consumption has been encouraged as a component of nutritional education for obese and insulin-resistant patients. However, the benefits of vegetable intake in a therapeutic diet on postprandial glycemic and lipidemic responses have not been clarified. We studied the effects of the intake of spinach, a green-leafy vegetable rich in dietary fiber and á-tocopherol, with a fat-rich meal on postprandial glycemic and lipidemic changes. Fourteen normal weight and 10 obese men consumed three test meals of bread, as a control, bread and butter, and bread and butter with boiled spinach. Blood samples were obtained prior to and 30, 60, 120, 180 and 240 min after consuming the test meals. Compared with the bread meal, consumption of the bread and butter meal showed a reduced peak glucose response at 30 min in normal (p<0.05) but not in obese subjects. The increase in triglyceride and decrease in LDL-cholesterol were greater after the butter-containing meal than after the bread meal (p<0.05). The á-tocopherol/lipid level decreased and remained low after the bread and butter meal, but the decrease was smaller with the spinach-containing meal in obese subjects (p<0.05). These results suggest that green-leafy vegetable intake with a fat-rich meal is effective for supplying postprandial á-tocopherol in obese subjects, but consumption of a regular-sized dish cannot be expected to improve abnormal postprandial hyperglycemic or hyperlipidemic responses.

Six hundred ninety-five mice received adeno-associated virus (AAV) vectors, mostly via portal vein injection. At necropsy, the livers were inspected for tumors, and tissue sections were prepared for histology. We observed only one tumor, a lipoma, resulting in a tumor frequency of 0.14%. This tumor contained fewer vector genomes per total DNA than the surrounding liver tissue, as shown by quantitative PCR. In another mouse we found a macroscopically visible nodule containing lymphocytes. Immunohistochemistry revealed cells not of monoclonal origin, and they contained fewer AAV genomes than the surrounding hepatocytes. There were no macroscopic tumors in 226 control mice. Upon microscopic examination, lymphocytic infiltrates were found in 5% of livers of both control and vector-treated mice; no transgene expression was seen in those infiltrates in AAV-injected animals. Compared to an average frequency of spontaneous liver tumors in C57BL/6 mice (0-10%), and given the absence of high levels of vector DNA in the observed tumor, we conclude that AAV vectors do not predispose these target animals to the formation of liver tumors.

Body composition can be assessed in many different ways. High-end medical equipment, such as Dual-energy X-ray Absorptiometry (DXA), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI) offers high-fidelity pixel/voxel-level assessment, but is prohibitive in cost. In the case of DXA and CT, the approach exposes users to ionizing radiation. Whole-body air displacement plethysmography (BOD POD) can accurately estimate body density, but the assessment is limited to the whole-body fat percentage. Optical three-dimensional (3D) scan and reconstruction techniques, such as using depth cameras, have brought new opportunities for improving body composition assessment by intelligently analyzing body shape features. In this paper, we present a novel supervised inference model to predict pixel-level body composition and percentage of body fat using 3D geometry features and body density. First, we use body density to model a fat distribution base prediction. Then, we use a Bayesian network to infer the probability of the base prediction bias with 3D geometry features. Finally, we correct the bias using non-parametric regression. We use DXA assessment as the ground truth in model training and validation. We compare our method, in terms of pixel-level body composition assessment, with the current state-of-the-art prediction models. Our method outperforms those prediction models by 52.69% on average. We also compare our method, in terms of whole-body fat percentage assessment, with the medical-level equipment-BOD POD. Our method outperforms the BOD POD by 23.28%.

The future paths of population ageing result from specific combinations of declining fertility and increasing life expectancies in different parts of the world. Here we measure the speed of population ageing by using conventional measures and new ones that take changes in longevity into account for the world as a whole and for 13 major regions. We report on future levels of indicators of ageing and the speed at which they change. We show how these depend on whether changes in life expectancy are taken into account. We also show that the speed of ageing is likely to increase over the coming decades and to decelerate in most regions by mid-century. All our measures indicate a continuous ageing of the world's population throughout the century. The median age of the world's population increases from 26.6 years in 2000 to 37.3 years in 2050 and then to 45.6 years in 2100, when it is not adjusted for longevity increase. When increases in life expectancy are taken into account, the adjusted median age rises from 26.6 in 2000 to 31.1 in 2050 and only to 32.9 in 2100, slightly less than what it was in the China region in 2005. There are large differences in the regional patterns of ageing. In North America, the median age adjusted for life expectancy change falls throughout almost the entire century, whereas the conventional median age increases significantly. Our assessment of trends in ageing is based on new probabilistic population forecasts. The probability that growth in the world's population will end during this century is 88%, somewhat higher than previously assessed. After mid-century, lower rates of population growth are likely to coincide with slower rates of ageing.

In urban environments, raccoons (Procyon lotor) may act as reservoirs for an array of pathogenic organisms, presenting spillover risks for human, domestic animal, and captive (zoo) animal populations. Over 5 yr, 159 raccoons from a high-density raccoon population in St. Louis, Missouri (USA), were surveyed for exposure to canine distemper virus (CDV), canine adenovirus 1 (CAV-1); feline parvovirus (FPV; =feline panleukopenia), and several serovars of Leptospira interrogans. Exposure to each of the viruses and two Leptospira serovars (grippotyphosa and icterohemorrhagiae) was detected (prevalence of CDV = 54.1%; FPV = 49.7%; CAV-1 = 6.9%; L. interrogans icterohemorrhagiae = 8.9%; L. interrogans grippotyphosa = 6.3%). Eighty percent of raccoons showed evidence of exposure to at least one of the five primary pathogens, and 39% were positive for multiple species. Among the viruses, there was a significant co-occurrence of CDV and CAV-1. Longitudinal data on a subset of animals revealed that among individuals who were diagnosed as seropositive on first capture, 33-100% became seronegative for the pathogen of interest when reexamined at a later date. Thus, free-ranging urban raccoons have been exposed to multiple infectious agents, some of which may pose risks to humans and to nonvaccinated domestic and captive animal populations.

BACKGROUND: The environmental contribution to autism spectrum disorders (ASD) is largely unknown, but household pesticides are receiving increased attention. We examined associations between ASD and maternally-reported use of imidacloprid, a common flea and tick treatment for pets.METHODS: Bayesian logistic models were used to estimate the association between ASD and imidacloprid and to correct for potential differential exposure misclassification due to recall in a case control study of ASD.RESULTS: Our analytic dataset included complete information for 262 typically developing controls and 407 children with ASD. Compared with exposure among controls, the odds of prenatal imidacloprid exposure among children with ASD were slightly higher, with an odds ratio (OR) of 1.3 (95% Credible Interval [CrI] 0.78, 2.2). A susceptibility window analysis yielded higher ORs for exposures during pregnancy than for early life exposures, whereas limiting to frequent users of imidacloprid, the OR increased to 2.0 (95% CI 1.0, 3.9).CONCLUSIONS: Within plausible estimates of sensitivity and specificity, the association could result from exposure misclassification alone. The association between imidacloprid exposure and ASD warrants further investigation, and this work highlights the need for validation studies regarding prenatal exposures in ASD.

SUMMARY: MASS is a command-line program to perform meta-analysis of sequencing studies by combining the score statistics from multiple studies. It implements three types of multivariate tests that encompass all commonly used association tests for rare variants. The input files can be generated from the accompanying software SCORE-Seq. This bundle of programs allows analysis of large sequencing studies in a time and memory efficient manner.AVAILABILITY AND IMPLEMENTATION: MASS and SCORE-Seq, including documentations and executables, are available at http://dlin.web.unc.edu/software/.CONTACT: [email protected].

MIF-1 (Pro-Leu-Gly-NH2), a hypothalamic tripeptide, has been demonstrated to stimulate naloxone in antagonizing the effects of opioid peptides in a number of experimental systems including enkephalin-induced analgesia in the tail-flick assay, beta-endorphin induced hypothermia and hypomotility, deprivation-induced drinking, and analgesia in goldfish. MIF-1, however, has no effect upon the activity of enkephalins in the mouse vas deferens or enkephalin binding in the rat striatum. We have studied the interactions of MIF-1 with Leu5-enkephalin (Leu5-ENK) in the conscious, chronically instrumented dog. Although naloxone inhibits both the elevations of heart rate and blood pressure produced by IV Leu5-ENK in the conscious state and the depressions in these variables produced by Leu5-ENK after pentobarbital anesthesia, MIF-1 has no effect upon the Leu5-ENK response in either state. However, both naloxone and MIF-1 seem to raise mean arterial pressure in the conscious dog. These results indicate that MIF-1 does not act like naloxone in antagonizing the peripheral effects of Leu5-ENK and lend further support to the existence of mechanistic differences among opiate-mediated behavior, analgesia, and cardiovascular activity.

Lung cancer remains the leading cause of cancer death worldwide. Overall 5-year survival is approximately 10-15% and despite curative intent surgery, treatment failure is primarily due to recurrent disease. Conventional prognostic markers are unable to determine which patients with completely resected disease within each stage group are likely to relapse. To identify a gene signature associated with recurrent squamous cell carcinoma (SCC) of lung, we analyzed primary tumor gene expression for a total of 51 SCCs (Stages I-III) on 22 323 element microarrays, comparing expression profiles for individuals who remained disease-free for a minimum of 36 months with those from individuals whose disease recurred within 18 months of complete resection. Cox proportional hazards modeling with leave-one-out cross-validation identified a 71-gene signature capable of predicting the likelihood of tumor recurrence and a 79-gene signature predictive for cancer-related death. These two signatures were pooled to generate a 111-gene signature which achieved an overall predictive accuracy for disease recurrence of 72% (77% sensitivity, 67% specificity) in an independent set of 58 (Stages I-III SCCs). This signature also predicted differences in survival [log-rank P=0.0008; hazard ratio (HR), 3.8; 95% confidence interval (CI), 1.6-8.7], and was superior to conventional prognostic markers such as TNM stage or N stage in predicting patient outcome. Genome-wide profiling has revealed a distinct gene-expression profile for recurrent lung SCC which may be clinically useful as a prognostic tool.

Microwave-induced thermoacoustic imaging (MITAI) is an imaging technique with great potential for detecting breast cancer at early stages. Thermoacoustic imaging (TAI) combines the advantages of both microwave and ultrasound imaging techniques. In the current study, a three-dimensional novel numerical simulation of TAI phenomenon as a multi-physics problem is investigated. In the computational domain, a biological breast tissue including three different tissue types along with a tumor is placed in a tank containing castor oil and is irradiated by a 2.45-GHz pulsed microwave source from a rectangular waveguide. The generated heat in the biological tissue due to the electromagnetic wave irradiation and its corresponding pressure gradient in the tissue because of the temperature variations are evaluated. Also, capability of the MITAI process with respect to the tumor location and size is investigated. To identify the required power level needed for producing thermoacoustic signals, different power levels of microwave sources are investigated. The study's results demonstrate a minuscule increase in temperature as a result of the absorption of pulsed microwave energy (for example, a maximum of 0.002472 °C temperature increase in tumor with 1 cm diameter which is located in fatty tissue of breast are obtained due to an excitation pulse of 1000 W, 1 ms). This small temperature variation in the tumor produces several kilopascals of pressure variations with maximum of 0.584016 kPa in tumor. This pressure variation will produce acoustic signals, which can be detected with an array of transducers and be used for image construction. Results demonstrate that the location of tumor in breast plays a vital role on the detecting performance of MITAI. Also, it is shown that very small tumors (with the diameter of 0.5 cm) can also be detected using MITAI technique. These simulations and procedures can be used for determining the amount of produced pressure variation, the acoustic pressure magnitude, and other complicated geometries. Graphical abstract A schematic of the thermoacoustic phenomenon.

In animals, histamine inhalation is known to increase either respiratory frequency or respiratory drive by stimulation of airway vagal sensitive endings. However, it is not well known whether these changes are concomitant in man. In order to elucidate this point, we carried out the present investigation in thirty-five asthmatic patients who underwent bronchial provocation test by progressively doubling the dose of inhaled histamine. Bronchial reactivity to histamine allowed two populations of patients to be defined: group I with moderate and group II with mild, increased reactivity. In the twenty-three group I patients, neuromuscular inspiratory drive, assessed by mouth occlusion pressure (P0.1), was found to be significantly increased while no significant changes in breathing pattern were noted. In the twelve group II patients histamine did not modify P0.1 or breathing pattern. However, we were able to separate in group I a sub-group of ten patients, as with atopic asthma, in which histamine-induced increase in P0.1 was paralleled by rapid and shallow breathing (RSB). Changes in P0.1 and breathing pattern did not depend on baseline airway calibre. In group I, after bronchoconstriction had been reversed by inhaling a beta 2-agonist bronchodilator agent (fenoterol), P0.1 decreased significantly and RSB was found to be reversed; however, these changes were not interrelated. We concluded that: in asthmatics, histamine-induced increase in P0.1 is not necessarily paralleled by, nor related with, change in breathing pattern and in atopics a 'sensitization' of vagal receptors could account for the concomitance of enhanced P0.1 with RSB.

Masked mycotoxins are biologically modified phase II metabolites formed by plant defense mechanisms through glucosylation catalyzed by uridine diphosphate -glucosyltransferases. Most of the current reports focus on the occurrence of masked mycotoxins in Europe, America, Africa, and cover other geographic regions, e.g. China and Japan. High proportions of masked mycotoxins co-occurring with their parent forms in various cereal-based food and feedstuff could clearly increase total exposures and pose additional health risks to humans and animals. In contrast to the parent mycotoxins, the data on the toxicity of masked mycotoxins are still scarce, however, the poor existing information showed that masked mycotoxins generally exhibit significant in vitro and in vivo toxicities lower than those of their parent forms, especially for deoxynivalenol-3-glucoside, which is the only thoroughly investigated masked mycotoxin. Although the lower toxicity level of masked mycotoxins, these are probably hydrolyzed into their free forms by intestinal microorganisms in the digestive tract of mammals and thus contribute to unpredicted toxicity. The metabolic characteristics of reported masked mycotoxins are species-specific. The most relevant animal model of human sensitivity, the pig, is most sensitive to masked mycotoxins. This review focuses on updates in the current knowledge on country-specific natural-occurrence data in global surveys, as well as in vitro and in vivo toxicology and metabolic investigations of masked mycotoxins.

PURPOSE: To evaluate the utility of transutricular seminal vesiculoscopy as a diagnostic and therapeutic option for symptomatic midline cyst of the prostate in patients with hematospermia and symptoms associated with prostatitis.MATERIALS AND METHODS: From January 2005 to July 2013, 61 patients with symptomatic (hematospermia, pain on ejaculation, scrotal discomfort) midline cyst of the prostate, who did not improve with medication within a 4-week period, were included. Diagnosis of a midline cyst of the prostate was based on an anechoic round or spheroid-shaped lesion in the median, above the level of the verumontanum, extending into the prostatic base on transrectal ultrasonography (TRUS). All patients underwent transutricular seminal vesiculoscopy using a 9.0 Fr rigid ureteroscope and Bugbee electrode. Medical records, the Chronic Prostatitis Symptom Index (NIH-CPSI), and TRUS were used for assessment for more than 3 months after the procedure.RESULTS: Of the 61 patients, 32 (52.4 %) had hematospermia, 20 (32.7 %) had symptoms associated with chronic pelvic pain syndrome, such as perineal pain, scrotal discomfort, and testicular pain, and nine (14.7 %) patients had ejaculatory disturbances, such as painful or uncomfortable ejaculation and anejaculation as major complaints/symptoms. In endoscopic findings, hemorrhage was present in the dilation of the prostatic utricle and in the seminal vesicle in 11 (18.0 %) and 21 (34.4 %) of the patients, respectively. Calculi were found in the dilation of the prostatic utricle and in the seminal vesicle in 12 (19.7 %) and six (9.8 %), respectively. Hematospermia resolved in 29 of 32 (90.6 %) patients after transutricular seminal vesiculoscopy. In 29 patients with chronic pelvic pain syndrome and ejaculatory disturbances, NIH-CPSI scores improved, from 19.0 ± 3.8 to 11.8 ± 3.6 (p < 0.001), after treatment. The pain domain and quality-of-life domain scores of the NIH-CPSI were better postsurgery than presurgery (p < 0.001). Acute epididymitis, as a postoperative complication, was observed in two patients (3.3 %).CONCLUSIONS: There are various endoscopic findings in the dilation of prostatic utricle and seminal vesicle such as hemorrhage, calculi or/and purulent material in the patients with midline cyst of the prostate. The role of transutricular seminal vesiculoscopy in reducing symptoms may be mediated through the effects of endoscopic fenestration, removal of blood clots, calculi, or whitish debris and/or electrocautery of intracystic hemorrhage. This endoscopic technique enables useful diagnostic and therapeutic approaches for symptomatic midline cysts of the prostate.

An extracorporeal shunt circuit interposed between the left carotid artery and the left coronary ostium employs an electromagnetic flowmeter to measure coronary blood flow in the closed-chest anesthetized dog. Flow may be measured with the animal's arterial pressure as the driving force; introduction of a roller pump, or a roller pump and a negative feedback pressure controller allows for constant flow or constant pressure modes. During occlusion of the circuit or cessation of pump flow, retrograde coronary blood flow can be collected for measurement. The construction of the circuit is relatively simple and inexpensive, using common laboratory materials and a commercially available electromagnetic flowmeter and probe.

Central Motor Conduction Time (CMCT) was investigated in 18 patients (5 m, 13 f; age range: 11-69 yrs) with clinical and electrophysiological features of HMSN type I, using Magnetic Coil (MC) stimulation. No one exhibited clinically pyramidal signs. Brain stimulation Motor Evoked Potentials (MEPs), recorded monolaterally from the left abductor digiti minimi (ADM) and tibialis anterior (TA) muscles, were evoked in all patients from upper extremities and absent in 11.1% from lower limbs. Total Motor Conduction Time (TMCT), as well as Peripheral Motor Conduction Time estimated by either magnetic nerve root stimulation (mag-PMCT) or F-wave latency values (F-PMCT), were markedly delayed in all patients. Central Motor Conduction Time was calculated by subtracting both the latency of mag-PMCT (mag-CMCT) and F-PMCT (F-CMCT) from that one obtained by cortical stimulation. F-CMCT was abnormal in 22.2% in upper extremities and in 27.8% patients from lower extremities, whereas mag-CMCT in 22.2% from ADM muscles and in 33.3% from TA muscles. Furthermore, CMCT to both methods was not possible to evaluate in 5.6% from upper and lower extremities and following magnetic root stimulation in 11.1% from lower limbs. These findings prove lower motor neuron involvement, in agreement with electroneurographic data, and suggest a possible central motor pathways impairment, even in patients without any clinical evidence, but they cannot explain which is the underlying pathophysiological mechanism, a true upper motor neuron involvement or an abnormal spinal motor neuron excitability.

OBJECTIVE: To estimate the extent to which cervical stromal invasion would predict survival.METHODS: Cases of stage II endometrioid endometrial adenocarcinoma from three academic institutions were reviewed. A gynecologic pathologist reevaluated archived slides and measured the depth of cervical stromal invasion. Clinical data were abstracted and statistical analysis performed.RESULTS: Of 116 cases, 31 (27%) had gland involvement and 85 (73%) cervical stromal invasion. Cervical stromal invasion was categorized as the inner two thirds (n=59 [69%]) compared with the outer third (n=26 [31%]). Women with outer third cervical stromal invasion compared with those with inner two-thirds cervical stromal invasion were more likely to be aged at least 65 years (69% compared with 46%, P=.038), have at least 50% myometrial invasion (77% compared with 44%, P=.004), lymphvascular space invasion (46% compared with 20%, P=.016), and to have died (50% compared with 19%, P=.004). Overall survival for patients with no invasion and inner two-thirds cervical stromal invasion did not differ (106 compared with 146 months, P=.89). Survival for outer third cervical stromal invasion was 91 months (P=.021). Multivariable analysis found deep myometrial invasion (hazard ratio 3.1; confidence interval [CI], 1.2-8.2), lymphvascular space invasion (hazard ratio 3.2; CI 1.2-8.4), and outer third cervical stromal invasion (hazard ratio 2.8; CI 1.1-7.2) were independent predictors of death.CONCLUSION: Deep (outer third) cervical stromal invasion is an independent predictor of death in stage II endometrial cancers and these patients should receive radiation therapy. Superficial cervical stromal invasion did not increase risk of death and adjuvant radiation for this patient group may not be necessary.LEVEL OF EVIDENCE: III.

We describe a patient with juvenile levodopa-responsive Parkinsonism who reported a dramatic response to cigarette smoking with transient but marked improvement of motor symptoms associated with oculogyric crises and psychotic behavior. His beta-CIT single-photon emission computed tomography scan showed a complete absence of presynaptic dopaminergic nerve terminals.

The recombinant heavy chain myosin of Brugia malayi (Bm-Myo) has earlier been reported as a potent vaccine candidate in our lab. Subsequently, we further enhanced its efficacy employing heterologous DNA prime/protein boost (Myo-pcD+Bm-Myo) immunization approach that produced superior immune-protection than protein or DNA vaccination. In the present study, we evaluated the efficacy of heterologous prime boost vaccination in combination with CpG, synthetic oligodeoxynucleotides (ODN) adjuvant in BALB/c mice. The results showed that CpG/Myo-pcD+Bm-Myo conferred 84.5 ± 0.62% protection against B. malayi infective larval challenge which was considerably higher than Myo-pcD+Bm-Myo (75.6 ± 1.10%) following immunization. Although, both the formulations of immunization elicited robust production of specific IgG antibody and their isotypes (IgG1, IgG2a, IgG2b, and IgG3); however, CpG/Myo-pcD+Bm-Myo predominantly enhanced the level of IgG2a suggesting Th1 biased immune response in presence of CpG. Furthermore, spleen isolated from mice that immunized with CpG/Myo-pcD+Bm-Myo had greater accumulation of CD4+, CD8+, and CD19+ B cells and there was an augmented expression of co-stimulatory molecules CD40, CD86 on host dendritic cells (DCs). In contrast to Myo-pcD+Bm-Myo group, the splenocytes of CpG/Myo-pcD+Bm-Myo immunized mice developed comparatively higher pro-inflammatory cytokines IL-2 and IFN-ã leaving anti-inflammatory cytokine levels unchanged. Moreover, CpG formulation also upregulated the RNA expression of IL-12 and TNF-á in spleenocytes. The current findings suggest that the use of CpG would be more advantageous as an adjuvant predominantly in DNA/protein prime boost vaccine against Bm-Myo and presumably also for filarial infection.

To determine the prevalence of cervical human papillomavirus (HPV) infection and risk factors in young women from Brazil, Canada, and the USA. Cross-sectional study in 3204 healthy women, aged 15 to 25 years. Cervical samples were collected for cytology and for HPV DNA detection (SPF 10-LiPA 25 system). Serum samples were collected for the measurement of HPV-16 and HPV-18 antibodies by enzyme-linked immunosorbent assay. Risk factors were obtained through a questionnaire. Overall, 26.6% of women had DNA detected for at least 1 HPV type. The prevalence for oncogenic HPV types was 21.7% (25% in Brazil, 16.9% in Canada, and 19.1% in the USA). HPV-16 was the most prevalent oncogenic type (5.2%). The next most common oncogenic HPV types were 51 (3.3%), 52 (3.3%), 31 (2.9%), 66 (2.3%), and 39 (2.0%). Multiple oncogenic types were detected in one-third of the infections. The prevalence of HPV-16 and/or HPV-18 infections detected by DNA and/or enzyme-linked immunosorbent assay was 24.8%. The majority of women (85%) had a normal cervical cytology. Sexual behavior was the main determinant for HPV-16/18 infections and squamous intraepithelial lesions. The prevalence of HPV oncogenic infections was high and linked to sexual behavior. Strategies to reduce the burden of oncogenic HPV infection, such as prophylactic vaccination programs, are likely to impact the burden of disease due to cervical precancer and cancer.

A non-aqueous capillary electrophoresis (NACE) method for quantifying the seven crocin metabolites that are the major biologically active ingredients of saffron was developed. Separation is done by using a fused silica capillary filled with a 12.5 mM H3BO3/37.5 mM sodium tetraborate methanolic solution as background electrolyte. The results obtained were compared with the total index "safranal value", widely used as a quality measure of saffron products. The comparison revealed that the proposed NACE method provides useful information not obtained in the safranal value. Infact, samples with a similar safranal value can contain crocin metabolites in different concentrations and relative proportions. This new method is very useful for quality control in commercial saffron samples.

A 3' -phosphoadenosine 5' -phosphosulfate (PAPS):chondroitin sulfate sulfotransferase from chicken embryo epiphyseal cartilage, which was partially purified, exhibited a molecular mass of 150 kDa. The enzymatic sulfation of totally desulfated chondroitin was activated up to 12-fold by protamine while the sulfation of partially sulfated chondroitin was activated only 3-fold. Protamine increased the affinity of the enzyme for PAPS about 4-fold when partially desulfated chondroitin was used as sulfate acceptor. The S 0.5 for the totally desulfated chondroitin was not affected by protamine, while high PAPS concentration slightly increased the affinity of the enzyme for the same sulfate acceptor. The possible role of these substances in the regulation of the sulfation of chondroitin sulfate is discussed.

Subcutaneous injections of a 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in monkeys induced distinct behavioural changes characterized by head weaving, hindlimb extension and upper limb fluttering. The effects were dose-dependent and were similar to the 5-HT syndrome induced in rats by 8-OH-DPAT. The 5-HT receptor antagonist, metergoline, attenuated the behavioural syndrome seen in response to 8-OH-DPAT. These results suggest that 8-OH-DPAT induces a 5-HT1A receptor-mediated behavioural syndrome in monkeys as well as in rodents.

BACKGROUND: Peptic ulcer disease is a common complication among renal transplant recipients and causes significant morbidity and mortality.METHODS: From 1990 through 2000, 465 renal transplant patients were followed-up in our institute. Most patients received corticosteroids and cyclosporine-based immunosuppressive regimen. About one third (n = 156) of them received mycophenolate mofetil. Patients with endoscopy-proved peptic ulcer disease were identified by reviewing medical records. Possible risk factors were analyzed by univariate analysis and multiple logistic regression analysis.RESULTS: Among 465 kidney transplant patients, there were 181 (38.9%) who suffered at least 1 episode of peptic ulcer disease. The most frequent types of peptic ulcer disease were gastritis, gastric ulcer, duodenal ulcer, esophagitis, duodenitis and esophageal ulcer. By multivariate analysis, the use of methylprednisolone pulse therapy (odds ratio = 3.954, 95% confidence interval = 3.154-18.312, p = 0.03) and history of pre-transplant peptic ulcer disease (odds ratio = 7.599, 95% CI = 1.211-12.905, p < 0.0001) were independent risk factors for posttransplant peptic ulcer disease.CONCLUSIONS: Our findings demonstrated that renal transplant patients who undergo methylprednisolone pulse therapy for acute rejection or who have a history of pre-transplant peptic ulcer disease carry a high risk for the development of peptic ulcer disease and deserve intensive antiulcer treatment.

The aim of the present study is to identify the optimal anticancer agents for use in combination with gene therapy using wild-type (wt) p53 gene transfer. We used adenoviral vectors expressing human wt p53 (AdCAp53) and investigated the effects of wt p53 gene transfer in combination with 12 anticancer agents on a human pulmonary squamous cell carcinoma cell line, NCI-H157, and a human pulmonary large cell carcinoma cell line, NCI-H1299. Solutions containing anticancer agents at various concentrations were added followed by the addition of recombinant adenovirus solutions; after a 5-day incubation period, the anticancer activity was then evaluated by a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carbo xanilide assay. Each 50% inhibitory concentration was calculated based on the dose-response curves. The agents showing a high degree of effectiveness on NCI-H157 cells were cisplatin (CDDP), 5-fluorouracil (5-FU), bleomycin, and 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan (CPT-11); conversely, cyclophosphamide and paclitaxel showed a low degree of effectiveness. Based on these data, an isobologram was performed to investigate the interaction between AdCAp53 and some anticancer agents. A supra-additive effect was thus observed for 5-FU and SN-38 on NCI-H157 cells. An additive effect was also observed for CDDP, paclitaxel, bleomycin, and cyclophosphamide on NCI-H157 cells. CDDP, paclitaxel, 5-FU, and SN-38 had an additive effect on NCI-H1299 cells. No drug showed any subadditive or protective effects. These findings suggest that CPT-11 and 5-FU may thus be useful as possible anticancer agents for use in a combination therapy regimen using wt p53 gene transfer. CDDP and CPT-11 had a significant antitumoral effect on H157 cell xenografts of nude mice in vivo. These results indicate that CPT-11 as well as CDDP would be a candidate for the combination of chemotherapy and gene therapy for non-small cell lung cancer.

This article presents a comparative study among people with cerebral palsy and healthy controls, of various ages, using a Brain-computer Interface (BCI) device. The research is qualitative in its approach. Researchers worked with Observational Case Studies. People with cerebral palsy and healthy controls were evaluated in Portugal and in Brazil. The study aimed to develop a study for product evaluation in order to perceive whether people with cerebral palsy could interact with the computer and compare whether their performance is similar to that of healthy controls when using the Brain-computer Interface. Ultimately, it was found that there are no significant differences between people with cerebral palsy in the two countries, as well as between populations without cerebral palsy (healthy controls).

A study was conducted to determine the degree to which social support and personality predict the use of reasoning and aggression by adolescents to resolve interpersonal conflict. Although all adolescents appeared to use reasoning to resolve conflict, those with less social support and those exhibiting a forceful personality were more likely to report using verbal and physical aggression to resolve conflict. By contrast, introverted adolescents were less likely to report using verbal aggression to settle their differences. The importance of social support, as well as measures that can be taken by mental health professionals to prevent the use of aggression by adolescents, are discussed.

BACKGROUND: Catecholamines are significantly elevated in inflammatory responses and play a regulatory role in sepsis. Nitric oxide (NO), also a key inflammatory mediator in sepsis, is produced in large amounts by the inducible nitric oxide synthase (iNOS) in the liver. The purpose of this study was to test the hypothesis that catecholamines play a role in the regulation of NO production by hepatocytes.METHODS: Primary hepatocytes were isolated from healthy male Sprague-Dawley rats and either cultured with normal medium or stimulated with cytomix (interleukin-1 beta, interferon-gamma, and tumor necrosis factor-alpha) in the presence or absence of epinephrine or norepinephrine at varying concentrations. Total RNA was isolated 6 hours after treatment and analyzed by Northern blotting for iNOS mRNA. Protein extracts were obtained at 12 hours and were analyzed by Western immunoblotting for iNOS. Cell culture supernatants were analyzed for NO, determined as the stable end-product NO(2)(-), at 24 hours.RESULTS: Epinephrine and norepinephrine significantly decreased NO(2)(-) levels in stimulated hepatocytes but had no effect on iNOS mRNA or protein levels. The decrease in NO(2)(-) was reproduced by the adenylate cyclase stimulator, forskolin. The catecholamine-induced decrease in NO(2)(-) was completely reversed by the protein kinase A inhibitor Rp-8-Br-cyclic adenosine monophosphate.CONCLUSIONS: Catecholamines decrease hepatocyte production of NO in response to cytokine stimulation. This effect seems to be due to post-translational events and appears to be mediated in part by cyclic adenosine monophosphate.

We have developed a restriction enzyme-mediated insertional mutagenesis (REMI) system for the maize pathogen Colletotrichum graminicola. In this report, we demonstrate the utility of a REMI-based mutagenesis approach to identify novel pathogenicity genes. Use of REMI increased transformation efficiency by as much as 27-fold over transformations with linearized plasmid alone. Ninety-nine transformants were examined by Southern analysis, and 51% contained simple integrations consisting of one copy of the vector integrated at a single site in the genome. All appeared to have a plasmid integration at a unique site. Sequencing across the integration sites of six transformants demonstrated that in all cases the plasmid integration occurred at the corresponding restriction enzyme-recognition site. We used an in vitro bioassay to identify two pathogenicity mutants among 660 transformants. Genomic DNA flanking the plasmid integration sites was used to identify corresponding cosmids in a wild-type genomic library. The pathogenicity of one of the mutants was restored when it was transformed with the cosmids.

The internationalization of Chinese acupuncture-moxibustion is inevitably accompanied by the localization of acupuncture-moxibustion. The localization of acupuncture-moxibustion will inevitably promote the diversified development of acupuncture-moxibustion technique and theory, which fully demonstrates the openness of modern acupuncture-moxibustion. In this study, the characteristics of localization of Chinese acupuncture-moxibustion in the United States are explored and studied from the following aspects: legal adjustment, technical adjustment, educational adjustment, service adjustment and theoretical adjustment.

OBJECTIVE: To evaluate glycemic variation and hypoglycemia in patients with well-controlled type 1 diabetes receiving multiple daily insulin injections during glargine and Ultralente use as basal insulin in a clinical trial.METHODS: Twenty-two patients (12 men and 10 women; median age, 43 years), with a hemoglobin A1c level <7.8%, were randomized in a crossover design to receive either insulin glargine or Ultralente insulin as basal insulin for 4 months each, with insulin aspart as prandial insulin. Continuous glucose monitoring and the Fear of Hypoglycemia questionnaire were used at baseline and at the end of each treatment period.RESULTS: Whereas the mean amplitude of glycemic excursions showed a correlation with the area under the curve of blood glucose <3.89 mmol/L per day, the number of periods during the day with hypoglycemia was significantly correlated with the M value. Measures of glycemic variation did not differ significantly between glargine and Ultralente treatment. With use of glargine therapy, the SD of blood glucose levels showed a tendency to be lower and the SD of nocturnal blood glucose concentrations was significantly lower. Glucose concentrations were significantly lower during the 1 hour before and the 3 hours after lunch with use of Ultralente. The "Worry" scale on the Fear of Hypoglycemia questionnaire was less during Ultralente therapy and correlated with the number of times blood glucose concentrations were <3.89 mmol/L daily.CONCLUSION: Measures of glycemic variability and hypoglycemia need to be studied more in clinical trials of glycemic control in patients with type 1 diabetes. Glycemic variability is less, particularly at night, with glargine as basal insulin.

16S rRNA gene sequences were determined for Eubacterium exiguum and Peptostreptococcus heliotrinreducens. These species were found to be closely related and, together with Eubacterium lentum, to constitute a branch of the Coriobacteriaceae. Two new genera are proposed on the basis of phenotypic characteristics and 16S rRNA gene sequence comparisons: Slackia to include the bile-sensitive species Eubacterium exiguum and P. heliotrinreducens, and Eggerthella to include the bile-resistant Eubacterium lentum. It is proposed that Eubacterium exiguum and Peptostreptococcus heliotrinreducens are transferred to the genus Slackia gen. nov. as Slackia exigua gen. nov., comb. nov. (type strain ATCC 700122T) and Slackia heliotrinireducens gen. nov., comb. nov. (type strain NTCC 11029T), respectively, and Eubacterium lentum is transferred to the genus Eggerthella gen. nov. as Eggerthella lenta gen. nov., comb. nov. with Eggerthella lenta as the type species.

President Trump and his administration have been regarded by news outlets and scholars as one of the most hostile administrations towards scientists and their work. However, no study to-date has empirically measured how federal scientists perceive the Trump administration with respect to their scientific work. In 2018, we distributed a survey to over 63,000 federal scientists from 16 federal agencies to assess their perception of scientific integrity. Here we discuss the results of this survey for a subset of these agencies: Department of Interior (DOI) agencies (the US Fish and Wildlife Service (FWS), the US Geological Survey, and the National Park Service); the Centers for Disease Control and Prevention (CDC); the US Environmental Protection Agency (EPA); the Food and Drug Administration (FDA); and the National Oceanic and Atmospheric Administration (NOAA). We focus our analysis to 10 key questions fitting within three core categories that relate to perceptions of integrity in science. Additionally, we analyzed responses across agencies and compare responses in the 2018 survey to prior year surveys of federal scientists with similar survey questions. Our results indicate that federal scientists perceive losses of scientific integrity under the Trump Administration. Perceived loss of integrity in science was greater at the DOI and EPA where federal scientists ranked incompetent and untrustworthy leadership as top barriers to science-based decision-making, but this was not the case at the CDC, FDA, and NOAA where scientists positively associated leadership with scientific integrity. We also find that reports of political interference in scientific work and adverse work environments were higher at EPA and FWS in 2018 than in prior years. We did not find similar results at the CDC and FDA. These results suggest that leadership, positive work environments, and clear and comprehensive scientific integrity policies and infrastructure within agencies play important roles in how federal scientists perceive their agency's scientific integrity.

Many macrofungus sclerotia are well-known medicinal herbs, health food and nutritional supplements. However, the prevalent adulterant commercial products are major hindrances to their incorporation into mainstream medical use in many countries. The mushroom sclerotia of Lignosus rhinocerotis, Poria cocos, Polyporus umbellatus, Pleurotus tuber-regium and Omphalia lapidescens are commonly used in traditional Chinese medicine. In this study, IR macro-fingerprint method was used in the identification of these sclerotia. The results showed that the spectrum of L. rhinocerotis (LR) was comparable with P. cocos with 94.4% correlation, except that the peak at 1543cm(-1) of LR appeared in lower intensity. The spectrum of P. umbellatus and P. tuber-regium was also correlated (91.5%), as both spectra could be clearly discriminated in that P. umbellatus spectrum has small base peaks located at the range of 1680-1500cm(-1). O. lapidescens was not comparable with all the other sclerotia as its spectrum was totally different. Its base peak was broad and derivated equally along the range. The first IR has revealed the dissimilarity among five mushrooms sclerotia. The second derivative and 2DIR further enhanced the identification in detail.

A study was made of the possibility of forming nicotine addiction in laboratory rats and using it as the basis for the design of experimental nicotine toxicomania. Experiments were carried out on 56 rats placed in individual cages with a possibility of free choice between water and 0.005% nicotine solution for 2 to 4 months. It was established that the population of intact laboratory rats with 8- and 16-week contact with nicotine solution could be divided into groups demonstrating 3 main types of attitude toward nicotine: aversion (68% of all the animals), moderate addiction (4%), and pronounced addiction (28%). These quantitative relationships remained unchanged whatever the time of contact with nicotine. Thus, the possibility has been shown of designing experimental nicotine toxicomania with marked elements of physical dependence in rats consuming nicotine on a voluntary basis.

Benign migratory stomatitis is a relatively rare entity, but because of its benign nature and clinical characteristics, it should be easily recognized by the general practitioner. Biopsy is usually not indicated and treatment consists of reassuring the patient that the lesions are benign even though they may disappear, reappear, and change location; the patient should report back for periodic follow-up.

Extemporaneous drug formulation is essential to provide optimal pharmaceutical care to veterinary patients. The need for this is exacerbated by the fact that commercially produced veterinary-specific products, without a human indication, require specialty veterinary manufacturing facilities and a new animal drug application process to gain marketing approval. This study examined the prescription patterns of extemporaneously compounded veterinary preparations in the compounding department at a large independent community pharmacy. Data was obtained from a total of 1348 prescriptions requiring extemporaneous compounding over the course of a two-year period (2014-2015). A database was constructed and each compounded prescription was allocated to a therapeutic category based on the American Hospital Formulary Service Drug Information. Data analysis showed that the most commonly prescribed preparations belonged to the central nervous system (39%), anti-infective agents (21%), and hormones (12%) therapeutic categories. Overall, suspensions were the most dispensed (47%), extemporaneously compounded dosage forms followed by solutions (28%), and capsules (10%). The majority (88%) of compounded preparations were administered by the oral route. The top three drugs that are compounded for veterinary medicine were (1) potassium bromide oral solution for canine epilepsy, (2) methimazole solution used to treat hyperthyroidism in cats, and (3) metronidazole suspension, an antibiotic for the treatment of diarrhea and other infections in dogs and cats. Remarkably, our findings are in good agreement with previously published survey data on the top drugs that are compounded for veterinary medicine. In the era of personalized medicine, veterinary extemporaneous compounding for specialized needs will continue to play an important role providing optimum therapy for veterinary patients.

PURPOSE: Intravitreal injection of conbercept (IVC) is the latest applied treatment that could be used in retinopathy of prematurity (ROP) patients. The structural outcomes and recurrence of ROP among patients treated with IVC or intravitreal injection of ranibizumab (IVR) were compared.METHODS: A consecutive case series of ROP treated with IVC or IVR were retrospectively studied. The primary outcome was treatment success defined as regression of plus disease. The secondary outcomes were recurrence of plus, times of injection, and the final regression of disease.RESULTS: A total of 48 eyes (24 patients) with ROP were included. Twenty eyes (10 patients) received IVC, and 28 eyes (14 patients) received IVR. For the IVC group, 18 eyes had Zone II 3+ ROP and 2 eyes had aggressive posterior ROP. Among the 28 eyes treated with IVR, 6 eyes had Zone I 2/3+ ROP, 6 eyes had aggressive posterior ROP, and 16 eyes had Zone II 3+ ROP. For the IVC group, the mean gestational age, birth weight, postmenstrual age at initial treatment, and follow-up period for the infants were 29.49 ± 1.37 weeks, 1,369.0 ± 161.9 g, 38.47 ± 2.72 weeks, and 52.6 ± 21.4 weeks, respectively. And for the infants who received IVR, these were 28.35 ± 1.62 weeks, 1,171.4 ± 279.9 g, 38.53 ± 3.54 weeks, and 42.9 ± 9.8 weeks, respectively. For the IVC group, 17 (85%) of 20 eyes received the injection only once, and the regression of plus disease occurred 4.3 ± 2.08 weeks later. Three eyes (15%) did not healed with one injection received a second IVC, and the regression of plus disease occurred within 3 weeks. For the IVR group, 15/28 (53.6%) eyes received a second IVR. Among them, 10 recurrent eyes and 5 eyes did not recover with one injection. No retinal detachment was observed in both group infants.CONCLUSION: Both conbercept and ranibizumab are effective choice for the treatment of ROP. Conbercept is a novel effective treatment strategy for ROP providing a new treatment option for ophthalmologists.

Ionizing radiation induces a diverse spectrum of DNA lesions, including strand breaks and oxidized bases. In mammalian cells, ionizing radiation-induced lesions are targets of non-homologous end joining, homologous recombination, and base excision repair. In vitro assays show a potential involvement of DNA polymerase lambda in non-homologous end joining and base excision repair. In this study, we investigated whether DNA polymerase lambda played a significant role in determining ionizing radiation sensitivity. Despite increased sensitivity to hydrogen peroxide, lambda-deficient mouse embryonic fibroblasts displayed equal survival after exposure to ionizing radiation compared to their wild-type counterparts. In addition, we found increased sensitivity to the topoisomerase inhibitors camptothecin and etoposide in the absence of polymerase lambda. These results do not reveal a major role for DNA polymerase lambda in determining radiosensitivity in vivo.

Bilirubin, an abundant pigment that causes jaundice, has long lacked any clear physiologic role. It arises from enzymatic reduction by biliverdin reductase of biliverdin, a product of heme oxygenase activity. Bilirubin is a potent antioxidant that we show can protect cells from a 10,000-fold excess of H2O2. We report that bilirubin is a major physiologic antioxidant cytoprotectant. Thus, cellular depletion of bilirubin by RNA interference markedly augments tissue levels of reactive oxygen species and causes apoptotic cell death. Depletion of glutathione, generally regarded as a physiologic antioxidant cytoprotectant, elicits lesser increases in reactive oxygen species and cell death. The potent physiologic antioxidant actions of bilirubin reflect an amplification cycle whereby bilirubin, acting as an antioxidant, is itself oxidized to biliverdin and then recycled by biliverdin reductase back to bilirubin. This redox cycle may constitute the principal physiologic function of bilirubin.

Efficient and tunable absorption is essential for a variety of applications, such as designing controlled-emissivity surfaces for thermophotovoltaic devices, tailoring an infrared spectrum for controlled thermal dissipation and producing detector elements for imaging. Metamaterials based on metallic elements are particularly efficient as absorbing media, because both the electrical and the magnetic properties of a metamaterial can be tuned by structured design. So far, metamaterial absorbers in the infrared or visible range have been fabricated using lithographically patterned metallic structures, making them inherently difficult to produce over large areas and hence reducing their applicability. Here we demonstrate a simple method to create a metamaterial absorber by randomly adsorbing chemically synthesized silver nanocubes onto a nanoscale-thick polymer spacer layer on a gold film, making no effort to control the spatial arrangement of the cubes on the film. We show that the film-coupled nanocubes provide a reflectance spectrum that can be tailored by varying the geometry (the size of the cubes and/or the thickness of the spacer). Each nanocube is the optical analogue of a grounded patch antenna, with a nearly identical local field structure that is modified by the plasmonic response of the metal's dielectric function, and with an anomalously large absorption efficiency that can be partly attributed to an interferometric effect. The absorptivity of large surface areas can be controlled using this method, at scales out of reach of lithographic approaches (such as electron-beam lithography) that are otherwise required to manipulate matter on the nanoscale.

Addition of thenoyltrifluoracetone to mitochondria oxidizing NAD-dependent substrates induced lipid peroxidation and uncoupling of oxidative phosphorylation. Butylated hydroxytoluene, an antioxidant, prevented accumulation of lipid peroxidation products but failed to prevent deenergization of the mitochondria.

BACKGROUND AND OBJECTIVE: In coupling laser with micromanipulator through fiberoptics, the resulting diameter of the spot is limited by the laws of geometrical optics, because of the high numerical aperture (N.A.) of fiberoptic radiation. A new method for the reduction of spot size diameter is suggested.STUDY DESIGN/MATERIALS AND METHODS: The output of a 2 mW He-Ne laser was couped via fiberoptic link, the fiberoptic output light collected by a single lens collimator and directed to the input of the micromanipulator.RESULTS: The spot size can be considerably reduced by the introduction of an aperture which reduces the numerical aperture (N.A.) of the fiberoptic. The resulting reduction in total power has little effect on the power density.CONCLUSION: This approach to the collimator design permits reduction in spot size without any significant changes in power density, thus avoiding damage to the tissue and obtaining optimum performance from the micromanipulator.

One hundred psychiatric patients seen for the first time on a private basis received a research interview that allowed a study of demographic and clinical characteristics. Eighty-five had a discrete psychiatric disorder and fifty were suffering affective disorders. Most sought psychiatric attention because of a situation defined as an emergency, and a large number were hospitalized at the time of the first interview. Most of the patients made six or more office visits within the ensuing eighteen to twenty-four months. Males were largely represented among patients who sought emergency treatment, had an initial hospitalization, and received longer office treatment.

BACKGROUND AND OBJECTIVE: To illustrate artifacts that may be encountered during measurement of the peripapillary retinal nerve fiber layer (RNFL) using scanning laser polarimetry (SLP).PATIENTS AND METHODS: A total of 426 patients with a variety of ocular diagnoses underwent RNFL measurements using SLP from June 1996 to April 1997. Scanning was performed by two operators whose reproducibility of measurements had been previously validated. Images were selected to illustrate clinical features that adversely affected measurement of the thickness of the RNFL.RESULTS: Image acquisition was difficult in eyes with corneal grafts or edema, keratic precipitates, anterior uveitis, posterior subcapsular cataract, vitreous opacity, peripapillary atrophy, posterior staphyloma, and high axial myopia. These scans resulted in poor clinical correlation with visual field tests and optic nerve examination, poor reproducibility of images, and unreadable images.CONCLUSION: Anterior and posterior segment pathologies, particularly those localized to the cornea and lens, may produce spurious RNFL measurements and should be carefully considered prior to clinical decision making.

OBJECTIVE: To investigate the potential efficacy of panaxadiol saponins component (PDS-C), a biologically active fraction isolated from total ginsenosides, to reverse chemotherapy-induced myelosuppression and pancytopenia caused by cyclophamide (CTX).METHODS: Mice with myelosuppression induced by CTX were treated with PDS-C at a low- (20 mg/kg), moderate- (40 mg/kg), or high-dose (80 mg/kg) for 7 consecutive days. The level of peripheral white blood cell (WBC), neutrophil (NEU) and platelet (PLT) were measured, the histopathology and colony formation were observed, the protein kinase and transcription factors in hematopoietic cells were determined by immunohistochemical staining and Western blot.RESULTS: In response to PDS-C therapy, the peripheral WBC, NEU and PLT counts of CTX-induced myelosuppressed mice were significantly increased in a dose-dependent manner. Similarly, bone marrow histopathology examination showed reversal of CTX-induced myelosuppression with increase in overall bone marrow cellularity and the number of hematopoietic cells (P<0.01). PDS-C also promoted proliferation of granulocytic and megakaryocyte progenitor cells in CTX-treated mice, as evidenced by significantly increase in colony formation units-granulocytes/monocytes and -megakaryocytes (P<0.01). The enhancement of hematopoiesis by PDS-C appears to be mediated by an intracellular signaling pathway, this was evidenced by the up-regulation of phosphorylated mitogen-activated protein kinase (p-MEK) and extracellular signal-regulated kinases (p-ERK), and receptor tyrosine kinase (C-kit) and globin transcription factor 1 (GATA-1) in hematopoietic cells of CTX-treated mice (P<0.05).CONCLUSIONS: PDS-C possesses hematopoietic growth factor-like activities that promote proliferation and also possibly differentiation of hematopoietic progenitor cells in myelosuppressed mice, probably mediated by a mechanism involving MEK and ERK protein kinases, and C-kit and GATA-1 transcription factors. PDS-C may potentially be a novel treatment of myelosuppression and pancytopenia caused by chemotherapy.

The K-Cl cotransporter KCC2 plays a crucial role in neuronal chloride regulation. In mature central neurons, KCC2 is responsible for the low intracellular Cl(-) concentration ([Cl(-)](i)) that forms the basis for hyperpolarizing GABA(A) receptor-mediated responses. Fast changes in KCC2 function and expression have been observed under various physiological and pathophysiological conditions. Here, we show that the application of protein synthesis inhibitors cycloheximide and emetine to acute rat hippocampal slices have no effect on total KCC2 protein level and K-Cl cotransporter function. Furthermore, blocking constitutive lysosomal degradation with leupeptin did not induce significant changes in KCC2 protein levels. These findings indicate a low basal turnover rate of the total KCC2 protein pool. In the presence of the glutamate receptor agonist NMDA, the total KCC2 protein level decreased to about 30% within 4 h, and this effect was blocked by calpeptin and MDL-28170, inhibitors of the calcium-activated protease calpain. Interictal-like activity induced by incubation of hippocampal slices in an Mg(2+)-free solution led to a fast reduction in KCC2-mediated Cl(-) transport efficacy in CA1 pyramidal neurons, which was paralleled by a decrease in both total and plasmalemmal KCC2 protein. These effects were blocked by the calpain inhibitor MDL-28170. Taken together, these findings show that calpain activation leads to cleavage of KCC2, thereby modulating GABAergic signaling.

Temporomandibular joint disorders (TMD) affect the joint, the masticatory muscles, or are expressed as a clinical combination of these two factors. The aims of this study were to: (i) identify the clinical and psychosocial factors that aid in the diagnosis and classification of acute and chronic TMD, (ii) determine specific initiating and perpetuating factors which may act as a guide to differentiate between acute and chronic TMD, (iii) identify factors which might predispose to conversion from acute to chronic TMD. Twenty-two patients were examined in the pain clinics at the Eastman Dental Institute. The assessment technique incorporated questionnaires, clinical history and examination including dental panoramic tomography. The results of this pilot study show a significant correlation between mood and enjoyment of life in both groups, mood and relationships in the chronic group, average pain and sleep in the chronic group, average pain and eating-chewing in the chronic group, and phobia for physical disease with trust in clinicians in the chronic group. The bio-psychosocial model of pain is an important appraisal tool. The newly designed TMD Pain Assessment is described with good results.

This paper concludes a series on the findings from a study on the emerging role of nurse teachers in Project 2000 programmes. The various aspects of the study, including the literature review and methodology, have been previously discussed (Crotty & Butterworth 1992, Crotty 1992, Crotty 1993a,b,c,d). This paper highlights the main findings and suggests recommendations regarding the key issues to be addressed in the future role and preparation of the nurse teacher. The study revealed two major changes which are contrary to the expectations of Project 2000. These are firstly, the teaching of academic subjects by nurse teachers, and secondly, the rejection of clinical teaching involving 'hands on care' by nurse teachers.

Targeting of the endothelial inflammatory adhesion molecule E-selectin by magnetic resonance imaging (MRI) was performed with a superparamagnetic contrast agent in the context of in vitro and in vivo models of inflammation. The specific contrast agent was obtained by grafting a synthetic mimetic of sialyl Lewis(x) (sLe(x)), a natural ligand of E-selectin expressed on leukocytes, on the dextran coating of ultrasmall particles of iron oxide (USPIO). This new contrast agent, called USPIO-g-sLe(x), was tested, in vitro, on cultured human umbilical vein endothelial cells (HUVECs) stimulated to express inflammatory adhesion molecules, and in vivo, on a mouse model of hepatitis. In vitro, HUVECs were stimulated with the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) and were then incubated with USPIO-g-sLe(x) or ungrafted USPIO. In vivo, hepatitis was induced on NMRI mice by injection of concanavalin A (Con A). USPIO-g-sLe(x) and ungrafted USPIO were injected intravenously. In vitro results showed an extensive retention of USPIO-g-sLe(x) on TNF-alpha stimulated HUVECs. Image intensity and R(2) measurements performed on T(2)-weighted MR images demonstrated a significantly higher binding of USPIO-g-sLe(x) on stimulated HUVECs. In vivo, USPIO are known to pass through the fenestrae of the liver and to be captured by Kupffer cells, inducing a loss of signal intensity on T(2)-weighted MR images. Unexpectedly, when injected to Con A-treated mice, USPIO-g-sLe(x) induced a significantly lower attenuation of liver signal intensity than USPIO or USPIO-g-sLe(x) injected to healthy mice, or USPIO injected to Con A-treated mice, suggesting that the specific contrast media is retained extracellularly by an interaction with E-selectin overexpressed on the vascular endothelium. Both in vitro and in vivo results therefore indicate that USPIO-g-sLe(x) is recognizing endothelial E-selectin. USPIO-g-sLe(x) is thus well suited for the MRI diagnosis of inflammation and for the in vitro evaluation of endothelial cells activation.

BACKGROUND: Left atrial (LA) remodeling is associated with structural, electric, and metabolic LA changes. Integrated evaluation of these features in vivo is lacking.METHODS: Patients undergoing 18F-fluorodeoxyglucose (FDG) PET-CT during a hyperinsulinemic-euglycemic clamp were classified into sinus rhythm (SR), paroxysmal AF (PAF), and persistent AF (PerAF). The LA was semiautomatically segmented, and global FDG uptake was quantified using standardized uptake values (SUVmax and SUVmean) in gated, attenuation-corrected images and normalized to LA blood pool activity. Regression was used to relate FDG data to AF burden and critical patient factors. Continuous variables were compared using t-tests or Mann-Whitney tests.RESULTS: 117 patients were included (76% men, age 66.4 ± 11.0, ejection fraction (EF) 25[22-35]%) including those with SR (n = 48), PAF (n = 55), and PerAF (n = 14). Patients with any AF had increased SUVmean (2.3[1.5-2.4] vs 2.0[1.5-2.5], P = 0.006), SUVmax (4.4[2.8-6.7] vs 3.2[2.3-4.3], P < 0.001), uptake coefficient of variation (CoV) 0.28[0.22-0.40] vs 0.25[0.2-0.33], P < 0.001), and hypometabolic scar (32%[14%-53%] vs 16.5%[0%-38.5%], P = 0.01). AF burden correlated with increased SUVmean, SUVmax, CoV, and scar independent of age, gender, EF, or LA size (P < 0.03 for all).CONCLUSIONS: LA structure and metabolism can be assessed using FDG PET/CT. Greater AF burden correlates with the increased LA metabolism and scar.

Sympathetic overactivity is associated with hyperhidrosis and cardiovascular diseases. Endoscopic thoracic sympathectomy (ETS) is a treatment for hyperhidrosis. We aimed to compare the risk for cardiovascular events between individuals with and without hyperhidrosis and investigate the effects of ETS on cardiovascular outcomes. We conducted a nationwide population-based cohort study using data acquired from the Korean Health Insurance Review and Assessment Service. Subjects newly diagnosed with hyperhidrosis in 2010 were identified and divided into two groups according to whether or not they underwent ETS. Propensity scores were calculated using a logistic regression model to match hyperhidrosis patients with control subjects. Combined cardiovascular events were defined as stroke and ischemic heart diseases. Subjects were followed up until the first cardiovascular event or 31 December 2017. The risk for cardiovascular events with hyperhidrosis and ETS was analyzed using Cox proportional hazards regression analysis. The risk for stroke was significantly higher in the hyperhidrosis group than in the control group (hazard ratio (HR), 1.28; 95% confidence interval (CI), 1.08-1.51); nonetheless, no significant difference in the risk for ischemic heart diseases was observed between the hyperhidrosis group and the control group (HR, 1.17; 95% CI, 0.99-1.31). Hyperhidrosis patients who did not undergo ETS were at significantly higher risk for cardiovascular events than the control group (HR, 1.28; 95% CI, 1.13-1.45). However, no significant difference in the risk for cardiovascular events was observed between hyperhidrosis patients who underwent ETS and the control group. Hyperhidrosis increases the risk for cardiovascular events. ETS could reduce this risk and needs to be considered for high-risk patients with cardiovascular diseases.

GCN4 is a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae whose expression is regulated by amino-acid availability at the translational level. GCD1 and GCD2 are negative regulators required for the repression of GCN4 translation under nonstarvation conditions that is mediated by upstream open reading frames (uORFs) in the leader of GCN4 mRNA. GCD factors are thought to be antagonized by the positive regulators GCN1, GCN2 and GCN3 in amino acid-starved cells to allow for increased GCN4 protein synthesis. Previous genetic studies suggested that GCD1, GCD2, and GCN3 have closely related functions in the regulation of GCN4 expression that involve translation initiation factor 2 (eIF-2). In agreement with these predictions, we show that GCD1, GCD2, and GCN3 are integral components of a high-molecular-weight complex of approximately 600,000 Da. The three proteins copurified through several biochemical fractionation steps and could be coimmunoprecipitated by using antibodies against GCD1 or GCD2. Interestingly, a portion of the eIF-2 present in cell extracts also cofractionated and coimmunoprecipitated with these regulatory proteins but was dissociated from the GCD1/GCD2/GCN3 complex by 0.5 M KCl. Incubation of a temperature-sensitive gcdl-101 mutant at the restrictive temperature led to a rapid reduction in the average size and quantity of polysomes, plus an accumulation of inactive 80S ribosomal couples; in addition, excess amounts of eIF-2 alpha, GCD1, GCD2, and GCN3 were found comigrating with free 40S ribosomal subunits. These results suggest that GCD1 is required for an essential function involving eIF-2 at a late step in the translation initiation cycle. We propose that lowering the function of this high-molecular-weight complex, or of eIF-2 itself, in amino acid-starved cells leads to reduced ribosomal recognition of the uORFs and increased translation initiation at the GCN4 start codon. Our results provide new insights into how general initiation factors can be regulated to affect gene-specific translational control.

Specific immunotherapy (SIT) or allergenic desensitization would be the only treatment capable to change the natural history of the atopic march for children. SIT has shown numerous proofs of efficacy in allergic asthma particularly in improving clinical and medication scores. It could also have the capacity to prevent asthma and new allergenic sensitization.

An antiserum with allotypic specificity for mouse gamma(2a)-globulins was prepared in a rabbit by injection of 7S gamma(2)-globulin of C(57)BL/6 mice. The antibody reacted with an isoantigen in the 7S gamma(2)-globulins of normal serum of mouse strains belonging to the lg-1(b) allotype class (C(57)BL/6, C(57)BL/10, and SJL strains). No precipitin reaction was observed with serum from 18 other inbred mice strains representing other lg-1 allotype classes.

The efficacy of stem cell-based bone tissue engineering has been hampered by cell death and limited fate control. A smart cell culture system with the capability of sequentially delivering multiple factors in specific growth stages, like the mechanism of the natural extracellular matrix modulating tissue formation, is attractive for enhancing cell activity and controlling cell fate. Here, a bone forming peptide-1 (BFP-1)-laden mesoporous silica nanoparticles (pep@MSNs) incorporated adhesion peptide, containing the arginine-glycine-aspartic acid (RGD) domain, modified alginate hydrogel (RA) system (pep@MSNs-RA) was developed to promote the activity and stimulate osteo-differentiation of human mesenchymal stem cells (hMSCs) in sequence. The survivability and proliferation of hMSCs were enhanced in the adhesion peptide modified hydrogel. Next, BFP-1 released from pep@MSNs induced hMSCs osteo-differentiation after the proliferation stage. Moreover, BFP-1 near the cells was self-captured by the additional cell-peptide cross-linked networks formed by the ligands (RGD) binding to receptors on the cell surface, leading to long-term sustained osteo-stimulation of hMSCs. The results suggest that independent and sequential stimulation in proliferation and osteo-differentiation stages could synergistically enhance the survivability, expansion, and osteogenesis of hMSCs, as compared to stimulating alone or simultaneously. Overall, this study provided a new and valid strategy for stem cell expansion and osteo-differentiation in 2D or 3D culture systems, possessing potential applications in 3D bio-printing and tissue regeneration.

Polyanions based on poly(methyl vinyl ether-alt-maleic acid) were investigated as materials for cell encapsulation. These water-soluble polyanions having molecular masses ranging from 20 to 1980 kDa were prepared by functionalization of poly(methyl vinyl ether-alt-maleic anhydride) with 5-aminofluorescein and/or á-methoxy-ù-amino-poly(ethylene glycol), followed by base hydrolysis of the residual anhydride groups to form the corresponding poly(methyl vinyl ether-alt-sodium maleate). Their potential to replace alginate both in the core and, in particular, the outer shell of calcium alginate-poly(L-lysine)-alginate (APA) capsules was determined using confocal fluorescence microscopy, osmotic pressure tests, permeability studies, protein binding and cell viability assays. These polymers were shown to be able to replace the outer layer of alginate, forming more resilient capsule shells. The resulting capsules showed similar permeability and resistance to bovine serum albumin binding, as well as superior viability for encapsulated cells, when compared to standard APA capsules. In addition, these polymers showed promise for use as functional additives to the capsule cores.

INTRODUCTION: Multimorbidity has been linked to elevated healthcare utilization and previous studies have found that socioeconomic status is an important factor associated with multimorbidity. Nonetheless, little is known regarding the impact of multimorbidity and socioeconomic status on healthcare costs and whether inequities in healthcare exist between socioeconomic classes within a universal healthcare system.METHODS: This longitudinal study employed the claims database of the National Health Insurance of Taiwan (959 990 enrolees), adopting medication-based Rx-defined morbidity groups (Rx-MG) as a measurement of multimorbidity. Mixed linear models were used to estimate the effects of multimorbidity and socioeconomic characteristics on annual healthcare costs between 2005 and 2010.RESULTS: The distribution of Rx-MGs and total costs presented statistically significant differences among gender, age groups, occupation, and income class (p < .001). Nearly 80% of the enrolees were classified as multimorbid and low income earners presented the highest prevalence of multimorbidity. After controlling for age and gender, increases in the number of Rx-MG assignments were associated with higher total healthcare costs. After controlling for the effects of Rx-MG assignment and demographic characteristics, physicians, paramedical personnel, and public servant were found to generate higher total costs than typical employees/self-employed enrolees, while low-income earners generated lower costs. High income levels were also found to be associated with lower total costs. It was also revealed that occupation and multimorbidity have a moderating effect on healthcare cost.CONCLUSIONS: Increases in the prevalence of multimorbidity are associated with higher health care costs. This study determined that instances of multimorbidity varied according to socioeconomic class; likewise there were inequities in healthcare utilization among individuals of various occupations and income levels, even when demographic characteristics and multimorbidity were controlled for. This highlights the importance of socioeconomic status with regard to healthcare utilization. These results indicate that socioeconomic factors should not be discounted when discussing the utilization of healthcare by patients with multimorbidity.

The jaw bones are the most common sites for epithelial cysts and tumors in the human skeleton due to their close relationship to the tooth and odontogenesis. Most of these cysts and tumors have in common an origin from the tissues of tooth formation and constitute a very diverse group of lesions that reflects the complex development of the dental structures. This group of odontogenic lesions occurs predominantly in the jaws, with a predilection for young people. Some aggressive lesions have attracted much attention as they often produce marked facial deformity and tend to recur after insufficient surgery. The most widely quoted classification of odontogenic tumors is that proposed in the WHO booklet published in 1992. There are, however, a number of controversial issues that need to be addressed with respect to clinicopathological subtypings, terminology, and diagnosis which all have direct bearings on therapeutic and/or prognostic implications. In the light of recent publication of the WHO new classification and a series of related studies undertaken by the author's group, this paper is to put together an overview on some of these important aspects related to unicystic ameloblastoma, clear cell odontogenic tumor, calcifying odontogenic cyst, odontogenic keratocyst, ameloblastic fibroma and its related lesions. Consequent upon a better understanding of the nature of these tumors and their variants, the various treatment protocols currently recommended by different surgeons will be better rationalized.

An effective and inexpensive method is developed to fabricate periodic arrays by sacrificial colloidal monolayer template route by chemical deposition and further physical deposition. By a colloidal template induced precursor solution dipping strategy, different periodic arrays of semi-hollow sphere array, inverse opal with monolayer pore arrays and hole arrays are obtained under different conditions. After magnetron sputtering deposition, their morphologies are changed to novel micro/nanostructured arrays of honeycomb-shaped arrays, hollow cavity arrays, and regular network arrays due to multiple direction deposition of sputtering deposition and shadow effect. After coating a gold thin layer, these periodic micro/nanostructured arrays are used as SERS active substrates and demonstrate a very stable SERS performance compared with periodic arrays achieved by direct colloidal template-induced chemical deposition. Additionally, a honeycomb-shaped array displays better SERS enhancement than that of a hollow cavity array or a regular network array. After optimization of honeycomb-shaped arrays with different periodicities, an array with periodicity of 350 nm demonstrates much stronger SERS enhancement and possesses a low detection limit of 10(-11) M R6G. Such stable SERS performance is useful for practical application in portable Raman detecting devices to detect organic molecules.

OBJECTIVES: Extensive skeletal muscle accumulation (ESMA) of F-FDG adversely affects the visual interpretation of F-FDG PET/computed tomography (CT) images. We mainly investigated factors related to ESMA that are based on food compositions.METHODS: From January 2018 to June 2018, a total of 5554 patients underwent F-FDG PET/CT imaging with at least a 4-hour fast. Among them, 49 patients who exhibiting ESMA and 50 sex-matched and age-matched patients without ESMA were included in the study. The following factors were analysed: BMI, plasma glucose, gastric residue, the total energy of food the patient had before F-FDG injection and the percentages of the food ingredients. Multivariate analysis was performed to evaluate related risk factors between two groups.RESULTS: In brief, 49 cases and 50 controls were identified. The BMI, gross energy, gross energy of protein, gross energy of carbohydrate and proportion of protein of case group were not significantly different from that of the controls (P ? 0.05). The plasma glucose was significantly higher in the case group than in the control group (P = 0.002). The positivity of gastric food residue would more easily demonstrate ESMA than those without gastric food residue (P < 0.0001). The fasting time before scan, gross energy of fat, proportion of fat and proportion of carbohydrate in case group were significantly different with control group. After multivariate analysis, fasting time, gastric food residue and proportion of carbohydrate were investigated as independent risk factors.CONCLUSION: To avoid ESMA, patients should take a lower proportion of carbohydrate before receiving an F-FDG administration.

In performing our experiment, impaired autophagy increased hepatocellular damage during the reperfusion period. It was demonstrated by the effect of blocking autophagy using bafilomycin A1 or knocking Atg5 gene out reduces the anti-apoptotic effect of Stat3. Here we focus on the role of signal transducer and activator of transcription 3 (Stat3) in regulating autophagy to alleviate hepatic IRI. We found that Stat3 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling pathway. This increased Stat3 expression, which was allied with high autophagic activity, alleviated liver damage to IR, an effect which was abrogated by Stat3 epletion as demonstrated in both in vivo and in vitro methods. The levels of Atg5 protein were decreased when Stat3 was inhibited by HO 3867 or siStat3. We conclude that Stat3 appeared to exert a pivotal role in hepatic IRI, by activating autophagy to alleviate hepatic IRI, and Atg5 was required for this process. The identification of this novel pathway, that links expression levels of Stat3 with Atg5-mediated autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.

UNLABELLED: We have recently completed a large 6-(18)F-fluoro-L-DOPA ((18)F-DOPA) PET study comparing rates of loss of dopamine terminal function in Parkinson's disease (PD) patients taking either the dopamine agonist ropinirole or L-DOPA. This trial involved a "distributed acquisition/centralized analysis" method, in which (18)F-DOPA images were acquired at 6 different PET centers around the world and then analyzed at a single site. To our knowledge, this is the first time such a centralized approach has been employed with (18)F-DOPA PET and this descriptive basic science article outlines the methods used.METHODS: One hundred eighty-six PD patients were randomized (1:1) to ropinirole or L-DOPA therapy, and (18)F-DOPA PET was performed at baseline and again at 2 y. The primary outcome measure was the percentage change in putamen (18)F-DOPA influx rate constant (K(i)) from Patlak graphical analysis. Dynamic images were acquired and reconstructed using each center's individual protocols before being transferred to the site performing the central analysis. Once there, individual parametric K(i) images were created using a single analysis program without file formats being transformed from the original. Parametric images were then normalized to standard space and K(i) values extracted with a region of interest analysis. Significant K(i) changes were also localized at a voxel level with statistical parametric mapping. These processes required numerous checks to ensure the integrity of each dataset.RESULTS: Three hundred twenty-five (170 baseline, 155 follow-up) dynamic PET datasets were acquired, of which 12 were considered uninterpretable due to missing time frames, radiopharmaceutical problems, lack of measured attenuation correction, or excessive head movement. In those datasets suitable for central analysis, after quality control and spatial normalization of the images had been applied, putamen (18)F-DOPA signal decline was found to be significantly (one third) slower in the ropinirole group compared with that of the L-DOPA group.CONCLUSION: Paired (18)F-DOPA-PET images acquired from multiple sites can be successfully analyzed centrally to assess the efficacy of potential disease-modifying therapies in PD. However, numerous options must be considered and data checks put in place before adopting such an approach. Centralized analysis offers the potential for improved detection of outcomes due to the standardization of the analytic approach and allows the analysis of large numbers of PET studies.

The power of the two-experimental arm trial depends on three choices: (1) when one arm is dropped (if at all); (2) the final testing procedure, assuming no dropping; and (3) the sampling ratio for the three arms. Multiple-arm designs require critical values which were calculated using Mathematica. Power calculations were exact based on probabilities from binomial distributions. The "drop the loser" strategy is optimal for the primary endpoint. The equal sized two treated arm trial gives reasonable power for the primary as well as good power to select the best treated arm. The best power was provided by the 3:3:4 sampling, but it was only marginally better.

In the absence of liver biopsy and transient elastography (TE), aspartate aminotransferase to platelet ratio (APRI), fibrosis-4 score (FIB-4), and gammaglutamyl transpeptidase to platelet ratio (GPR) are simple and inexpensive methods for the detection of liver fibrosis.AIMS: We compared the performance of APRI, FIB-4, and GPR scores against TE in predicting the presence of liver fibrosis and cirrhosis, determined the optimal cut-off values for fibrosis and cirrhosis prediction, and reviewed the need for further TE assessment in resource-limited areas in China.METHODS: TE and basic laboratory tests were performed in 2014 consecutive patients with chronic hepatitis B (CHB), and then compared to APRI, FIB-4, and GPR.RESULTS: For the detection of significant fibrosis, the areas under the receiver operating characteristic (AUROC) curves for APRI, FIB-4, and GPR were 0.83, 0.75, and 0.77, respectively. For the detection of cirrhosis, the AUROC curves for APRI, FIB-4, and GPR were 0.90, 0.84, and 0.84, respectively. The cutoff of APRI was 0.35, with 78% sensitivity and 63% negative predictive value (NPV), to exclude significant fibrosis (F ? 2). At an APRI of 0.6, results showed a 94% specificity, 100% positive predictive value (PPV) and 7.9 positive likelihood ratio (PLR) in detecting significant fibrosis. Thus, patients with an APRI of <0.35 or >0.6 demonstrated correct prediction of liver fibrosis. These results translated to 1250 out of the 2014 patients avoiding the need for TE with a diagnostic accuracy of >80%.CONCLUSIONS: The APRI score accurately assessed fibrosis and reduced the need for TE in almost two-thirds of Chinese patients with CHB.

Although there are multiple pathways to successful aging, little is known of what it means to age successfully among black women. There is a growing body of literature suggesting that black women experience a number of social challenges (sexism and racism) that may present as barriers to aging successfully. Applying aspects of the Strong Black Women ideal, into theoretical concepts of successful aging, may be particularly relevant in understanding which factors impair or promote the ability of black women to age successfully. The Strong Black Women archetype is a culturally salient ideal prescribing that black women render a guise of self-reliance, selflessness, and psychological, emotional, and physical strength. Although this ideal has received considerable attention in the behavioral sciences, it has been largely absent within the gerontology field. Nevertheless, understanding the dynamics of this cultural ideal may enhance our knowledge while developing an appreciation of the black woman's ability to age successfully. Rather than summarize the social, physical, and mental health literature focusing on health outcomes of black women, this conceptual review examines the Strong Black Women archetype and its application to the lived experiences of black women and contributions to current theories of successful aging. Focusing on successful aging exclusively among black women enhances our understanding of this group by considering their identity as women of color while recognizing factors that dictate their ability to age successfully.

We report a 49-year-old female who had circumferential urethral diverticulum. She was admitted to our department for urinary retention. A cystic lesion surrounding the urethra had been detected by magnetic resonance imaging. We diagnosed the lesion as a urethral diverticulum after injecting dye to the cystic mass from vagina and confirming its discharge from the urethra at the pubic side by urethroscopy. Transvaginal resection of the diverticulum was peformed. In general, 4% of female urethral diverticula cause urinary retention. On the other hand, 1% of female bladder outlet obstruction is caused by urethral diverticula. It is neccessary for us to keep in mind urethral diverticulum when we evaluate female patients with urinary retention.

Vertebrates diverged from other chordates ~500 Myr ago and experienced successful innovations and adaptations, but the genomic basis underlying vertebrate origins are not fully understood. Here we suggest, through comparison with multiple lancelet (amphioxus) genomes, that ancient vertebrates experienced high rates of protein evolution, genome rearrangement and domain shuffling and that these rates greatly slowed down after the divergence of jawed and jawless vertebrates. Compared with lancelets, modern vertebrates retain, at least relatively, less protein diversity, fewer nucleotide polymorphisms, domain combinations and conserved non-coding elements (CNE). Modern vertebrates also lost substantial transposable element (TE) diversity, whereas lancelets preserve high TE diversity that includes even the long-sought RAG transposon. Lancelets also exhibit rapid gene turnover, pervasive transcription, fastest exon shuffling in metazoans and substantial TE methylation not observed in other invertebrates. These new lancelet genome sequences provide new insights into the chordate ancestral state and the vertebrate evolution.

Choroideremia is a progressive tapetochoroidal dystrophy with X-linked transmission leading frequently to blindness in affected males. The choroideremia-locus (TCD) has recently been assigned to the long arm of the X chromosome by linkage to polymorphic DNA markers. In order to further define the location of the gene defect, two families segregating for choroideremia were examined for DNA restriction fragment length polymorphisms. A search was undertaken for linkage with cloned DNA probes from the proximal short and long arm as well as from the mid-portion of the long arm of the X chromosome. Our data suggest that the most plausible gene order on the Xq is: Xcen-DXYS1-DXS3-TCD-DXS11-Xqter.

Studies of physicians' attitudes and knowledge of the acquired immunodeficiency syndrome (AIDS) and the clinical precautions they take against exposure to the human immunodeficiency virus (HIV) have focused on urban physicians. To determine rural physicians' knowledge and attitudes about AIDS, a questionnaire was mailed to 321 physicians practicing in rural Utah. Of the 169 physicians who completed questionnaires, 96% thought that their community or area of service had only a minor or no problem with AIDS; 89%, however, thought that their chance of seeing a patient who was HIV-positive was fair to moderate. Of the 169 respondents, 3% were not sure whether they would even treat a patient who had AIDS, 67% said they would, and 30% said they would not. Although all physicians are at risk of seeing a patient who has had exposure to HIV and other blood-borne diseases such as hepatitis B, only 55% of the respondents felt a need to take clinical precautions to prevent their exposure to the virus. Our study shows the need for all rural Utah physicians to reevaluate their risk of exposure to HIV, to increase precautionary measures for their own protection, to consider the ethical responsibility of treating AIDS patients, and to take a more active role in teaching their patients how to protect themselves from exposure to the virus.

BACKGROUND: There is little published evidence that any aspect of vocational training for general practice improves the quality of care provided by general practitioners (GPs).AIM: To investigate whether aspects of education and vocational training predict whether GPs provide intrapartum care.METHOD: A five-year prospective cohort study was carried out in the United Kingdom (UK) using responders to a 1990 national survey of GPs for whom a current UK address could be found. Main outcome measures were factors associated with provision of GP intrapartum care in 1995.RESULTS: In 1995, a minority of ex-trainees (65 out of 349, 18%) provided intrapartum care as GPs, although 28% would ideally have wished to do so; 8% provided home delivery care. Four education and training variables were associated with ex-trainees booking women for GP delivery in 1995: the number of partners in the ex-trainee's GP training practice providing GP intrapartum care (odds ratio (OR) = 1.30); performing forceps deliveries as an obstetric senior house officer (SHO) (OR = 1.24), witnessing episiotomies as a student (OR = 1.17), and witnessing twin deliveries as a student (OR = 0.75).CONCLUSIONS: In the case of GP intrapartum care, future service provision is associated with certain education and training variables. There is a mismatch between GPs' ideal and actual maternity care provision. Changes to enhance such care would be needed at least at three levels: selection and approval of training practices, content and base for SHO posts, and practice arrangements for maternity cover.

OBJECTIVE: This paper reflects on the collaborative research relationship between university and community researchers. It identifies emergent themes expressed in the words of researchers and recommends strategies to assist with other research collaborations.CONCLUSIONS: Emergent themes included: Initial reticence by community members followed by positive experiences; the value of empowerment frameworks in research; building trust between community and university researchers; capacity building, management, and workloads; and community politics, misunderstandings and wealth disparity. The paper recommends strategies for successful research collaborations and identifies challenges to research collaborations.

A three-stage context amplification model was tested with a sample of 345 African-American parent-child dyads. The model combined the conceptual structure of stress generation with recent findings regarding genetic susceptibility. Because the 7R + allele of the dopamine transporter (DRD4) has the potential to enhance contextual priming and arousal, this allele was examined as a potential moderator of each stage of the amplification process. Particular attention was given to the hypothesized influence of parental negative arousal on valence of parent-child interactions. The literature on genetic susceptibility led to the hypothesis that DRD4 would moderate each stage of the model in a "for better or for worse" manner. The model was partially supported. DRD4 moderated effects at all three stages of the model and, as hypothesized, DRD4 moderated contextual effects on negative arousal in a "for better or for worse" manner. Effects on parent-child interaction, however, were moderated in a "for worse" manner only. These results indicate that parenting interactions may amplify the effects of positive and negative contexts in a stress-generating manner, and that a susceptibility framework captures the way in which DRD4 moderates the impact of context on negative arousal.

Renal cell carcinoma is known to invade the inferior vena cava and may extend its entire length. Profound hypothermic circulatory arrest has been demonstrated to be a very effective technique to facilitate removal of tumor thrombus from the cava while limiting the amount of blood loss. We describe an innovative method of ensuring complete removal of tumor thrombus from the retrohepatic cava with a fiberoptic bronchoscope introduced through the right atrium during profound hypothermic circulatory arrest. Fiberoptic examination of the cava and hepatic vein orifices under these circumstances will prevent incomplete removal of tumor.

Mycobacterium abscessus and Kocuria species are rare causes of infections in humans. Endocarditis by these agents has been reported in only 11 cases. M. abscessus is a particularly resistant organism and treatment requires the association of antibiotics for a prolonged period of time. We report a case of native mitral valve bacterial endocarditis due to M. abscessus and Kocuria species in a 48-year-old man with a history of intravenous drug use. The case was complicated by a perforation of the posterior mitral valve leaflet, leading to surgical mitral valve replacement. Cultures from the blood and mitral valve disclosed M. abscessus and Kocuria species. The patient was treated for 6 months with clarithromycin, imipenem and amikacin, with resolution of symptoms. Repeated blood cultures were negative. Acid-fast staining should be done in subacute endocarditis in order to identify rapidly growing mycobacteria.

Though the serum total amylase test has been used for the diagnosis of pancreatitis for over 50 years, both its clinical sensitivity and specificity are far from perfect. We first present the results of serial serum total amylase, pancreatic isoamylase, lipase, and immunoreactive trypsin tests in nine patients during the week after their admission to the hospital with a diagnosis of acute pancreatitis, and then compare the serum total amylase, lipase, and immunoreactive trypsin levels in the initial serum submitted for amylase analysis from 100 patients because of the clinical suspicion of acute pancreatitis. In the former group of patients, the serum total amylase test was the least sensitive of the tests for pancreatitis after the first hospital day. In the latter group of patients, the largest discordance was found in patients with elevated serum total amylase levels, but normal lipase and immunoreactive trypsin levels. In 90% of these discordant cases, the elevation of serum total amylase was due to salivary amylase, yielding a maximum clinical specificity of only 71% for serum total amylase. Based on these data, we conclude that alternate tests deserve careful consideration as replacements for the serum total amylase test.

A prospective study evaluated the utility of renal computed tomography (CT) and ultrasonography in 35 patients hospitalized for treatment of urinary tract infection. Renal computed tomograms were abnormal in 18 of 28 patients with acute pyelonephritis and three of four patients with urosepsis, showing findings consistent with pyelonephritis in 17 patients and intrarenal abscess or focal bacterial nephritis in four patients. Renal sonograms were abnormal in only eight patients, showing findings compatible with pyelonephritis in four and intrarenal abscess or focal bacterial nephritis in the other four. Flank tenderness was absent in only four patients with CT findings of pyelonephritis, of whom three were diabetic. We therefore found that (1) renal CT is a sensitive test for acute upper urinary tract infection, (2) ultrasonography detects focal bacterial nephritis and abscesses but is insensitive to uncomplicated upper urinary tract infection, and (3) painless pyelonephritis may be more common in patients with diabetes mellitus.

1. Slow inward and outward after-currents follow action potentials in the bursting pacemaker neurone, R 15, of Aplysia californica. These experiments were performed to examine the role of axo-dendritic calcium influx in activating these after currents. 2. Depolarizing voltage-clamp commands issued at the soma were used to elicit the after-currents. The earlier inward depolarizing after-current of DAC was followed by the hyperpolarizing after-current or HAC. The DAC and HAC appeared at a threshold following depolarizing commands in normal sea water, presumably due to triggering of action potentials in inadequately space-clamped axon. In 100 microM-tetrodotoxin (TTX), the after-currents were graded, increasing gradually in amplitude with increasing voltage or duration of the command. 3. After-current amplitudes varied with the holding potential through the range tested, -40 to -80 mV. DACs were maximum at -40 to -50 mV and decreased in amplitude with hyperpolarization. HACs were maximum at -40 mV and decreased with hyperpolarization to disappear between -70 and -80 mV. 4. The dependence of after-currents upon intracellular calcium accumulation during the depolarizing command was tested in several ways. Bathing R15 in 0 Ca2+-2 mM-EGTA (ethyleneglycol-bis-(beta-aminoethylether)-N,N'-tetraacetic acid) sea water eliminated the after-currents. Bathing in 1 mM-Ca2+ sea water reduced the DAC by 76% and the HAC by 87% following 10 ms long depolarizations to +40 mV. Application of Mn2+ (25 mM) or La3+ (5 mM) blocked the after-currents. Injection of EGTA intracellularly practically eliminated after-currents. Greatly prolonged depolarizations were required to elicit them after EGTA injection. Substitution of Ba2+ for Ca2+ also eliminated after-currents. 5. Sodium-free sea water eliminated the DAC. The HAC following brief (less than 30 ms) depolarizing commands was also eliminated in zero sodium, although longer commands were followed by an outward tail current. 6. Although the after-currents seemed dependent upon calcium influx, they were not suppressed by depolarizing commands whose voltage exceeded the calcium equilibrium potential at the soma as indicated by suppression of the calcium-activated potassium current, or IK(Ca), observed during the depolarization. However, if the extracellular calcium was lowered to 1 mM, large depolarizations did suppress the DAC. 7. Dopamine blocked the after-currents when applied to the axo-dendritic area but not when applied to the soma. Similarly, synaptic inhibition of long duration blocked the after-currents.(ABSTRACT TRUNCATED AT 400 WORDS)

Previously, we reported that repeated oral administration of etoposide (ETP) activates the ezrin/radixin/moesin (ERM) scaffold proteins for P-glycoprotein (P-gp) via Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil containing protein kinase (ROCK) signaling, leading to increased ileal P-gp expression. Recent studies indicate that phosphatidyl inositol 4,5-bisphosphate [PtdIns(4,5)P2] regulates the plasma-membrane localization of certain proteins, and its synthase, the type I phosphatidyl inositol 4-phosphate 5-kinase (PI4P5K), is largely controlled by RhoA/ROCK. Here, we examined whether PtdIns(4,5)P2 and PI4P5K are involved in the increased expression of ileal P-gp following the ERM activation by ETP treatment. Male ddY mice (4-week-old) were treated with ETP (10 mg/kg/day, per os, p.o.) for 5 days. Protein-expression levels were measured by either western blot or dot blot analysis and molecular interactions were assessed using immunoprecipitation assays. ETP treatment significantly increased PI4P5K, ERM, and P-gp expression in the ileal membrane. This effect was suppressed following the coadministration of ETP with rosuvastatin (a RhoA inhibitor) or fasudil (a ROCK inhibitor). Notably, the PtdIns(4,5)P2 expression in the ileal membrane, as well as both P-gp and ERM levels coimmunoprecipitated with anti-PtdIns(4,5)P2 antibody, were increased by ETP treatment. PtdIns(4,5)P2 and PI4P5K may contribute to the increase in ileal P-gp expression observed following the ETP treatment, possibly through ERM activation via the RhoA/ROCK pathway.

In summary, therefore, to effectively apply invasive methods and beneficially use data derived from these procedures, it is essential that physicians have an understanding of the pathophysiology of ischemic heart disease and power failure, and of other situations in cardiology including the management of the complex problems of the critically ill from a variety of causes. There should be an experience and proficiency in the techniques from the optimal application and use of invasive methods including direct arterial puncture and recording of arterial blood pressure, and the use of the Swan-Ganz catheter systems. This must be reinforced by continuous educational experiences and updating with the newer techiniques as they become available. All personnel concerned must have a knowledge of and respect for the complications inherent in any invasive procedure, particularly involving the vascular system. In addition, they must have the ability to translate the relative hemodynamic measurements into meaningful diagnostic and therapeutic decisions. Under these circumstances, invasive methods have a major and valuable role to play in the management of all forms of critical illness.

Microscopy of the serial block-sections of the entire bronchial tree of all the resected specimens of roentgenographically occult bronchogenic carcinoma revealed new findings with respect to the histological patterns of longitudinal growth within the bronchial wall. Twenty-seven lesions which were non-polypoid on gross appearance with longitudinal extension of 16 mm and above were classified into the following four categories. (A) In standard superficial extension, transmural invasion by carcinoma became shallower and the area involved on section became smaller gradually from the site of the origin of carcinoma to the proximal and distal ends. (B) In intraepithelial extension, carcinoma was confined within the epithelium throughout the bronchi involved except at and near the site of the origin at which it penetrated the basement membrane. (C) In lymphatic extension, carcinoma extended from the site of the origin to the proximal and distal ends in a dual pattern so that it extended longitudinally within the epithelium in parallel with an invasion into the lymphatic vessels in the lamina propria and submucosa. At the site of the origin carcinoma invaded down to the level of the submucosa or adventitia. (D) In massive extension, a massive invasion by carcinoma from the site of the origin to the proximal and distal ends, and a simultaneous invasion and destruction by carcinoma of the epithelium, basement membrane, lamina propria, submucosa, and of adventitia in places were demonstrated. There was no marked difference in bronchoscopic finding among (A), (B) and (C). The length of the lesion as estimated by histology was different from that observed at bronchoscopy. Bronchoscopic examination was not always successful in determining the line of resection precisely. Therefore it is indispensable to examine frozen sections and/or imprint specimens of the margin of resection.

BACKGROUND: The study was designed to analyze the underlying relationship between psychiatric comorbidities and postoperative outcomes in patients undergoing primary total knee arthroplasty (TKA).METHODS: We used the National Inpatient Sample data from 2002 to 2014. On the basis of the International Classification of Disease, Ninth Revision, Clinical Modification, we divided TKA patients into 4 subgroups: those diagnosed with depression, those diagnosed with anxiety, those concomitantly diagnosed with both depression and anxiety, and those without depression or anxiety. The chi-squared test and analysis of variance were performed to measure differences among these 4 subgroups. Multiple logistic regression analysis was used to determine whether psychological comorbidities were independent risk factors for postoperative complications and surgery-related pain.RESULTS: A total of 7,153,750 patients in the United States were estimated to have undergone TKA between 2002 and 2014. The prevalence of depression, anxiety, or both diagnoses in TKA patients significantly increased over time. Patients with psychiatric disorders showed higher hospital costs but shorter periods of hospitalization, with higher odds ratios for most complications and all pain-related symptoms observed in this study.CONCLUSION: The prevalence of depression and anxiety in TKA patients is increasing steadily each year. Psychiatric disorders were closely correlated with the outcomes of TKA. The mental health of patients undergoing TKA needs more attention to ensure adequate relief from postoperative pain-related symptoms as well as quality of life.

The correlation of three colorimetric oxytocinase determination methods used in clinics was compared and assessed. It was found that the new methods, the method of Kleiner and Brounet-Yager, and that of Usategui-Gomez et al., show a high correlation with respect to the Tuppy and Nesvadba method (modified by Klimek) the usefulness of which has already been proved. The method of Usategui-Gomez et al., using L-cystine-bis-p-nitroanilide as substrate, is more sensitive and has more advantages.

INTRODUCTION: Using numerical simulations, we predict that nonsustained reentry occurs following a strong, premature stimulus through a unipolar electrode.METHODS AND RESULTS: Our simulations were based on the bidomain model of cardiac tissue, and the active membrane properties were represented by the Beeler-Reuter model. An outwardly propagating wavefront was excited by an initial stimulus (S1). A second stimulus (S2) was then applied through the same electrode. Nonsustained reentry or reentrant-like behavior followed the S2 stimulus for both cathodal and anodal stimulation, and were associated with "break" stimulation but not with "make" stimulation. The direction of spiral-wave rotation was reversed when the polarity of the stimulus was reversed. These complex dynamics occur only for a narrow window of S1-S2 intervals. During anodal S2 stimulation, two different modes of reentry exist. Our simulations also explain the "no response" phenomenon.CONCLUSION: Our mathematical model predicts that both anodal and cathodal unipolar S2 stimulation results in reentry. This behavior arises from an interaction of virtual anodes and cathodes surrounding the stimulating electrode.

Of 97 nondirected T4 thymidylate synthase-defective (td) mutations, 27 were mapped to the intron of the split td gene. Clustering of these intron mutations defined two domains that are functional in splicing, each within approximately 220 residues of the respective splice sites. Two selected mutations, tdN57 and tdN47, fell within phylogenetically conserved pairings, with tdN57 disrupting the exon I-internal guide pairing (P1) in the 5' domain and tdN47 destabilizing the P9 helix in the 3' domain. A splicing assay with synthetic oligonucleotides complementary to RNA junction sequences revealed processing defects for T4tdN57 and T4tdN47, both of which are impaired in cleavage at the 5' and 3' splice sites. Thus prokaryotic genetics facilitates association of specific residue changes with their consequences to splicing.

Insoluble BaSO4 scale is a costly and time-consuming problem in the petroleum industry. Clearance of BaSO4-impeded pipelines requires chelating agents that can efficiently bind Ba2+, the largest nonradioactive +2 metal ion. Due to the poor affinity of currently available chelating agents for Ba2+, however, the dissolution of BaSO4 remains inefficient, requiring very basic solutions of ligands. In this study, we investigated three diaza-18-crown-6 macrocycles bearing different pendent arms for the chelation of Ba2+ and assessed their potential for dissolving BaSO4 scale. Remarkably, the bis-picolinate ligand macropa exhibits the highest affinity reported to date for Ba2+ at pH 7.4 (log K' = 10.74), forming a complex of significant kinetic stability with this large metal ion. Furthermore, the BaSO4 dissolution properties of macropa dramatically surpass those of the state-of-the-art ligands DTPA and DOTA. Using macropa, complete dissolution of a molar equivalent of BaSO4 is reached within 30 min at room temperature in pH 8 buffer, conditions under which DTPA and DOTA only achieve 40% dissolution of BaSO4. When further applied for the dissolution of natural barite, macropa also outperforms DTPA, showing that this ligand is potentially valuable for industrial processes. Collectively, this work demonstrates that macropa is a highly effective chelator for Ba2+ that can be applied for the remediation of BaSO4 scale.

Therapeutic glycoproteins have played a major role in the commercial success of biotechnology in the post-genomic era. But isolating recombinant mammalian cell lines for large-scale production remains costly and time-consuming, due to substantial variation and unpredictable stability of expression amongst transfected cells, requiring extensive clone screening to identify suitable high producers. Streamlining this process is of considerable interest to industry yet the underlying phenomena are still not well understood. Here we examine an antibody-expressing Chinese hamster ovary (CHO) clone at single-cell resolution using flow cytometry and vectors, which couple light and heavy chain transcription to fluorescent markers. Expression variation has traditionally been attributed to genetic heterogeneity arising from random genomic integration of vector DNA. It follows that single cell cloning should yield a homogeneous cell population. We show, in fact, that expression in a clone can be surprisingly heterogeneous (standard deviation 50 to 70% of the mean), approaching the level of variation in mixed transfectant pools, and each antibody chain varies in tandem. Phenotypic variation is fully developed within just 18 days of cloning, yet is not entirely explained by measurement noise, cell size, or the cell cycle. By monitoring the dynamic response of subpopulations and subclones, we show that cells also undergo slow stochastic fluctuations in expression (half-life 2 to 11 generations). Non-genetic diversity may therefore play a greater role in clonal variation than previously thought. This also has unexpected implications for expression stability. Stochastic gene expression noise and selection bias lead to perturbations from steady state at the time of cloning. The resulting transient response as clones reestablish their expression distribution is not ordinarily accounted for but can contribute to declines in median expression over timescales of up to 50 days. Noise minimization may therefore be a novel strategy to reduce apparent expression instability and simplify cell line selection.

Microbiological and biochemical parameters of lactic acid bacterial lyophilized concentrates obtained by continous cultivation were investigated during their storage at 3 to 5 degrees C. Under these conditions lyophilized bacterial concentrates retained high activity for three months and after six months their cell survival and biochemical activity decreased by 60--65% on the average.

Lesions of distal aortic arch and proximal descending thoracic aorta require a posterolateral thoracotomy approach and total circulatory arrest. Retrograde cerebral perfusion through the superior vena cava is technically difficult in such situations. We describe a simplified technique for delivery of retrograde cerebral perfusion through the left internal jugular vein.

BACKGROUND: Perioperatively, patients' hemodynamics are modulated predominantly by intravenous fluid administration and vasoactive pharmacological support. Vasopressor agents are suspected to be detrimental on free flap survival by the cause of vasoconstriction of the pedicle with consecutive reduced overall flap perfusion and by aggravation of flap dissection.OBJECTIVE: A novel, standardized fluid restrictive perioperative hemodynamic management was assessed for its feasibility in clinical practice in free flap patients undergoing breast reconstruction.METHODS: Patients were randomized to two perioperative regimens with different fluid and vasopressor limits. The primary endpoint regarded flap survival. Secondary endpoints included surgery times, time of patient ambulation and length of hospital stay.RESULTS: There was one total flap failure with liberal fluid administration (LFA). No total or partial flap failure was noted in the fluid restrictive regimen with norepinephrine administration up to 0.04ìg/kg/min (FRV). No delay regarding operation time (p = 0.217), patient mobilization (p = 0.550) or hospital discharge (p = 0.662) was registered in the FRV study subpopulation compared to LFA.CONCLUSIONS: The results of this prospective interventional trial could not detect any negative impact of vasopressors, neither for the primary endpoint of flap survival nor for the overall patient outcome. The fear of vasopressor associated flap complications has led to a traditional liberal fluid administration, which failed to demonstrate any benefits when compared to a fluid restrictive vasopressor strategy.

Personal computers have become common-place in physicians' practices and their use in cardiac pacing for programming and follow-up is increasing. The most commonly used media for mass data storage are ferromagnetic. That the toroidal and bar magnets used to activate reed switches pose a threat to such data is well known but the degree of care necessary in handling magnets around storage media, especially the vulnerable floppy diskettes, is not generally appreciated. The basic principles of magnetic data storage discussed herein elucidate the mechanism of data alteration by extraneous magnetic fields. The properties of the surface coatings, the requirements of applicable industry standards, and the field strengths of the pacemaker magnets suggest that data on diskettes should be secure if kept at least 6-7 cm from an isolated pacemaker magnet. Experiments with typical bar and toroidal magnets demonstrated that data recorded on representative diskettes actually remained unaltered until the magnets were placed < 1 cm from the recording surfaces.

Two techniques to separate the lower incisors prior to mandibular symphyseal distraction osteogenesis (MSDO) were evaluated with respect to avoiding tooth damage.METHODS: Fifty patients (20.2 ± 7.0 years) requiring MSDO were treated with a tooth-borne appliance by utilizing two preoperative protocols to separate the central incisors: i) brackets and a V-bent wire with an open coil spring (two-step; TS; n = 24) and ii) a wire attached from the appliance to the central incisors with subsequent dento-alveolar expansion prior to surgery (one-step; OS; n = 26). The distance between the lower incisors was measured preoperatively on radiographs and measurements at the cast models were performed. Complications and radiographs were analyzed.RESULTS: The mean distance (±SD) between the lower central incisors for OS and TS prior to surgery was 3.44 ± 1.05 and 3.18 ± 1.13 mm, respectively. The mean expansion for OS and TS was 4.3 ± 2.9 and 4.3 ± 2.7 mm at the dental level and 3.8 ± 3.2 and 4.0 ± 2.1 mm at the bone level, respectively. Four patients undergoing the TS and one patient undergoing the OS showed transient dental complications.CONCLUSION: Pre-surgical dento-alveolar expansion by utilizing a one-step technique to separate the lower central incisors reduces the risk of permanent tooth damage and weakens the mandibular bone in the midline.

Importance: A physician's prior experience caring for a patient may be associated with patient outcomes and care patterns during and after hospitalization.Objective: To examine differences in the use of health care resources and outcomes among hospitalized patients cared for by hospitalists, their own primary care physicians (PCPs), or other generalists.Design, Setting, and participants: This retrospective study analyzed admissions for the 20 most common medical diagnoses among elderly fee-for-service Medicare patients from January 1 through December 31, 2013. Patients had at least 1 previous encounter with an outpatient clinician within the 365 days before admission, and diagnoses were restricted to the 20 most common diagnosis related groups. Data were collected from Medicare Parts A and B claims data, and outcomes were analyzed from January 1, 2013, through January 31, 2014.Exposures: Physician types included hospitalists, PCPs (ie, the physicians who provided a plurality of ambulatory visits in the year preceding admission), or generalists (not the patients' PCPs).Main Outcomes and Measures: Number of in-hospital specialist consultations, length of stay, discharge site, all-cause 7- and 30-day readmission rates, and 30-day mortality.Results: A total of 560 651 admissions were analyzed (41.9% men and 59.1% women; mean [SD] age, 80 [8] years). Patients' physicians were hospitalists in 59.7% of admissions; PCPs, in 14.2%; and other generalists, in 26.1%. Primary care physicians used consultations 3% more (relative risk, 1.03; 95% CI, 1.02-1.05) and other generalists used consultations 6% more (relative risk, 1.06; 95% CI, 1.05-1.07) than hospitalists. Lengths of stay were 12% longer among patients cared for by PCPs (adjusted incidence rate ratio, 1.12; 95% CI, 1.11-1.13) and 6% longer among those cared for by other generalists (adjusted incidence rate ratio, 1.06; 95% CI, 1.05-1.07) compared with patients cared for by hospitalists. However, PCPs were more likely to discharge patients home (adjusted odds ratio [AOR], 1.14; 95% CI, 1.11-1.17), whereas other generalists were less likely to do so (AOR, 0.94; 95% CI, 0.92-0.96). Relative to hospitalists, patients cared for by PCPs had similar readmission rates at 7 days (AOR, 0.98; 95% CI, 0.96-1.01) and 30 days (AOR, 1.02; 95% CI, 0.99-1.04), whereas other generalists' readmission rates were greater than hospitalists' rates at 7 (AOR, 1.05; 95% CI, 1.02-1.07) and 30 (AOR, 1.04; 95% CI, 1.03-1.06) days. Patients cared for by PCPs had lower 30-day mortality than patients of hospitalists (AOR, 0.94; 95% CI, 0.91-0.97), whereas the mortality rate of patients of other generalists was higher (AOR, 1.09; 95% CI, 1.07-1.12).Conclusions and Relevance: A PCP's prior experience with a patient may be associated with inpatient use of resources and patient outcomes. Patients cared for by their own PCP had slightly longer lengths of stay and were more likely to be discharged home but also were less likely to die within 30 days compared with those cared for by hospitalists or other generalists.

Nicotinic stimulation and high K+ depolarization of bovine chromaffin cells cause disassembly of cortical filamentous actin networks. Previous work from our laboratory has demonstrated that disassembly of actin filaments is Ca(2+)-dependent, precedes exocytosis and occurs in cortical areas of low cytoplasmic viscosity which are the sites of exocytosis. It has also been suggested that protein kinase C is involved in catecholamine secretion from chromaffin cells. Therefore, the possibility that protein kinase C activation might be implicated in cortical filamentous actin disassembly was investigated. Here we report that phorbol myristate acetate, a protein kinase C activator, causes cortical filamentous actin disassembly. Short-term phorbol ester treatment does not alter the morphology of chromaffin cells; however, 1 h after phorbol ester exposure an increase in cell flattening and membrane ruffling is observed. Phorbol ester-induced cortical filamentous actin disassembly is inhibited by protein kinase C activity inhibitors, is independent of extracellular Ca2+ and has a slower time course than that induced by either nicotinic receptor stimulation or K(+)-depolarization. Phorbol ester effects are likely to be mediated by activation of protein kinase C and not by any changes in intracellular Ca2+ levels, as indicated by measurements of Ca2+ transients. Pretreatment of chromaffin cells with phorbol myristate acetate increases the initial rate of nicotine-evoked catecholamine release. Nicotine-induced cortical actin filament disassembly and catecholamine secretion are partially (29-40%) inhibited by pretreatment of cells with either calphostin C, staurosporine or sphingosine. The results suggest that protein kinase C may be involved in the reorganization of the cortical actin filament network priming the cells for release by removing a barrier to secretory granule mobility. However, its role in exocytosis is modulatory but not essential.